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Compliance with this Guideline is Recommended 1
SLHD Guideline
Newborn Infants Exposed to SSRI / SNRI Antidepressant Medication during Pregnancy and Lactation
TRIM Document No
Policy Reference SLHD_GL2020_028
Related MOH Policy Neonatal Abstinence Syndrome Guidelines GL2013_0081
Keywords Newborn; Adaptation; Syndrome; Serotonin; Reuptake;
Inhibitors; Depression; Antidepressant; SSRI; SNRI
Applies to All clinical staff providing maternity care in SLHD
Clinical Stream Women’s Health, Neonatology & Paediatrics
Tier 2 Sign-off Executive Director Clinical Governance and Risk SLHD
Clinical Director Women’s Health, Neonatology & Paediatrics
Date approved by SLHD
Policy Committee 13/08/2020
Authors Jill Martin RN, Newborn Family Support Team
Clinical Associate Professor David Osborn, Neonatologist
Status Active
Review Date 13/08/2020
Risk Rating H
Replaces N/A
Version History
Current Version V.1 – 13/08/2020
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 2
Newborn Infants Exposed to SSRI/SNRI Antidepressant Medication during Pregnancy and Lactation
Contents
1. Introduction ................................................................................................................ 3
2. The Aims / Expected Outcome of this Guideline ........................................................ 3
3. Risk Statement .......................................................................................................... 3
5. Implementation .......................................................................................................... 3
6. Key Performance Indicators and Service Measures................................................... 4
7. Overview ................................................................................................................... 4
8. Guideline ................................................................................................................... 7
9. Summary of Practice Guidelines ................................................................................ 9
10. Definitions ................................................................................................................ 10
11. Consultation ............................................................................................................ 10
12. References .............................................................................................................. 10
11. National Safety and Quality Standards, 2nd Ed ....................................................... 12
12. Appendix ................................................................................................................. 13
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 3
Newborn Infants Exposed to SSRI/SNRI Antidepressant Medication during Pregnancy and Lactation
1. Introduction
Adequate treatment of depression in pregnancy is very important for the health and well-
being of both mother and baby. An individual risk-benefit decision must be made concerning
antidepressant use in pregnancy including selective serotonin reuptake inhibitors (SSRIs)
and serotonin-noradrenaline reuptake inhibitors (SNRIs), bearing in mind the following:
Untreated prenatal depression is associated with pre-eclampsia, low birth weight and
prematurity, as well as an increased risk of adverse effects on the mother and child;
SSRI neonatal behavioural syndrome (poor neonatal adaptation syndrome – PNAS) is
common but usually mild and transient;
The absolute risk for persistent pulmonary hypertension is low; and,
Evidence suggests SSRIs as a group may result in a small increase risk of congenital
malformation.
While other classes of antidepressants are prescribed to pregnant and lactating women,
these guidelines will primarily focus on SSRIs and SNRIs.
2. The Aims / Expected Outcome of this Guideline
Babies with late-trimester SSRI / SNRI exposure should be observed in hospital for neuro-
behavioural or respiratory symptoms for a minimum of 24 hours. Families should receive
anticipatory guidance on the possible effects of SSRIs on their infant, including the need for
observation after birth.
3. Risk Statement
SLHD Enterprise Risk Management System (ERMS) Risk #1 - Unwarranted Deviation from standards of clinical care:
Failure to identify infants with serotonin toxicity.
Failure to identify infants who develop Poor Neonatal Adaptation Syndrome (PNAS),
which may impact feeding and weight gain.
Failure to identify infants with respiratory distress and/or persistent pulmonary
hypertension of the newborn.
4. Resources
MHPOD: Pharmacological Interventions. This 30 minute eLearning module is accessible via
My Health Learning (MHL) and gives clinical staff an overview of commonly used
psychotropic and antidepressant drugs.
5. Implementation
This guideline will be published on the SLHD intranet and accessible to all staff.
Distribution and notification of this policy to midwifery, nursing and medical staff
within SLHD via usual processes (i.e. Memo, emails, staff meetings).
Neonatal nursing and medical staff responsible for the Neonatal Abstinence follow-up
clinic (The Pygmy Possum clinic) RPAH, are available on request to deliver unit-based
in-service presentations throughout SLHD.
NSW Health required training accessible via MHL responding to policy risk statement.
Completion of current mandatory infant and adult resuscitation annual requirements.
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 4
6. Key Performance Indicators and Service Measures
Monitoring admissions to the neonatal nursery with Poor Neonatal Adaptation
Syndrome (PNAS), respiratory distress and/or Persistent Pulmonary Hypertension of
the Newborn (PPHN) attributed to SSRI/SSNI use in pregnancy.
Staff completion of online education resources is recorded in MHL.
Managers monitor staff completion of mandatory training requirements.
7. Overview
7.1 Perinatal Depression (PND) - Incidence
The World Health Organization listed depression as the leading cause of disability worldwide
in 2015. The proportion of the global population with depression in 2015 was estimated to be
4.4%, with depression more common among females (5.1%) than males (3.6%) 2. Rates in
women of childbearing age range from 4.5% in 15-19 year olds to 7% in 40-44 year olds.
There is limited data for prevalence of depression among pregnant and postpartum women.
However, the estimated prevalence of depression among pregnant and postpartum women
in the US was 9.1 and 10.2 percent, respectively in 2004-2005 3, 4. Australian studies have
reported the 4-year period prevalence of antenatal depression as up to one in ten women
and the 12-month period prevalence of postnatal depression as one in six in the first
postnatal year. 5
7.2 Perinatal Depression – effect on the mother and infant
Untreated prenatal depression is associated with pre-eclampsia 6, 7, low birth weight and
prematurity 8, 9, as well as negative effects on the mother and child 3, 4, 8. Although acts of
harming oneself or others during PND remain rare, depression increases the risk of suicide
and suicidal ideation among postpartum women 3. Depressed mothers report more thoughts
of harming their infants, exhibit higher levels of negative maternal behaviours and
disengagement from their infants, and display lower levels of positive maternal behaviour 3, 8.
Elevated risks of sudden infant death syndrome have also been reported in relation to
depression in pregnancy and the postnatal period 8. Infants of mothers with depression
receive fewer preventive health services (e.g. vaccinations), are at risk for early
breastfeeding cessation, and mothers are also more likely to engage in smoking and not
place their children in car seats as frequently 3. Depression in pregnancy has been
associated with internalising and externalising disorders in the children, and depression in
adolescents and young adults 8.
7.3 Perinatal Depression – Management Overview
Early detection of perinatal depression and anxiety is essential in the management and
support of mental health and wellbeing. A variety of psychological treatments (e.g. cognitive
behavioural therapy; interpersonal therapy), and other psycho-social measures (e.g. physical
activity, education, support, sleep, debriefing, expressive writing) and pharmacologic
interventions have been found to be effective in the treatment of mild perinatal depression 3,
4. Interventions with clinical trial proven effectiveness for prevention of perinatal depression
include counselling interventions, cognitive behavioural therapy and interpersonal therapy,
physical activity, education, peer support and sleep 4.
For a woman with moderate or severe depression in pregnancy or the postnatal period,
either a tricyclic antidepressant, selective serotonin reuptake inhibitor (SSRI) or serotonin-
noradrenalin reuptake inhibitors (SNRI) is recommended 8.
Information should be provided to the woman about the risk of relapse if medication is
ceased, as well as risks associated with continuing medication 8.
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 5
7.4 Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs)
Selective serotonin reuptake inhibitors (SSRIs) and, to a lesser extent, serotonin-
noradrenalin reuptake inhibitors (SNRIs), are commonly used in the treatment of depression
during pregnancy. Published data show that 2.4% of pregnant women in Sweden during
years 2006–2012 10, and 6% in USA during the years 2001–2013 who were treated with
SSRIs 11.
Selective serotonin reuptake inhibitors and SNRIs carry potential risks to the fetus and
mother. The NICE guideline review 8 identified a statistically significant association between
all SSRIs and congenital malformations (p=0.04) with an absolute risk difference of 9 more
per 1000. Significant associations were found for paroxetine and congenital (p=0.05), major
congenital (p=0.04) and cardiac (p=0.006) malformations, and fluoxetine with major
congenital (p=0.008) and cardiac (p=0.02) malformations, citalopram and escitalopram and
ventral septal defects.
SSRIs use in late pregnancy is associated with persistent pulmonary hypertension
(p=0.00001), although the absolute risk difference is low with only 2 more per 1000 in the
SSRI exposed group 8, 12, 13. Larger effect sizes were found for an association between any
antidepressant and poor neonatal adaptation syndrome (PNAS) (280 more per 1000),
respiratory distress (90 more per 1000) and tremor (352 more per 1000). There was also
some evidence for greater risk of preterm delivery (17 more per 1000) and miscarriage (12
more per 1000) associated with the SSRI group. There are also several case reports of
serotonin syndrome (toxicity) in newborn infants or mothers on fluoxetine 14, 15, 16, 17,
paroxetine 18 and citalopram 19, but not for sertraline 20.
PNAS (withdrawal) should be distinguished from serotonin syndrome (toxicity). PNAS is
more likely with agents with shorter plasma elimination half live (e.g. sertraline 20), whereas
toxicity has been reported with agents with a longer elimination half live of the agent and/or
its metabolite (fluoxetine, paroxetine and citalopram).
7.5 Poor Neonatal Adaptation Syndrome (PNAS)
Poor Neonatal Adaptation Syndrome (PNAS), also described as SSRI neonatal behaviour
syndrome 21, 22, 23, comprises of central nervous system, respiratory, and gastrointestinal
symptoms 21, 22, 23, 24, 25, 26, 27. Most symptoms develop within 48 hours of birth and resolve
without treatment within two to six days. Severe PNAS reaching treatment criteria on the
Finnegan score (Neonatal Abstinence Score) was reported to be uncommon, occurring in 7
of 220 infants (3%) exposed to SSRIs or SNRIs. In contrast, hypoglycaemia (plasma glucose
<2.6 mmol/L) was reported in 42 infants (19%) 24.
Infants should be observed for signs of SSRI withdrawal including increased muscle tone,
loose or watery stools, mild or marked tremors while undisturbed, less than 1 or 2 hour sleep
after feeding, poor feeding (breastfeeding code <5) or a markedly hyperactive Moro reflex
(i.e. startle) 28. If present, infants can be monitored for severe withdrawal using the Finnegan
Neonatal Abstinence Score 23. Severe withdrawal has been variably defined as two or three
consecutive scores of 8 or over 23. An adapted Finnegan Neonatal Abstinence Score (see
Appendix) comprising of 8 items has been validated a sensitivity of 97.7% and specificity of
37.0% using a cut-off of 1, and a sensitivity of 41.9% and specificity of 86.2% using a cut-off
of 2 28. Guidelines for the monitoring and observation of SSRI / SNRI exposed infants vary,
however, where available predominantly suggest an initial observation period of 48 – 72
hours, continuing until symptoms are resolved 22, 23.
If severe withdrawal is present (3 modified Finnegan NAS scores ≥8) obtain paediatric
review and consider commencing Phenobarbital which has been recommended as per the
Neonatal Abstinence Syndrome Guideline 29.
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 6
7.6 Serotonin toxicity (syndrome)
Serotonin syndrome is a drug induced syndrome characterised by a cluster of dose related
adverse effects that are due to increased serotonin concentrations in the central nervous
system. 30 Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter with many effects,
including modification of mood, sleep, vomiting, and pain. Severe or life threatening effects
(rigidity and hyperthermia) result from stimulation of 5-HT2 receptors. The mothers of
symptomatic infants should be assessed for signs of serotonin toxicity by history and
examination. The Hunter Serotonin Toxicity Criteria Decision Rules are more accurate for
diagnosis of serotonin toxicity31: In the presence of a serotonergic agent:
1. IF (spontaneous clonus=yes) THEN serotonin toxicity=YES;
2. ELSE IF (inducible clonus=yes) AND [(agitation=yes) OR (diaphoresis=yes)] THEN
serotonin toxicity=YES;
3. ELSE IF (ocular clonus=yes) AND [(agitation=yes) OR (diaphoresis=yes)] THEN serotonin
toxicity=YES;
4. ELSE IF (tremor=yes) AND (hyperreflexia=yes) THEN serotonin toxicity=YES;
5. ELSE IF (hypertonic=yes) AND (temperature > 38C) AND [(ocular clonus=yes) OR
(inducible clonus=yes)] then serotonin toxicity=YES;
6. ELSE serotonin toxicity=NO.
In adults and children, moderate to severe serotonin toxicity is managed with sedation to
reduce muscle hyperactivity (such as midazolam infusion or oral diazepam), active cooling
(fans with water sprays, ice packs, or cooling blankets), and even paralysis and ventilation
may be useful in severe cases30. Serotonin antagonists including intravenous
chlorpromazine and oral cyproheptadine have been used to treat moderate serotonin. With
intravenous chlorpromazine, fluid loading is essential to prevent hypotension.
There are several case reports of serotonin syndrome (toxicity) in newborn infants or
mothers on fluoxetine 14, 15, 16, 17, paroxetine 18 and citalopram 19, but not for sertraline.
Fluoxetine has a long elimination half-life reported to range 1 to 3 days after a single dose,
and 4 to 6 days after long-term use. Its active metabolite, norfluoxetine has a half-life up to
16 days 14, 15.
In the newborn, reported signs of serotonin toxicity include irritability; increased muscle tone;
mild or marked tremors while undisturbed; ankle clonus elicitable on examination; and low
grade fever. These infants may still be feeding efficiently as serotonin is involved in appetite.
Continued mother’s milk feeding is a risk factor for toxicity, particularly with fluoxetine.
Perform a plasma drug level of the relevant agent and its active metabolite to differentiate
PNAS from serotonin toxicity. Reports of toxicity have usually been associated with plasma
levels of the agent and / or active metabolite in the therapeutic range for adults:
Fluoxetine and norfluoxetine (active metabolite) 14, 15;
Paroxetine 18;
Citalopram and desmethylcitalopram 19.
Treatment of neonatal toxicity includes changing or reducing the mother’s medication (as
directed by her physician or psychiatrist), or changing the infant’s feed 14. The half-life of
many agents and their metabolites may very prolonged. Serial plasma levels of the agent
and its active metabolite may be required to guide management.
Diazepam has been used to treat neonatal serotonin toxicity 19 and has not been the agent of
choice in RPAH Newborn Care. We have used phenobarbital with good effect as per the
Neonatal Abstinence Syndrome Guideline 29.
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 7
There are no reports of use of serotonin antagonists in newborn infants with serotonin
toxicity although chlorpromazine has been used for neonatal abstinence syndrome
secondary to opioids or sedatives, 32 and cyproheptadine use has been reported in infants
with feeding difficulties. 33 The dosages, efficacy and safety of these agents is unclear in
newborn infants.
7.7 SSRIs and Breastfeeding
If serotonin toxicity is suspected, plasma drug and metabolite levels should be taken and
exposure eliminated along with supportive therapy. Preferred medications during the
perinatal period include sertraline and citalopram 13, 34.
For infants with SSRI withdrawal, postpartum use of SSRIs is not a contraindication to
breastfeeding, and women who choose to breastfeed should be supported 20, 34, 35. The NICE
guidelines 8 recommend that when assessing the risks and benefits of tricyclic
antidepressants (TCAs), SSRIs or SNRIs for a woman who is considering breastfeeding,
taking into account:
the benefits of breastfeeding for the woman and baby;
the uncertainty about the safety of these drugs for the breastfeeding baby; and,
the risks associated with switching from or stopping a previously effective medication.
SSRI-exposed infants have detectable serum levels of antidepressants due to placental and
breast milk transfer. Serotonin syndrome (toxicity) has been reported in newborn infants of
mothers on fluoxetine 14, 15, 16, 17, paroxetine 18 and citalopram 19, but not for sertraline.
Developmentally delayed maturation of CYP2D6 over the first 2 to 4 weeks of life may
contribute to symptoms consistent with serotonin toxicity in neonates exposed to fluoxetine
or paroxetine during pregnancy 36, 37.
Breastfeeding is encouraged with sertraline recommended as a preferred medication.
Undetectable sertraline levels in infant serum have been reported 87% of exposed infants
with no reported adverse events 20.
8. Guideline
8.1 Practice points: Women
All women, on their first antenatal visit, are asked questions relating to mental well-being
and a psychosocial assessment. The Edinburgh Postnatal Depression Scale (EPDS) is
used.
If a woman scores 13 or more on the EDS, she may have high anxiety or be
experiencing depression.
If there is any concern about responses to the questions in the screening tools, the
woman is to be offered referral to the Perinatal Mental Health CNC and/or Perinatal
Consultation Liaison Psychiatry, via the relevant sites Perinatal Psychosocial Referral
pathway.
Women with a history of moderate or severe depression, or currently on antidepressants,
should be offered referral to the Perinatal Mental Health CNC and/or Perinatal
Consultation Liaison Psychiatry, via the relevant sites Perinatal Psychosocial Referral
pathway.
8.2 Practice points: Newborns
Babies with late-trimester SSRI / SNRI exposure should be observed in hospital for
neuro-behavioural or respiratory symptoms for a minimum of 24 hours.
Babies may have signs of SSRI withdrawal or serotonin toxicity (more common with
fluoxetine use).
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 8
Signs of serotonin toxicity:
o Irritability;
o Increased muscle tone;
o Mild or marked tremors while undisturbed;
o Ankle clonus elicitable on examination;
o Low grade fever;
o These infants may still be feeding efficiently as serotonin is involved in appetite.
Continued mother’s milk feeding is a risk factor for toxicity, particularly with
fluoxetine.
Signs of SSRI withdrawal (PNAS) in the infant include:
o increased muscle tone;
o loose or watery stools;
o mild or marked tremors while undisturbed;
o less than 1 or 2 hour sleep after feeding, poor feeding (persistent breastfeeding
codes <5) or a markedly hyperactive Moro reflex (i.e. startle).
A plasma drug and its active metabolite level can be taken to differentiate between signs of serotonin toxicity and SSRI withdrawal.
If present, commence the modified Finnegan NAS score as per the NSW Health
Neonatal Abstinence Syndrome Guidelines GL2013_008.1
If severe withdrawal is present (3 modified Finnegan NAS scores ≥8) obtain paediatric
review and consider commencing phenobarbital (phenobarbitone) which has been
recommended as per the MoH Neonatal Abstinence Syndrome Guideline GL2013_008.1
Families should receive anticipatory guidance on the possible effects of SSRIs on their
infant, including the need for observation after birth. An extended postpartum hospital
stay should be offered.
Babies with late-trimester SSRI / SNRI exposure with neuro-behavioural or respiratory
symptoms should have a screening blood glucose performed to exclude hypoglycaemia,
and a paediatric assessment to exclude serious or other morbidity.
8.3 Practice point: Breastfeeding
For infants with SSRI withdrawal, postpartum use of SSRIs is not a contraindication to
breastfeeding, and women who choose to breastfeed should be supported.
If serotonin toxicity is suspected, plasma drug and metabolite levels should be taken and
exposure eliminated along with supportive therapy.
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 9
9. Summary of Practice Guidelines
Antenatal Identification and documentation of women prescribed antidepressant
medication (including medication, dosage, commencement and / or cessation
date), by midwifery and obstetric staff.
Provision of balanced information regarding risks of relapse if medication
ceased, and risks to neonates exposed to antidepressant medication during
pregnancy and lactation.
Offer referral to Perinatal Psychiatry/mental health services.
Provide information about Poor Neonatal Adaptation Syndrome and non-
pharmacological care of infants exhibiting signs of neonatal withdrawal to
women and their families.
Delivery Ward
/ Birth Centre
Midwives to document risk during transfer of care to the Postnatal Unit and to
the Newborn Care Unit where infants require admission.
Postnatal
Unit
Newborn
Care Unit
Oxygen saturations (PPHN risk –Neonatal Early Assessment Program).
Maximise supportive care:
o Skin-to-skin
o Encourage breast feeding
o Frequent demand feeding
o Quiet environment
Skin care, particularly where loose stools present.
Newborn vital signs to be documented electronically via iView on the BTF
SNOC in the newborn’s eMR.
Observe for signs of withdrawal:
o Increased muscle tone
o Loose or watery stools
o Mild or marked tremors while undisturbed
o Less than 1 hour sleep after feeding
o Poor feeding, or
o Hyperactive Moro reflex (startle).
o If present, commence the Modified Finnegan Neonatal Abstinence
Syndrome Score, 4/24 TPR and oxygen saturation levels, 6/24 blood
glucose monitoring
Assess for risk of serotonin toxicity:
o Maternal use of fluoxetine, paroxetine or citalopram
o Irritability
o Increased muscle tone
o Mild or marked tremors while undisturbed
o Ankle clonus elicitable on examination
o Low grade fever
Perform a plasma level for the drug and its active metabolite if serotonin
toxicity is suspected.
If 3 consecutive NAS scores ≥8, then Paediatric review and admission to
Newborn Care Unit.
Cardio-respiratory observations to continue 4/24 until ceased by a medical
officer.
Blood glucose monitoring to continue 6/24 until three consecutive normal
levels and full enteral feeds well tolerate.
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 10
10. Definitions
BTF Between the Flags
eMR Electronic medical record
PND Perinatal depression
Poor Neonatal Adaptation
Syndrome (PNAS)
A collection of symptoms suggesting a withdrawal syndrome
including: jitteriness, irritability, insomnia and poor feeding.
PPHN Persistent pulmonary hypertension of the newborn
Serotonin toxicity Manifest in the newborn as tachypnoea, jitteriness, irritability,
hypertonia, hyperreflexia and clonus, fever and a compensated
metabolic acidosis.
SNOC Standard Newborn Observation Chart
SNRI Serotonin-noradrenaline reuptake inhibitors
SSRI Selective serotonin reuptake inhibitor
11. Consultation
Centre for Education and Workforce Development SLHD
Clinical Nurse Consultants, Perinatal Mental Health RPAH
Director National Poisons Register & Clinical Toxicology RPAH
Medicines Information-Mental Health Pharmacist, Department of Pharmacy RPAH
Neonatologist, RPAH
P&FDH Team, SLHD
Perinatal Psychiatrist RPAH
SLHD Maternity Policy Committee
12. References
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11. National Safety and Quality Standards, 2nd Ed
Clinical Governance Standard
Partnering with Consumers Standard
Medication Safety
Recognising and Responding to Acute Deterioration
Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020
Compliance with this Guideline is Recommended 13
12. Appendix