current position: professor & head, department of ...dr prakash a current position: professor...
TRANSCRIPT
DR PRAKASH A
Current Position
Professor amp Head Department of
Neonatology SRIHER Chennai
Research amp Area of Interest Published more than 20 papers in
national and international Journals
Interested in Community neonatology amp Preterm neurology
Awards Active Pediatrician award
and several awards for best
performance for conducting IAP NNF
FGM courses throughout Tamilnadu
CMV - The Hidden Danger in NICU
Dr Prakash A
Professor amp Head
Senior consultant
SRMC Chennai
Hidden danger
bull Serious consequencesDiagnosis is missed rarr
bull Non treatment rarr complications
bull Not following uprarr development of complications
Consequences
Maternal CMV
Baby symptomatic
Treat
Maternal CMV
Baby asymptomatic
Hidden Danger
Postnatal CMV
Symptomatic or
asymptomatic
Hidden Danger
Hidden threat Situations
1Maternal CMV and Baby asymptomatic
2 Anything unusual at birth - thrombocytopenia
hepatosplenomegaly IUGR hepatitis CNS and
ocular diseaseand Hearing loss- as manifestation
of congenital CMV infection
3 Sepsis not responding to antibioticsantifungal
persistent hepato-spenomegaly or pneumonia
and thrombocytopenia as manifestation of Post
natal CMV
Anything new about CMV virus
CMV is a genetically diverse organism both between
and within hosts
Multiple episodes of reinfection between breastfeeding
infants and mothers without evidence of strain-specific
seroconversion introducing the question of whether an
antigenically distinct strain is even necessary for
reinfection
Materenal sero-positivity
RefBoucoiran I Mayer BT Krantz EM et al Nonprimary maternal CMV
infection following viral shedding in infants Pediatr Infect Dis J 2018
Jul37(7)627-631
Let us clarify
What is congenital CMV
What is perinatal CMV
What is acquired CMV
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
CMV - The Hidden Danger in NICU
Dr Prakash A
Professor amp Head
Senior consultant
SRMC Chennai
Hidden danger
bull Serious consequencesDiagnosis is missed rarr
bull Non treatment rarr complications
bull Not following uprarr development of complications
Consequences
Maternal CMV
Baby symptomatic
Treat
Maternal CMV
Baby asymptomatic
Hidden Danger
Postnatal CMV
Symptomatic or
asymptomatic
Hidden Danger
Hidden threat Situations
1Maternal CMV and Baby asymptomatic
2 Anything unusual at birth - thrombocytopenia
hepatosplenomegaly IUGR hepatitis CNS and
ocular diseaseand Hearing loss- as manifestation
of congenital CMV infection
3 Sepsis not responding to antibioticsantifungal
persistent hepato-spenomegaly or pneumonia
and thrombocytopenia as manifestation of Post
natal CMV
Anything new about CMV virus
CMV is a genetically diverse organism both between
and within hosts
Multiple episodes of reinfection between breastfeeding
infants and mothers without evidence of strain-specific
seroconversion introducing the question of whether an
antigenically distinct strain is even necessary for
reinfection
Materenal sero-positivity
RefBoucoiran I Mayer BT Krantz EM et al Nonprimary maternal CMV
infection following viral shedding in infants Pediatr Infect Dis J 2018
Jul37(7)627-631
Let us clarify
What is congenital CMV
What is perinatal CMV
What is acquired CMV
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Hidden danger
bull Serious consequencesDiagnosis is missed rarr
bull Non treatment rarr complications
bull Not following uprarr development of complications
Consequences
Maternal CMV
Baby symptomatic
Treat
Maternal CMV
Baby asymptomatic
Hidden Danger
Postnatal CMV
Symptomatic or
asymptomatic
Hidden Danger
Hidden threat Situations
1Maternal CMV and Baby asymptomatic
2 Anything unusual at birth - thrombocytopenia
hepatosplenomegaly IUGR hepatitis CNS and
ocular diseaseand Hearing loss- as manifestation
of congenital CMV infection
3 Sepsis not responding to antibioticsantifungal
persistent hepato-spenomegaly or pneumonia
and thrombocytopenia as manifestation of Post
natal CMV
Anything new about CMV virus
CMV is a genetically diverse organism both between
and within hosts
Multiple episodes of reinfection between breastfeeding
infants and mothers without evidence of strain-specific
seroconversion introducing the question of whether an
antigenically distinct strain is even necessary for
reinfection
Materenal sero-positivity
RefBoucoiran I Mayer BT Krantz EM et al Nonprimary maternal CMV
infection following viral shedding in infants Pediatr Infect Dis J 2018
Jul37(7)627-631
Let us clarify
What is congenital CMV
What is perinatal CMV
What is acquired CMV
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Maternal CMV
Baby symptomatic
Treat
Maternal CMV
Baby asymptomatic
Hidden Danger
Postnatal CMV
Symptomatic or
asymptomatic
Hidden Danger
Hidden threat Situations
1Maternal CMV and Baby asymptomatic
2 Anything unusual at birth - thrombocytopenia
hepatosplenomegaly IUGR hepatitis CNS and
ocular diseaseand Hearing loss- as manifestation
of congenital CMV infection
3 Sepsis not responding to antibioticsantifungal
persistent hepato-spenomegaly or pneumonia
and thrombocytopenia as manifestation of Post
natal CMV
Anything new about CMV virus
CMV is a genetically diverse organism both between
and within hosts
Multiple episodes of reinfection between breastfeeding
infants and mothers without evidence of strain-specific
seroconversion introducing the question of whether an
antigenically distinct strain is even necessary for
reinfection
Materenal sero-positivity
RefBoucoiran I Mayer BT Krantz EM et al Nonprimary maternal CMV
infection following viral shedding in infants Pediatr Infect Dis J 2018
Jul37(7)627-631
Let us clarify
What is congenital CMV
What is perinatal CMV
What is acquired CMV
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Hidden threat Situations
1Maternal CMV and Baby asymptomatic
2 Anything unusual at birth - thrombocytopenia
hepatosplenomegaly IUGR hepatitis CNS and
ocular diseaseand Hearing loss- as manifestation
of congenital CMV infection
3 Sepsis not responding to antibioticsantifungal
persistent hepato-spenomegaly or pneumonia
and thrombocytopenia as manifestation of Post
natal CMV
Anything new about CMV virus
CMV is a genetically diverse organism both between
and within hosts
Multiple episodes of reinfection between breastfeeding
infants and mothers without evidence of strain-specific
seroconversion introducing the question of whether an
antigenically distinct strain is even necessary for
reinfection
Materenal sero-positivity
RefBoucoiran I Mayer BT Krantz EM et al Nonprimary maternal CMV
infection following viral shedding in infants Pediatr Infect Dis J 2018
Jul37(7)627-631
Let us clarify
What is congenital CMV
What is perinatal CMV
What is acquired CMV
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Anything new about CMV virus
CMV is a genetically diverse organism both between
and within hosts
Multiple episodes of reinfection between breastfeeding
infants and mothers without evidence of strain-specific
seroconversion introducing the question of whether an
antigenically distinct strain is even necessary for
reinfection
Materenal sero-positivity
RefBoucoiran I Mayer BT Krantz EM et al Nonprimary maternal CMV
infection following viral shedding in infants Pediatr Infect Dis J 2018
Jul37(7)627-631
Let us clarify
What is congenital CMV
What is perinatal CMV
What is acquired CMV
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Let us clarify
What is congenital CMV
What is perinatal CMV
What is acquired CMV
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Clinical manifestation
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Pregnancy
cCMV
1 to 4
Fetal infection
30 - 40
Symptomatic
10
Mortality
20-30
Long term sequalae
50-90
Asymptomatic
90
Long term sequalae
10-15
Women socioeconomic
Immunity 50-85
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Classification of congenital CMV
infection
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Concerns
Hearing
Vision
Neurodevelopment
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Hearing loss and CMV
Incidence of hearing loss
Method of screening ndash Can newborn hearing screen
miss hearing deficit in cCMV
How long to follow up for hearing
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
According to a 2014 systematic review by Goderis
et al 37 studies
1 in 3 children with symptomatic cCMV
1 in 10 children with asymptomatic cCMV
Hearing-impaired childrencCMV is the likely
causative agent 10-20 of the time
This systematic review underscores the importance
of cCMV as a cause of sensorineural hearing loss in
childhood
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Hearing screen follow up
One study found that more than half of SNHL
caused by cCMV would be missed with an
initial newborn hearing screen
Usually by 5 years but Progression and delayed
onset of SNHL have been documented up to
adolescence
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Vision
1 The most common sequelae were strabismus
chorioretinal scars cortical visual impairment
nystagmus and optic nerve atrophy
2 The study demonstrated that visual defects are not
typically progressive or delayed in onset unlike SNHL
Jin HD Demmler-Harrison GJ Coats DK et al Long-term visual and ocular sequelae in patients with
congenitalcytomegalovirus infection Pediatr Infect Dis J 2017 Sep36(9)877-882 doi
101097INF0000000000001599
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Asymptomatic cCMV
They found no significant differences in intelligence and
academic achievement between the children who
were congenitally CMV infected and had normal
hearing and the control groupRefLopez AS Lanzieri TM Claussen AH et al Intelligence and academic achievement with asymptomatic congenital
cytomegalovirus infection Pediatrics 2017 Nov140(5) Pii e20171517 doi 101542peds2017-1517
More studies with carefully matched cases and controls
rigorous neurodevelopmental testing and diverse
settings would be helpful to pick up subtle outcomes in
this population
Boppana SB Fowler KB Insight into long-term neurodevelopmental outcomes in
asymptomatic congenital cmv infection Pediatrics 2017 Nov140(5) pii e20172526
doi 101542peds2017-2526
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Findings on neuroimaging
One study examined neurologic imaging of babies
with cCMV
Germinolytic cysts
lenticulostriate vasculopathy
White matter signal intensity abnormalities
Polymicrogyria
periventricular calcifications
white matter cysts
Cerebellar hypoplasia
Ventriculomegaly
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
CT and MRI PERIVENTRICULAR
Calcification
Cerebellar
defect
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Cranial ultrasound for all infants diagnosed with
cCMV
Follow-up magnetic resonance imaging (MRI) for any
neonates with abnormality on cranial ultrasound
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Diagnostic aids
PCR
Urine PCR
Saliva PCR
Blood PCR
Dried blood PCR
Serology- not recommended
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Performance of DBS PCR assays for testing cCMV
was more suitable for retrospective diagnosis than
screening
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Treat or not to treat
The consensus recommendations published in 2017
stated that the evidence to treat infants with only
hearing loss was not sufficient
A study published in 2018 by Pasternak et al showed
benefit for this group of children with many infants
demonstrating improved hearing on treatment but
did not have a control groupRef
Rawlinson WD1 Lancet Infect Dis 2017 Jun17(6)e177-e188 doi
101016S1473-3099(17)30143-3 Epub 2017 Mar 11 Congenital
cytomegalovirus infection in pregnancy and the neonate consensus
recommendations for prevention diagnosis and therapy
Pasternak Y J Pediatr 2018 Aug199166-170 Valganciclovir Is Beneficial in
Children with Congenital Cytomegalovirus and Isolated Hearing Loss
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Screening for cCMV amp treatment
A 2016 cost effectiveness analysis by Gantt et al
concluded that both targeted and universal
screening would result in net savings assuming an
improvement in hearing outcomes with antiviral
therapy given to infants with clinical manifestations at
birth as well as benefits from earlier interventions in
infants with hearing loss
Gantt S JAMA Pediatr 2016 Dec 1170(12)1173-1180 doi
101001jamapediatrics20162016 Cost-effectiveness of Universal and
Targeted Newborn Screening for Congenital Cytomegalovirus Infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Consensus on treatment of
congenital CMV
The general agreement is to treat infants who are
moderately to severely symptomatic at birth
Many experts also recommend treating infants with
hearing loss only
Ref
Recommendations Group convened at the 5th International Congenital
Cytomegalovirus Conference in 2015 the 2017 European expert consensus
statement drafted by the European Society for Paediatric Infectious Diseases
and the American Academy of Pediatrics Red Book314868
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Classification of congenital CMV
infection- Whom should we treat
Moderately to severely symptomatic cCMV - have multiple manifestations or have central nervous system involvement
Mildly symptomatic cCMV- one or two isolated manifestations that are mild and transient
Asymptomatic cCMV with isolated sensorineural hearing loss
Asymptomatic cCMV- no apparent abnormalities at birth and have normal hearing
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Treatment
Treatment consists of oral valganciclovir at a dose
of 32 mgkgday divided twice daily (16
mgkgdose) for a duration of 6 months
If oral treatment is not possible ganciclovir may be
given intravenously at a dose of 12 mgkgday
divided twice daily
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
How long
N Engl J Med 2015 Mar 5372(10)933-43 doi 101056NEJMoa1404599
Valganciclovir for symptomatic
congenital cytomegalovirus disease
Treating symptomatic congenital CMV disease with
valganciclovir for 6 months as compared with 6 weeks
did not improve hearing in the short term but appeared
to improve hearing and developmental outcomes
modestly in the longer term
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Recent advances
Letermovir for the prevention of cytomegalovirus
infection
The vaccine development process has been
challenging given the significant genetic diversity of the
virus and its ability to evade immune mechanisms and
At this time the optimal vaccine targets are unclear
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Treatment monitoring
Ref3148
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Follow up
Ref3148
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
pCMV
What are the ways of transmission
How to prevent
Can seropositive mother give breast milk
Term neonate
Preterm neonate
Clinical features of pCMV
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Breast feeding
One study showed that approximately one-third of
breastfeeding infants acquired the virus from their
mothers with a mean incubation time of 42 days
Ref
Jahn G Epidemiology of transmission of cytomegalovirus from mother to
preterm infant by breastfeeding Lancet 2001 Feb17357(9255)513-518 doi
01016S0140-6736(00)04043-5
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Transmission in colostrum
Little or no virus is detected in colostrum Peak
milk 4-8 weeks and starts declining
PPROM rarr increases the chances of fetal CMV
infection
Cell-free virus in the whey has been
associated with a higher transmission risk
Mothers with earlier onset of CMV excretion in
breast milk higher CMV milk viral loads and
who excrete for longer are more likely to
transmit CMV to their infants
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Of 170 infants no CMV transmission in 80 infants of
seronegative mothers and in the 3 infants of
seropositive mothers who did not shed CMV DNA into
breast milk
Transmission occurred in 33 of 87 CMV-exposed
infants
16 had hepatopathy neutropenia
thrombocytopenia and sepsis-like deterioration
Risk was associated- LBW and early postnatal virus
transmission were risk factors for symptomatic
infection VLBW infants of CMV-sero+ mothers are at
high risk of acquiring a symptomatic CMV infection
via breast milk
Maschmann J Hamprecht K Dietz K et al Cytomegalovirus infection of
extremely low-birth weight infants via breast milk Clin Infect Dis
2001331998ndash2003
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Among the 539 VLBW infants the cumulative incidence of
postnatal CMV infection at 12 weeks was 69
5 of 29 infants (172) with postnatal CMV infection developed
symptomatic disease or died
None of the CMV infections was linked to transfusion resulting in
a CMV infection incidence of 00 (95 CI 00-03) per unit
of CMV-seronegative and leukoreduced blood
Twenty-seven of 28 postnatal infections occurred among infants
fed CMV-positive breast milk The retrospective analysis of dried blood spots as a diagnostic
method has been studied but the sensitivity of this method is
low
The residual risks of TT-CMV with CMV-seronegative or leukoreduced transfusions were estimated to be 1 to 3
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
preterm infants born in settings of high CMV seropositivity
are as susceptible to CMV infection from raw maternal
milk as those born to maternal populations of lower
seroprevalence rates high frequency (908) of CMV
reactivation in expressed milk of seropositive mothers
An overall higher DNA load in the milk of transmitter
mothers than in nontransmitter mother estimated 50 days or
36 weeks of corrected GA after initial exposure to raw
maternal milk
125 of the CMV-infected infants exhibited SLS
Faacutebia Pereir et al Incidence Risk Factors and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among
Preterm Infants Fed Maternal Milk in a Highly Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1
October 2016 Pages 929ndash936
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Preterm at higher risk
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Factors influencing
PROM and the amount of CMV virus in breast milk
were independently associated with an increased
risk of postnatal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Prevention Pasteurising milk
For feeding breast milk to VLBW infants born to
seropositive mothers pasteurization of breast milk
until a corrected gestational age of 34 weeks as is
recommended by the Austrian Society of
Pediatricsand routine screening for postnatal CMV
infection may be warranted
Ref Meier J Lienicke U Tschirch E Kruumlger DH
Wauer RR Proumlsch S Human cytomegalovirus reactivation
during lactation and mother-to-child transmission in preterm
infants J Clin Microbiol 200543(3)1318-1324
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Method of pasteurization
HoPndashHolder Pasteurization HTSTndashHigh-Temperature Short-Time HPPndashHigh
Pressure Processing MIndashMicrowave Irradiation
Studies with human participants are needed to be carried out with the
most promising new techniques of human milk processing in comparison
to holder pasteurization
Innovative Techniques of Processing Human Milk to Preserve Key
Components Nutrients 2019 11 1169 doi103390nu11051169
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
But recommendation differs AAP
The American Academy of Pediatrics19 states that
ldquothe value of routinely feeding [fresh] human milk
from [CMV] seropositive mothers to preterm infants
outweighs the risks of clinical disease especially
because no long-term neurodevelopmental
abnormalities have been reportedrdquo
Ref Breastfeeding and the use of human milk Pediatrics
2012129(3)e827-e841
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Other Prevention measures
Education
Seronegative pregnant women in Italy to wash
their hands frequently
Avoid intimate contact such as kissing the child
on the mouth or cheek and
Avoid sharing of utensils food drinks and
washcloths
In the intervention group 12 (4331) of the
women seroconverted while 76 (24315)
seroconverted in the control group
Ref 1617
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Short term outcome 302 neonatal intensive care units 273 Infants with CMV diagnosed
beyond 21 days of life
Result
Hearing screen failure occurred in 45 of 273 infants (165)
Postnatal CMV was also associated with an increased postnatal age
at discharge of 1189 days (95 CI 672 to 1706 days Pthinspltthinsp001) and
lower weight-for-age z score (minus023 95 CI minus039 to minus007 Pthinsp=thinsp005)
Analysis confirmed an increased risk of BPD (RR 130 95 CI 117 to 144 Pthinspltthinsp001) previously reported on infants from this cohort from 1997
to 2012
Conclusions
Prospective studies are needed to determine the full effects of
postnatal CMV infection and whether antiviral treatment reduces the
associated morbidity
Ref Weimer KED Kelly MS Permar SR Clark RH Greenberg RG Association of Adverse Hearing Growth and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight JAMA Pediatr Published online December 02 2019
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
ROP and BPD
CMV-infected infants showed a 2 times higher incidence of
outcomes related to sequelae of prematurity than CMV-
uninfected infants -BPD overall ROP and stage 2 or 3
ROP whereas the proportion of stage 1 ROP was similar
for both groups
Death was also more frequent among infected infants
although the deaths could not be directly attributable to the
CMV infection
Faacutebia Pereira Martins-Celini Aparecida Yulie Yamamoto Deacutebora Manzione Passos Suely Dornellas do Nascimento
Edineacuteia Vaciloto Lima Ceacutelia Mara Di Giovanni Ellen Regina Sevilla Quadrado Roberta Barta Davi Casale Aragon Seila Israel do Prado Maria Fernanda Branco de Almeida Marisa Maacutercia Mussi-Pinhata Incidence Risk Factors and
Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly
Seropositive Population Clinical Infectious Diseases Volume 63 Issue 7 1 October 2016 Pages 929ndash936
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Treatment
Given the toxicity of antiviral therapy further
research is needed to determine whether antiviral
treatment in infants with asymptomatic CMV
infection is beneficial especially because it is
unclear which infants will progress to CMV disease
Ref Marshall BC Koch WC Antivirals for cytomegalovirus infection in
neonates and infants focus on pharmacokinetics formulations dosing and
adverse events Paediatr Drugs 200911(5)309-321
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Clinical features warranting treatment
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Treatment
Severe organ disease including hepatitis bone
marrow suppression (anaemia neutropaenia
thrombocytopaenia) severe intestinal
manifestations pneumonitis or possibly worsening
BPD SLS
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Viral load and outcome
No data to comment
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Two weekly therapy until suppressed viral load max 0f 8 weeks
Severe CMV disease (End organ damage amp CMV test positive after 21 days)
Two weekly therapy until suppressed viral load max 0f 8 weeks
If ANC lt500 THEN stop until recovery gt 750 or
give CSF
If there is a need gt 8
weeks treatment then
consider
immunosuppression
including HIV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Forty-one preterm children (born before 32 weeks of gestation or
birth weight lt1500 g 20 HCMV positive 21 HCMV negative)
Cognitive and motor function in preterm children with early
postnatally acquired HCMV infection transmitted via breast milk
was within the normal range
However the findings suggest that their outcome is poorer than
outcome in preterm children without HCMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection
Take home message
Yes CMV is a hidden danger especially in premature
babies
High index of suspicion of CMV in non-responders to
routine therapy after 21 days of life
No answer to the outcome of treatment of post natal
CMV
Only way to prevent is by pasteurizing the human
milk but not recommended
There is a dire need to innovate a novel method of
pasteurization to prevent post natal CMV infection