Newborn Infants Exposed to SSRI / SNRI Antidepressant …content/pdf... · 2020. 8. 18. · Newborn Infants Exposed to SSRI/SNRI Antidepressant Medication during Pregnancy and Lactation

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

https://www1.health.nsw.gov.au/pds/Pages/doc.aspx?dn=GL2013_008

Sydney Local Health District Policy No: SLHD_GL2020_028 Date Issued: August 2020


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



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.



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.



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.

https://www.slhd.nsw.gov.au/rpa/neonatal%5Ccontent/pdf/guidelines/nas.pdf




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.




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).



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.





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.



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

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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




12. Appendix

Documents

Newborn Infants Exposed to SSRI / SNRI Antidepressant …content/pdf... · 2020. 8. 18. · Newborn Infants Exposed to SSRI/SNRI Antidepressant Medication during Pregnancy and Lactation