fetal infection: a pragmatic approach to recognition and management
TRANSCRIPT
CASE-BASED LEARNING
Fetal infection: a pragmaticapproach to recognitionand managementPriya Agrawal
Joanna Gillham
AbstractViruses and parasites can be transmitted from a pregnant woman to her
fetus via the placenta and can affect development of the fetus. Maternal
infection is often asymptomatic or mild. The implications for the fetus are
dependent on gestation and the presence of maternal immunity. Fetal
infections are a potentially preventable cause of perinatal mortality.
Prenatal diagnosis is often initiated due to exposure of mother to an
infectious contact. Management involves confirmation of maternal infec-
tion and careful consideration of the risks and benefits of fetal diagnosis,
fetal surveillance, intrauterine treatment and possibly a termination of
pregnancy. Empathic and effective counselling of the parents is crucial
and a multidisciplinary approach is important for optimal care. This
review uses cases of two fetal infections to highlight a pragmatic
approach to prenatal diagnosis and management. There is also an over-
view of three other fetal infections which can potentially cause serious
morbidity and mortality.
Keywords cytomegalovirus; parvovirus B19; prenatal diagnosis
Introduction
Fetal infections are a potentially preventable cause of perinatal
mortality. Viruses like rubella, cytomegalovirus, parvovirus,
varicella-zoster virus and parasites like Toxoplasma gondii can
be transmitted from a pregnant woman to her fetus via the
placenta and can affect fetal development. Transplacental
transmission and thus likelihood of fetal infection as well as
consequences for the fetus are dependent on gestation and
possible maternal immunity. This review discusses two fetal
infections in detail, highlighting current approaches to prenatal
diagnosis and management. Routine serum screening is carried
out at booking for rubella, syphilis and hepatitis B. testing is
otherwise initiated, for example for cytomegalovirus, parvovirus
B19 and varicella-zoster, if markers of fetal infection are elicited
on a routine ultrasound scan or in response to maternal exposure
to infection and rarely symptoms of maternal infection. Knowl-
edge of the methods available for prenatal diagnosis and their
Priya Agrawal BMBCh MA MPH is a Specialist Registrar and Academic
Clinical Fellow at St Mary’s Hospital, University of Manchester, UK.
Joanna Gillham MD MRCOG is a Consultant Obstetrician and Sub-specialist
in Maternal and Fetal Medicine at Fetal Management Unit, St Mary’s
Hospital, Hathersage Road, Manchester M13 0JH, UK.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 20:1 22
benefits and limitations is essential for accurate counselling and
treatment of affected pregnant women.
Case 1 (parvovirus)
A 22-year-old woman who is 19 weeks pregnant presents to
you in the antenatal clinic. She has been referred by her
community midwife, as she had contact with a child two weeks
ago who has been diagnosed with parvovirus. She is very
anxious about the well being of her baby.
What would you do?
1. Confirm that the patient has had significant contact
Up to 50% of women are non-immune and thus susceptible to
parvovirus infection. Significant contact is defined as being in the
same room for over 15 min, or face-to-face contact. Transmission
of parvovirus B19 most commonly occurs through respiratory
secretions and hand-to-mouth contact. The incubation period is
5e7 days following exposure, the infected person generally is
infectious for 5e10 days after exposure prior to the onset of the
rash. The person is no longer infectious with the onset of the
rash. The rash can appear up to 18 days following exposure. The
transmissibility of the virus is found to be approximately
50e90% among susceptible household contacts.
2. If contact is confirmed, the pregnant woman should be
investigated for evidence of parvovirus B19 infection
Serum should be collected as soon as possible after contact. The
laboratory will test for parvovirus and rubella despite the clinical
history. Investigation of the serum will facilitate determination of
whether the patient has had a previous infection, susceptibility or
has an acute parvovirus infection (see Figure 1). Serum stored
from booking blood can be tested for evidence of past infection to
help assess the likelihood of an acute seroconversion.
Adults are frequently asymptomatic, although they may
present with erythema infectiosum (fifth disease) e transient
fever, arthralgia and malaise. Transient maternal aplastic crises
can occur in patients with sickle cell anaemia, thalassaemia,
spherocytosis and pyruvate kinase deficiency. Children have
a mild illness presenting with the ‘slapped cheek’ facial rash and
fever. Fetal infection, however, can be serious with fetal hae-
molytic anaemia causing cardiac failure, hydrops and potentially
intrauterine death.
The likelihood of fetal infection and damage to fetus does not
depend on whether maternal infection is asymptomatic or
symptomatic. The risk of adverse outcome to the fetus may be
reduced by active management of the infected fetus.
The presence of IgG is an evidence of previous infection and
confers lifelong immunity. Approximately 50e60% of adults will
have evidence of previous infection. The seroconversion rate in
pregnant women is an indirect measurement of the primary
infection rate and is approximately 1% per year.
Acute parvovirus B19 infection is confirmed on serology. What is
your ongoing management?
3. Seek advice from the Regional Fetal Management Unit
The patient may need to be managed there rather than her
district hospital, depending on local scan expertise.
� 2009 Elsevier Ltd. All rights reserved.
Test for parvovirus B19, IgM and IgG
IgG+
IgM–
IgG–
IgM–
IgG+
IgM+
IgG–
IgM+
Likely past infection
Reassure*
Susceptible to infection
(possibly seroconverting)Possible acute infection
Possible acute infection
Could be false positive
Repeat tests 2–4 weeks later
or consider PCR
Confirm primary infection by
testing for IgG seroconversion
using pre-exposure booking
blood or DNA PCR
Repeat test in 1–2 weeks
Repeat testing negative:
No acute infection but
is susceptible
Acute maternal infection If IgG+ acute maternal
infection confirmed
Investigations for parvovirus B19 infection
* Parvovirus B19 IgM lasts
approximately 4 weeks. Thus failure
to detect parvovirus B19 specific IgM
excludes infection if the serum was
collected within 4 weeks of exposure
in women with no rash or within 4
weeks after onset of rash.
Figure 1
CASE-BASED LEARNING
A multidisciplinary team including virology, neonatologists
and fetal medicine specialists should be involved.
4. Counsel the woman regarding potential risks to the fetus and
the management plan
The risk of maternal infection crossing the placenta to the
fetus is 15% from 5 to 15 weeks, 25% after 15 weeks, increasing
up to 70% towards term. Infection before 20 weeks can lead to
intrauterine death with a 9% excess fetal loss rate. Hydrops
usually occurs 2e4 weeks after maternal parvovirus infection.
On average, there is a 3e10% risk of hydrops following parvo-
virus infection, with approximately a 50% fetal death rate. The
mechanisms suggested include fetal anaemia as the human
parvovirus B19 targets rapidly dividing cells thereby interrupting
red cell production. This, combined with a shorter half-life of
fetal red blood cells leads to the severe anaemia, hypoxia, high
output cardiac failure associated with fetal hydrops. A prospec-
tive study showed that 7.5% of third trimester fetal deaths in
utero were positive for parvovirus B19 in the placental tissues.
Figure 2 Ascites secondary to parvovirus at 23 weeks gestation.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 20:1 23
Thus, testing for parvovirus B19 should be offered in this
scenario.
5. Fetal surveillance
Fetal monitoring to identify fetal anaemia, ascites and hydrops
(accumulation of fluid in two compartments) using weekly
ultrasound examinations for up to 12 weeks after maternal
exposure should be performed (see Figure 2). Doppler ultrasound
measurements of the middle cerebral artery peak systolic velocity
(MCA-PSV) are now used to help predict fetal anaemia (see
Figure 3). A study assessing the predictive value of MCS-PSVs
reported that these Doppler studies had 100% sensitivity for
predicting fetal anaemia in the presence of parvovirus.
Fetal MCAs suggest severe anaemia. What are the options?
6.Active management has been shown to improve outcome
30% of cases with fetal hydrops will spontaneously resolve.
However, there is no robust method to distinguish these cases
Figure 3 Transverse head section showing Doppler colour flow on the
middle cerebral artery.
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Figure 4 Echogenic bowel. Figure 6 Ventriculomegaly and increased echogenicity of ventricles.
CASE-BASED LEARNING
from those that will progress to intrauterine death. Thus active
management is considered in all cases.
Cordocentesis is used for fetal blood sampling to diagnose
fetal anaemia. It should be done with full facilities available for
immediate intrauterine blood transfusion if fetal anaemia is
confirmed by the laboratory.
Cordocentesis can be performed from 18 weeks onwards.
There is a 1% risk of procedure-associated miscarriage. The
preferred transfusion site is at the umbilical vein insertion into
the placenta, but the intrahepatic umbilical vein or the cardiac
ventricles can be utilized. At later gestations the risk of cor-
docentesis and intrauterine transfusion should be balanced
against the risk of possible premature delivery and neonatal
transfusion.
Fetal transfusion has been shown to improve outcome
although the time taken for resolution of hydrops can vary but
normally occurs within 6 weeks. The woman can be reassured
that following resolution of hydrops, there is no evidence to
show that there are any adverse long-term effects to be
expected.
Figure 5 Severe ventriculomegaly in a fetus with þve CMV-PCR from
amniotic fluid.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 20:1 24
Case 2 (cytomegalovirus)
A 27-year-old woman is 17 weeks pregnant. She is a late
booker and gives a vague history of contact with someone with
a rash. She cannot give any more details on the rash or when
she had this contact. The booking midwife requested a TORCH
screen at the time of seeing the patient who has now come to
see you (the obstetrician) at 19 weeks with the following blood
results: CMV IgG negative, CMV IgM positive.
How do you interpret these results?
1. She has an acute cytomegalovirus infection
CMV infection is one of the most common congenital infections
with a reported incidence of 0.5e2%. 50e70% of women have
had previous CMV infection (IgGþ). Both primary and recurrent
infections can lead to fetal infection but risk of transmission and
severity is greater in a primary infection. Primary infection is
usually asymptomatic but can present with vague symptoms of
fever, malaise and lethargy.
CMV IgG is present within 2 weeks of primary infection and is
lifelong.
Figure 7 Large placenta, anhydramnios and intrauterine growth restriction
on a fetus with positive CMV from a chorionic villus biopsy.
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A summary of other common fetal infections (presentation, diagnosis and management)
Toxoplasmosis Rubella Varicella-zoster
Proportion of young women susceptible 90% 1e2% 10%
Infection acquired
through.
Ingestion of toxoplasma
tissue cysts in undercooked
meat/cat excrement/contaminated
soil/water
Close contact Close contact
Presentation of primary infection Asymptomatic (60e70%) or
malaise, fever, lymphadenopathy
Asymptomatic or malaise, headache, coryza,
fine maculopapular rash
Fever, malaise, pruritic maculopapular rash
(vesicular)
Risk of transplacental transmission Increases with gestation
<4 weeks e less than 1%
13 weeks e 4e15%
36 weeks e >60%
<11 weeks e 90%
11e16 weeks e 55%
>16 weeks e 45%
<28 weeks e 5e10%
28e36 weeks e 25%
>36 weeks e 50%
Risk of adverse fetal outcome Decreases with gestation <11 weeks e 90%
11e16 weeks e 20%
16e20 weeks e small risk of deafness
>20 weeks e no increased risk
Fetal varicella syndrome (FVS):
<13 weeks e 1%
13e20 weeks e 2%
4 weeks prior to delivery to 7 days post
delivery e 20% neonatal varicella
Sequelae of fetal infection Mainly affects the central nervous
system (CNS) and eyes
Congenital rubella syndrome includes hearing
loss, learning difficulties, cardiac and ocular
defects
FVS includes limb defects, damage to eyes,
skin and CNS
Diagnosis of maternal infection Serological testing for toxoplasma-
specific IgG and IgM
Serological testing for rubella-specific IgG
seroconversion (compared to booking serum)
Serological testing for VZV-specific IgG. It
appears within 10 days and confers lifelong
immunity OR immunofluorescence of lesion
scraping
Diagnosis of fetal infection Amniocentesis for detection of
Toxoplasma gondii DNA in
amniotic fluid
Usually only performed for infections occurring
at 16e20 weeks: amniocentesis for detection
of viral nucleic acid in amniotic fluid or
cordocentesis for detection of RNA or rubella-
specific IgM
Amniocentesis for detection of VZV DNA in
amniotic fluid and ultrasound surveillance
Management Spiramycin if maternal infection
(reduces risk of fetal infection
by 60e70%)
Pyrimethamine/sulfadiazine if
fetal infection confirmed
Ultrasound surveillance
Termination
Termination
Ultrasound surveillance/echocardiography
Termination if FVS on USS <20 weeks
Ultrasound surveillance
VZIG may help
Table 1
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CASE-BASED LEARNING
What do you do next?
2. Counsel the woman regarding potential risks to the fetus and
the management plan and offer amniocentesis
The risk of transplacental transmission to the fetus is 40% in the
first and second trimesters. The risk of fetal injury is greatest after
primary CMV and when maternal infection occurs in the first or
early second trimester. The risk of transmission is greater (80%) in
the third trimester but usually asymptomatic after 27 weeks.
Transplacental passage of CMV and thus presumed fetal infec-
tion can be confirmed by detection of CMV DNA in amniotic fluid
by polymerase chain reaction (PCR). If the amniotic fluid CMV-PCR
is negative, the woman can be reassured. Amniocentesis should be
delayed for a minimum of 6 weeks after maternal serum is positive
to allow levels of CMV in the amniotic fluid to be detectable. The
amniocentesis should also be performed after 20e22 weeks
gestation, as fetal diuresis is not established until then. A negative
result before this should be treated with caution as it could be
a false negative due to the CMV levels being too low to be detected.
Fetal infection leads to a variety of sequelae including ocular
defects, sensorineural deafness, intrauterine growth restriction,
microcephaly, hepatosplenomegaly, jaundice, thrombocytopenic
purpura, pneumonitis and neurodevelopmental consequences
such as cerebral palsy. The earlier the fetus is affected, the worse
the severity of disease.
The overall risk of damage in fetuses infected as a result of
primary CMV is approximately 25%. 10% of infected fetuses are
clinically symptomatic at birth, with a reported mortality of 30%
and 90% of the survivors can have severe neurological sequelae.
In the babies who are asymptomatic at birth, a further
10e15% of these develop some long-term sequlae, primarily
sensorineural hearing loss.
3. She should have a detailed ultrasound scan looking for
sonographic features of CMV disease
Sonographic features of CMV include: intrauterine growth
restriction, microcephaly, ventriculomegaly, intracerebral or
hepatic calcifications, leukomalacia and echogenic bowel (see
Figures 4e7).
The fetus is of normal size and there are no fetal abnormalities
seen.
The patient asks you ‘Does this mean my baby is okay doctor?’
What do you say?
Not all infected fetuses will have features of disease seen on
ultrasound imaging. Though the absence of sonographic features
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 20:1 26
is reassuring, monthly ultrasound surveillance is needed as the
disease may manifest later in pregnancy, at birth or even later as
an infant.
It has been reported that in cases of confirmed CMV vertical
transmission, 19% of cases had postnatal neurological abnor-
malities despite having no prenatal ultrasound abnormalities.
CMV is detected in the amniotic fluid. Another ultrasound scan
shows no fetal abnormalities. The woman understands about
fetal surveillance and wants to know about alternative manage-
ment options.
There are no treatments that are licensed and proven to be
effective in pregnancy. Experimental treatment includes CMV-
specific hyperimmue globulin which may be effective. A termi-
nation of pregnancy can be offered and most centres would offer
this before 24 weeks gestation. However, there may be a case for
a late termination due to the possibility of disease presenting at
birth or later and the associated mortality.
Table 1 gives an overview of other important fetal infections
to be considered. A
FURTHER READING
Greenough A, Osborne J, Sutherland S, eds. Congenital, perinatal and
neonatal infections. Edinburgh: Churchill Livingstone, 1991.
Komischke K, Searle K, Enders G. Maternal serum alpha feto protein and
human chorionic gonadotrophin in pregnant women with acute
parvovirus B19 infection with and without fetal complications. Prenat
Diag 1997; 17: 1039e46.
Morgan-Capner P, Crowcroft NS. Guidelines on the management of, and
exposure to, rash illness in pregnancy (including consideration of
relevant antibody screening programmes in pregnancy). Commun Dis
Public Health 2002; 5: 59e71.
Prediction of fetal anaemia with Doppler measurement of the middle
cerebral artery peak systolic velocity in pregnancies complicated by
maternal blood group alloimmunization or parvovirus B19 infection.
Ultrasound Obstet Gynecol 2001 Sep; 18: 232e6.
RCOG Green-top Guideline No. 13, September 2007 e chickenpox in
pregnancy.
Skjoldebrand-Sparre L, Tolfvenstam T, Papadogiannakis N, Wahren B,
Broliden K, Nyman M. Parvovirus B19 infection: association
with third-trimester intrauterine fetal death. BJOG 2000 Apr; 107:
476e80.
Stagno S, Pass RF, Dworski ME, Alford CA. Congenital and perinatal
cytomegalovirus infections. Semin Perinatol 1983; 7: 31e42.
To M, Kidd M, Maxwell D. Prenatal diagnosis and management of fetal
infections. TOG 2009; 11: 108e16.
� 2009 Elsevier Ltd. All rights reserved.