review antidepressant use in pregnancy: a critical review ... use in pregna… · maternal...

Review

Antidepressant use in pregnancy: a criticalreview focused on risks and controversies

Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use inpregnancy: a critical review focused on risks and controversies.

Objective: Conflicting data have led to controversy regardingantidepressant use during pregnancy. The objectives of this study are toi) review the risks of untreated depression and anxiety, ii) review theliterature on risks of exposure to antidepressants during pregnancy, iii)discuss the strengths and weaknesses of the different study designs usedto evaluate those risks, and iv) provide clinical recommendations.Method: MEDLINE/PubMed was searched for reports and studies onthe risk of first-trimester teratogenicity, postnatal adaptation syndrome(PNAS), and persistent pulmonary hypertension (PPHN) with in uteroantidepressant exposure.Results: While some individual studies suggest associations betweensome specific major malformations, the findings are inconsistent.Therefore, the absolute risks appear small. PNAS occurs in up to 30%of neonates exposed to antidepressants. In some studies, PPHN hasbeen weakly associated with in utero antidepressant exposure, while inother studies, there has been no association.Conclusion: Exposures of concern include that of untreated maternalillness as well as medication exposure. It is vital to have a carefuldiscussion, tailored to each patient, which incorporates the evidence todate and considers methodological and statistical limitations. Pastmedication trials, previous success with symptom remission, andwomen’s preference should guide treatment decisions.

N. Byatt1, K. M. Deligiannidis2,M. P. Freeman31Psychiatry and Obstetrics & Gynecology, PsychosomaticMedicine, Women’s Mental Health, University ofMassachusetts Medical School/UMass MemorialMedical Center, Worcester, MA, USA, 2Psychiatry andObstetrics & Gynecology, Depression Specialty Clinic,Women’s Mental Health Specialty Clinic, Center forPsychopharmacologic Research and Treatment,University of Massachusetts Medical School/UMassMemorial Medical Center, Worcester, MA, USA and3Psychiatry, Perinatal and Reproductive PsychiatryProgram, Harvard Medical School/MassachusettsGeneral Hospital, Boston, MA, USA

Key words: antidepressant; in utero; teratogenicity;postnatal adaptation syndrome; persistent pulmonaryhypertension

Nancy Byatt, Psychiatry and Obstetrics & Gynecology,Psychosomatic Medicine, Women’s Mental Health,University of Massachusetts Medical School/UMassMemorial Medical Center, 55 Lake Avenue North,Worcester, MA 01655, USA.E-mail: [email protected]

Accepted for publication October 10, 2012

Summations

• No single type of malformation has been consistently observed across studies with any commonlyused antidepressant. Some individual studies suggest associations between particular selective seroto-nin reuptake inhibitors (SSRIs) and specific birth defects.

• Postnatal adaptation syndrome (PNAS) occurs in up to 30% of neonates exposed to antidepressantsin late pregnancy.

• Some studies find a small association between persistent pulmonary hypertension of the newborn(PPHN) and SSRI use, although other studies do not.

Considerations

• SSRIs remain the most studied antidepressants in pregnancy. Less data are available for serotonin–norepinephrine reuptake inhibitors (SNRIs), mirtazapine, nefazodone, trazodone and vilazodone.

• The current evidence base is limited by data that do not i) systematically assess infants, ii) use appro-priate control groups, iii) use blind raters of the neonates and iv) take into account maternal diagno-sis or symptoms or other confounding variables.

• The evidence regarding the risk of PPHN because of in utero antidepressant exposure is inconclusive.

94

Acta Psychiatr Scand 2013: 127: 94–114 © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing LtdAll rights reservedDOI: 10.1111/acps.12042

ACTA PSYCHIATRICA SCANDINAVICA

Introduction

During the reproductive years, a significant pro-portion of women experienced depressive and anx-iety disorders (1). Approximately 18.4% of womensuffer from antenatal depression, and as many as19.2% of mothers develop a depressive disorderwithin several weeks of delivery (2). Anxiety disor-ders are also common, with a prevalence rate of21.7% during the 3rd trimester of pregnancy, and11.1% during the first 3 postpartum months (3, 4).

Untreated depression and anxiety during preg-nancy negatively impacts mother and fetus/child.Women are more likely to experience inadequatematernal weight gain (5) and abuse substances (6).Depression in pregnancy is also associated withpreeclampsia, preterm birth (7–10), increased riskfor delivery of a low birth weight infant (11), elec-tive termination of the pregnancy (12), postpartumdepression (13), and anxiety. Depression is associ-ated with fetal distress (14) and an increased riskof neonatal care unit admission and caesariandelivery (15).

Postpartum depression can negatively impactchild development and has been associated withdifficult infant and childhood temperament (16,17) and attachment insecurity (16). Maternaldepression may also lead to emotional and func-tional disability in children including cognitivedelays (18), behavioural problems (16), and diffi-culties with social interaction (19). Children ofdepressed mothers are at increased risk of develop-mental delay, impaired language development, andlower IQ scores (20, 21). The impact of maternaldepression has effects beyond infancy, as one-thirdof school-aged children of depressed mothers suf-fer from depressive, anxiety, or disruptive disor-ders (22). Effective treatment of maternaldepression mitigates this negative impact (23).Perinatal depression can also be fatal; maternalsuicide accounts for up to 20% of postpartumdeaths in depressed women (24).

Stress and anxiety during pregnancy influencematernal behaviour and birth outcomes: maternaltobacco smoking, caffeine consumption, poornutrition and exercise, preterm labor, pretermbirth, and low birth weight are associated with pre-natal anxiety (25). Antenatal anxiety may increasethe risk of childhood developmental and psychiat-ric disorders. It may adversely affect infant emo-tional development (26) and has been associatedwith reductions in gray matter density in youngchildren (27). Treatment of perinatal depressiveand anxiety disorders is of paramount importanceto mitigate these risks. Despite the risk of relapseto depressive episodes and anxiety and associated

adverse effects, women are likely to stop antide-pressant treatment during attempts to conceive orpregnancy (28, 29).

Due to conflicting reports in the literature on therisk of first-trimester teratogenicity, postnataladaptation syndrome (PNAS), and persistent pul-monary hypertension (PPHN) with in utero anti-depressant exposure, a review of these topics is ofgreat clinical importance. In this review, selectedtopics of controversy regarding antidepressant usein pregnancy are presented, to provide clarificationduring clinical decision-making and risk/benefitassessment and discussion. A review of all possibleoutcomes is beyond the scope of this study.Although not reviewed in this article, there areassociations between antidepressant in utero expo-sure and measures of birth outcome, including anincreased rate of spontaneous abortion (30–35)(36–39), low birth weight (35, 40, 41), and reducedgestational age or preterm birth (35, 40, 42–44) indepressed women exposed to antidepressants.Recent studies have raised questions about possi-ble associations with antidepressant use inpregnancy, including autism (45) and effects onlong-term neurocognitive development (46). Whileall associations with in utero exposure are impor-tant, we limited our review to topics that havebecome the main controversies in antidepressantuse during pregnancy in recent years.

Aims of the study

The purposes of this review are to i) review therisks of untreated depression and anxiety, ii)review the literature on risks of exposure to com-monly used antidepressants during pregnancy, iii)discuss the strengths and weaknesses of the differ-ent study designs used to evaluate those risks, andiv) provide clinical recommendations.

Material and methods

A search was performed for the English languageliterature indexed on MEDLINE/PubMed for theperiod between 1966 and 2012 using the followingkey terms: antidepressant, selective serotonin reup-take inhibitor (SSRI), serotonin-norepinephrinereuptake inhibitor (SNRI), noradrenergic and spe-cific serotonin antidepressant (NaSSA), norepi-nephrine reuptake inhibitor (NRI), fluoxetine,paroxetine, sertraline, citalopram, escitalopram,fluvoxamine, venlafaxine, mirtazapine, reboxetine,duloxetine, bupropion, trazodone, nefazodone,and vilazodone in association with antenataldepression, maternal, pregnancy, prenatal expo-sure, malformation, in utero exposure, neonatal

95

Antidepressant use in pregnancy

complications, gestational, neonatal health, neona-tal outcome, birth outcome, PPHN, birth defects,and congenital heart defect. To determine whetherother relevant articles were not identified in the ini-tial search, all articles were cross-referenced. Origi-nal observational studies, case reports, and caseseries were included.

Results

First-trimester exposure: is there evidence of teratogenicity?

In the USA, approximately 1 in every 33 infants(3%) is born with a major birth defect (47). Majorbirth defects or malformations typically requiremedical or surgical intervention for a structural orfunctional abnormality. Antidepressants that affectserotonergic tone could putatively increase theincidence of congenital malformations becauseserotonin is important in aspects of early embry-onic development that impact development of theneural tube, branchial arch, and heart.

Despite the high prevalence of birth defectsoverall in the population, each specific type ofmajor birth defect is generally rare, and studiesthat are inadequately powered or controlled mayoverestimate risk and association. For example, ofthe major birth defects studied in association withantidepressant use, omphalocele occurs in 1 per5386 births, gastroschisis occurs in 1 per 2229,anencephaly 1 in every 4859, and craniosynostosisin 4–10 per 10 000 births in the general population(47). While congenital heart disease is relativelycommon (48, 49), studies examining the effects ofdrug exposure should ideally use the rate of unex-posed infants with identical ascertainment methodsas a comparison rate for the malformation(s)under study, rather than the 1% incidence of con-genital heart disease (48, 49) in the general popula-tion, which makes interpretation of findingsdifficult.

Different methodologies have been used to studythe risks of teratogenicity with antidepressant usein pregnancy. Some use retrospective case–controlstudies, which carry the risk of recall bias and largenon-response rates. Other prospective controlledstudies, often performed in teratology informationcenters, use detailed drug use information in asmall number of women. A final type of study usesdata from drug registries and administrative data-bases, which carry the risk of exposure misclassifi-cation given that it is not clear whether womenwho purchased the drug took it as prescribed.When they recently compared interview data withdata from a prescription registry, Kallen et al.found the most valid results are obtained through

prospective interview data on drug use. For pre-scription data, they recommended avoiding the useof prescriptions given earlier than 1 month beforethe last menstrual period because of the increasedpercentage of women who did not use the medica-tion in pregnancy (50).

Across all study types, the risks of the underly-ing untreated disorder and other associated con-founding factors are rarely taken into account.The strategy of using depressed women withoutdrug treatment as a comparison may not be ade-quate given the likelihood that illness severity cov-aries with medication use. Comparisons ofdifferent SSRI effects may also be complicated bythe fact that this class of medications is used formany conditions other than depression, includinganxiety disorders (51). SSRI preference may alsodiffer according to indication, and prescribing pat-terns may differ between populations. To controlfor maternal illness severity, Oberlander et al. useda propensity score method that allowed them tocontrol for maternal illness severity and othercharacteristics that impact neonatal outcomes.Unfortunately, even with their large populationlevel data set, propensity score matching led to areduced sample size for comparison groups (52).

The use of different study designs and limita-tions of each may explain why findings of malfor-mations are inconsistent. The data presented inTable 1 are difficult to interpret because it is diffi-cult to differentiate whether adverse outcome isassociated with underlying illness, the medicationitself, or other unknown factors associated witheither or both.

Selective serotonin reuptake inhibitors. Prior to2005, studies had not suggested an increased riskof major congenital malformations with in uteroexposure to SSRIs (35, 36, 43, 53–59). These stud-ies, as well as those since, were generally limited byinsufficient power, confounding variables, con-cerns with the method of birth outcome classifica-tion, and limited exposure information (60). Overthe past several years, a number of studies havefound associations between specific SSRIs andmalformations, although the findings are inconsis-tent across studies, making their interpretation dif-ficult. A teratogen would be expected to cause asimilar type of malformation consistently acrossstudies. While this has not been the case withSSRIs, sporadic reports have generated concerns.

Since 2005, the data have been conflicting andinconsistent (61) with regard to whether individualSSRIs are associated with an increased risk of con-genital malformations. Discrepant findings havefueled confusion, and it is unclear whether un-rep-

96

Byatt et al.

Table1.

Maternaluse

ofantidepressantsandtheriskofcongenitaldefects

Study

Design

Antidepressantstudied

NFindings

Pedersen,etal.(2009)(79)

Population-based,

cohortstudy

Fluoxetine,citalopram

,paroxetine,sertraline

493113unexposedinfantsand

1370

infantsexposedtoSSRI

Increasedprevalence

ofseptaldefectswith

prescription

of>1SSRI(2.1%)vs.asingleSSRI(0.9%)vs.not

prescribed

anSSRI(0.5%)

Increasedprevalence

ofseptalheartdefectsafter

first-trimesterexposuretosertraline(1.5%)or

citalopram

(1.1%)yetnotfluoxetine(0.6%)or

paroxetine(0.3%)

Overallnoassociationwith

majormalformations

ornon-cardiacmalformations

Wogelius,et

al.(2006b)(64)

Population-based,

cohort


,paroxetine,sertraline

150780wom

enwith

noSSRI

prescriptionvs.1,051

wom

enwho

filledSRRIprescription

30days

beforeconceptionto

endoffirsttrimestervs.453

filledprescriptionduring

second

orthird

trimester

Increasedriskofcongenitalm

alformations

with

prescribed

SSRIearly

inpregnancycomparedwith

unexposedinfants(3.4%

vs.4.9%)

(aRR

=1.34;95%

1.00–1.79)andlateinpregnancy

(6.8%)(aRR=1.85;95%

CI1.25–2.71)

SSRIusenotassociatedwith

anyspecificmalformation

Wen

SW,etal.(2006)(80)

Population-based,

retrospectivecohort


,paroxetine,sertraline,

fluvoxamine

972wom

enexposedtoan

SSRI;3878notexposed

Noincreasedriskofmajor(OR=0.98;95%

CI0.59–1.64)

orminormalformations

(OR=1.02;95%

0.69–1.51)

with

prenatalSSRIexposure

ReisandKallen(2010)(41)

Population-based,

prospectivecohort

SSRIs,bupropion,

trazodone,SNRIs,

TCAs,M

AOIs,

unspecified

antidepressant

14821wom

enwith

15017

infantswith

early

exposure,

laterexposureorbothand

comparedwith

1236053

infantsinthegeneralpopulation

Increasedriskofgeneralteratogenicity

afterexposure

tofluoxetine(OR=1.31;95%

CI0.85–2.02)andof

cardiovasculardefectsafterparoxetineexposure

(OR=1.66;95%

CI1.09–2.53)

Risk

ofhypospadiaswith

SSRIexposure

(OR=1.30;95%

CI0.94–1.80)andhigherwith

paroxetine(OR=2.45;95%

CI1.12–4.64)

TCAs

(prim

arily

clom

ipramine)associated

with

ahigherriskofteratogenicityoverall

Risk

ofcystickidney

diseasewas

elevated

forS

SRI

(n=9)(OR=2.39;95%

CI1.09–4.54)

KallenandOtterbla

Olausson

(2007)(51)

Population-based,

prospectivecohort

Citalopram

,sertraline,

fluoxetine,paroxetine

6555

infantsexposedto

first-trimesterS

SRIuse

Increase

intheriskofheartdefectsandatrialand

ventriculardefectswith

paroxetineexposure

Nooverallincreaseincongenitalm

alformations

with

SSRIexposure(AOR

=0.89;95%

CI0.79–1.07)

Paroxetinewas

associated

with

anincreasedrisk

ofventricularandatrialseptumdefects

(OR=1.81;95%

CI=0.96–3.09)

Noassociationbetweencraniosynostosisor

omphaloceleandmaternalSSRIuse

Einarson

A,et

al.(2008)(74)

Prospective,cohort

Paroxetine

3379

infantswith

first-trimester

paroxetineexposurevs.1174

unpublishedcasesvs.2061

infantsfrompublisheddatabases

vs.anunexposedcohort

Paroxetineisnotassociatedwith

anincreasedrisk

ofcardiovascularbirth

defects

97


Table1.

(Continued)

Study

Design


NFindings

Einarson

A,et

al.(2009)(81)

Prospective,cohort

Bupropion,citalopram

,escitalopram

,fluvoxamine,

nefazodone,paroxetine,

mirtazapine,fluoxetine,

trazodone,venlafaxine,

sertraline

928wom

enexposedto

antidepressantsinpregnancy

vs.928

controls

Prevalence

ofcardiacmalformations

was

belowthe

prevalence

rateat0.6%

Einarson

A,et

al.(2011)(82)

Prospective,cohort

Bupropion,citalopram

,fluvoxamine,nefazodone,

paroxetine,mirtazapine,

fluoxetine,trazodone,

venlafaxine,sertraline

1243

with

first-trimester

antidepressantexposurevs.89

wom

enexposedto>1antidepressant

vs.,89

exposedto1antidepressant

vs.89notexposed

Noassociationbetweenantidepressantexposure

andmalformations

Klieger-G

rossman,

etal.(2011)(85)

Prospective,cohort

Escitalopram

212wom

enexposedtocitalopram

vs.

212exposedtootherantidepressants

vs.212

exposedtonon-teratogens

Escitalopram

notassociatedwith

increasedriskof

majormalformation

MalmH,

etal.(2011)(73)

Population-based,

retrospectivecohort



fluvoxamine,escitalopram

6881

motherand

child

pairs

with

first-trimesterS

SRIexposurevs.618

727motherand

child

pairs

with

noexposure

Overallm

ajorcongenitalabnormalities

werenot

associated

with

SSRIexposure

(AOR

=1.08;95%

CI0.96–1.22)

Fluoxetineassociated

with

increasedriskof

ventricularseptaldefects

(AOR

=2.03;95%

CI1.28–3.21)

Paroxetineassociated

with

increasedriskof

ventricularoutflow

defects

(AOR

4.68;95%

CI1.48–14.74)

Citalopram

associated

with

neuraltube

defects

(AOR

=2.46;95%

CI1.20–5.07)

ColeJA,etal.(2007)(66)

Case

control

Paroxetineas

compared

with

allotherantidepressants

includingSSRIs,SN

RIs,

TCAs,serotonin-2antagonist

reuptake

inhibitors,M

AOIs

815infantswith

exposureto

paroxetinemonotherapy

vs.1020

infantswith

mono-orpolytherapy

exposurevs.4936infantswith

otherantidepressantm

ono-or

polytherapyexposurevs.and

asubsetof4198

infantswith

other

antidepressantm

onotherapy

exposure

Increasedoverallrateofmalformations

ininfantsafter

first-trimesterparoxetinemonotherapy

exposure

(AOR

=1.89;95%

CI1.20–2.98),m

ono-orpolytherapy

(AOR

=1.76;95%

CI1.18–2.64)

Noincrease

incardiovascularmalformations

with

paroxetinemonotherapy

(AOR

=1.46;95%

CI0.74–2.88)

orform

ono-orpolytherapy

(AOR

=1.68;95%

CI0.95–2.97)

Coleet

al.(2007)(93)

Case

control

Bupropioncomparedwith

all

otherantidepressants

includingSSRIs,SN

RIs,

TCAs,serotonin-2antagonist

reuptake

inhibitors,M

AOIs

1213

infantswith

first-trimester

bupropionexposurevs.4743infants

with

first-trimesterother

antidepressantexposurevs.1049

infantswith

bupropionexposure

outsidefirsttrimester

Noincrease

inmalformations

with

first-trimester

bupropionexposure

98

Byatt et al.

Table1.

(Continued)

Study

Design


NFindings

Louik,et

al.(2007)(62)

Case

control



fluvoxamine,venlafaxine,

escitalopram

,bupropion

9849

infantswith

malformations

vs.

5860

controlinfants


increasedriskof

craniosynostosis(OR=0.8;95%

CI0.2–3.5)om

phalocele

(OR=1.4;95%

CI0.4–4.5)orheartdefectsoverall

(OR=1.2;95%

0.9–1.6)

Sertralineassociated

with

omphalocele

(OR=5.7;95%

CI1.6–20.7)and

septaldefects

(OR=2.0;95%

CI1.2–4.0)

Paroxetineassociated

with

rightventricularoutflow

tractobstructiondefects(OR=3.3;95%

CI1.3–8.6)

Berard,etal.(2007)(69)

Case

control

Paroxetinecomparedwith

all

otherantidepressantsincluding

SSRIs,bupropion,trazodone,

SNRIs,TCAs

serotonin-2antagonistreuptake

inhibitors,M

AOIs

1403

wom

enwith

antidepressant

exposurevs.infantswithout

malformations

Noassociationbetweenfirst-trimesterexposureto

paroxetine(OR=1.38;95%

CI0.49–3.92)orother

SSRIs(OR=0.89;95%

CI0.28–2.84)andmajorcongenital

malformations

Infantsexposedto>25

mgofparoxetinehadan

increased

riskofmajorcongenitalanomalies

(AOR

=2.23;95%

CI1.19–4.17)ormajorcardiac

malformations

(AOR

=3.07;95%

CI1.00–9.42)

Alwan

S,et

al.(2007)(60)

Population-based,

case

control

Citalopram

,sertraline,

fluoxetine,paroxetine

9622

infantswith

majorbirth

defectsvs.4092controlinfants


mostcongenitalheartdefects

orotherbirthdefects

SSRIusewas

associated

with

anencephaly

(AOR

=2.4;95%

CI1.1–5.1),cranosynostosis

(AOR

=2.5;95%

CI1.5–4.0),and

omphalocele

(AOR

=2.8,95%

CI1.3–5.7)

Bakker,etal.(2010)(72)

Population-based,

case

control

Paroxetine

678caseswith

heartdefectsvs.

615controls

IncreasedOR

foratrialseptaldefects

(AOR

=5.7;95%

CI1.4–23.7)butnotforheartdefects

overall(AO

R=1.5;95%

0.5–4.0),afterpreconception

and/orfirst-trimesterparoxetineexposure

Bakker,etal.(2010)(76)

Population-based,

case

control

Fluoxetine

4255

infants,178ofwhich

were

exposedtofluoxetineinthefirst

trimester

Associationbetweenfluoxetineandinfantile

hypertrophic

stenosis(1.7%

infantsexposedtofluoxetinevs.0.2%

non-exposedvs.infantswith

otherm

alformations

(AOR

=9.8;95%

CI1.5–62.0).

Ramos,etal.(2008)(83)

Retrospectivecase

control

SSRIs,TCAs,SNRIs,

bupropion,mirtazapine,

moclobemide,trazodone,

nefazadone

2329

wom

en,ofw

hich

189infants

hadmajorcongenitalm

alformation,

vs.2140withoutm

alformation

Noassociationbetweenantidepressantuse

inthefirst

trimesterand

majorcongenitalm

alformations

(AOR

=1.10;95%

0.75–1.62)

Noassociationbetweendurationofantidepressant

exposureandtheprevalence

ofmajorcongenital

malformations

Antidepressantclass

exposurewas

notassociated

with

majorcongenitalm

alformations

Wisner,et

al.(2009)(84)

Prospective,controlled

observational

SSRIs

238wom

en;131

withoutS

SRI

exposureorMDD

vs.71with

partialorcontinuous

SSRIexposure

vs.partialorcontinuous

MDD

(n=36)

Noassociationbetweencontinuous

orfirsttrimesterand

minorormajormalformations

99


licated results represent true associations. Oneexample of conflicting findings is the retrospectivecase–control studies by Alwan et al. and Louiket al. that linked the use of SSRI drugs with raremalformations. Both studies carry a risk for recallbias and have a high rate of non-responders (60,62). Other studies have other methodological limi-tations, for example, Wogelius et al. (63) identifiedmalformations from discharge diagnoses in womenwith and without intrauterine SSRI exposure.Examining physicians were aware of SSRI expo-sure, which may have increased vigilance duringexaminations, and led to surveillance bias andoverestimation of risks because of the identifica-tion of less serious malformations, for example,mild cardiac defects that would not otherwise havebeen identified. Other studies are so small that theylack statistical power to detect anything, butextreme risk increases that are unlikely to occurwith SSRI exposure.

A small increased absolute risk of rare defectssuch as omphalocele, anencephaly, craniosynosto-sis (60), cystic kidney, and congenital heart defects(51, 64–66) has also been reported. Importantly,specific patterns of congenital malformations havenot been demonstrated with SSRIs across studies,and teratogenicity is usually determined by a con-sistent risk and pattern of malformation. Amongthe SSRIs, paroxetine has become the most com-plicated in terms of reported risks and recommen-dations for use in pregnancy.

Paroxetine. In 2005, a small study performed byGlaxoSmithKline suggested an increase in cardiacmalformations in infants exposed to paroxetine inutero compared with controls. As a result, Glaxo-SmithKline modified the prescribing informationto include a warning regarding the risk of cardiacmalformations with antenatal paroxetine exposure.This study was not peer-reviewed or published, butwas presented to the US FDA and cited elsewhere(67). As this recommendation was based on non-peer-reviewed, unpublished data, and a relativelysmall sample size, its findings are difficult to inter-pret (68). Since then, multiple studies (41, 51, 60,66, 69–73), although not all (65, 74), have foundan association between prenatal paroxetine expo-sure and an increased risk of congenital malforma-tions, yet the causality and magnitude of that riskare unclear.

A recent meta-analysis based on research priorto 2006 found that paroxetine was associated with1.7-fold risk increase of cardiac malformation (71).A later review, however, concluded that it is notpractical to use a meta-analysis to examine thesafety of paroxetine in pregnancy given the limita-Ta

ble1.

(Continued)

Study

Design


NFindings

Merlob,et

al.(2009)(61)

Prospective,controlled,

observational

Sertraline,fluvoxamine,

fluoxetine,paroxetine,

citalopram

,escitalopram

Congenitalheartdefectsidentified

in8of235(3.4%)vs.congenital

heartdefectsin1083

of67

636

(1.6%)non-exposed

newborns

SSRIexposureassociated

with

two-foldincreased

riskofnon-syndromiccongenitalheartmalformations

vs.1.6%

ofnon-exposednewborns

(RR=2.17;95%

CI1.07–4.39)

Kornum

JB,etal.(2010)(78)

Population-basedprevalence

study

Sertraline,fluvoxamine,

fluoxetine,paroxetine,

citalopram

,escitalopram

2062

of216042wom

enhadSSRI

prescriptions

duringearly

pregnancy

SSRIexposurewas

associated

with

anoverallincreased

riskofcardiacmalformations

(OR=1.7;95%

CI1.1–2.5)

andoverallm

alformations

(OR=1.3;95%

CI1.1–1.6)

Sertralinewas

associated

with

anincreasedriskof

septaldefects,1.7%

(n=6)(OR=3.3;95%

CI1.5–7.5)

TCA,

tricyclic;A

OR,adjustedodds

ratio;SSRI,selectiveserotoninreuptake

inhibitor;RR,relativerisk;aRR,adjusted

relativerisk;OR

,oddsratio;CI,confidence

interval;M

AOI,monoamineoxidaseinhibitor;SN

RI,serotoninnorepinephrinereuptake

inhibitor.

100

Byatt et al.

tions in the methodology of the published studies(75). Another meta-analysis that examined 37studies from January of 1992 through September2008 provides further evidence of an increased riskof major congenital malformations with paroxetineexposure. The authors concluded that first-trimes-ter paroxetine exposure is associated with anincreased prevalence of combined cardiac defects[prevalence odds ratio (POR) = 1.46%; 95% CI1.17–1.82] and aggregated defects (POR = 1.24;95% CI 1.08–1.43) (70).

Other SSRIs. Specific individual studies havefound malformations associated with specificSSRIs as isolated reports. These include hypertro-phic stenosis (76), congenital heart defects, andother major abnormalities (41, 65, 73, 77) with flu-oxetine, omphalocele (62, 77–79) and cardiac sep-tal defects (62, 77, 79) with sertraline, andomphalocele (62, 77–79), congenital heart defects(62, 77, 79), and neural tube defects (73) with cita-lopram. Other studies, however, have not sug-gested an association between fluoxetine (62, 64,69, 77–84), sertraline (41, 51, 69, 73, 80–84), or cit-alopram (41, 80–82, 84) and major congenitalabnormalities. While the data are very limited,escitalopram has not been associated with risk ofmajor malformation (62, 73, 81, 85).

Meta-analyses. When interpreting this data, it isimperative to consider meta-analyses, because thepower of individual studies may not be adequateand large numbers of subjects are needed to dem-onstrate association with congenital malforma-tions. Five meta-analyses have investigated the riskfor major malformations in association with anti-depressant use during pregnancy. Four of thesestudies found no statistically significant increasedrisk of major malformations in the first trimesterof pregnancy (31, 86–88). The fifth meta-analysisfound an increased risk of cardiac malformationsin infants exposed to paroxetine in the firsttrimester (71).

In summary, paroxetine and other SSRIs havenot consistently been demonstrated to be associ-ated with particular birth defects. Paroxetine useduring early pregnancy has been the most contro-versial, as it has been associated with an increasedrisk of overall major malformations, particularlyatrial and ventricular septal defects in severalstudies (51, 60, 66, 69, 72), but assessments oflarge databases have not supported this finding(65, 74).

Serotonin–norepinephrine reuptake inhibitors (SNRIs),norepinephrine reuptake inhibitors (NRI), and other

antidepressants. Compared with the SSRIs, thereare fewer reports on the reproductive safety pro-files of other antidepressants. While the availableevidence is extremely limited, studies examiningvenlafaxine, duloxetine, nefazodone, and mirtaza-pine do not suggest an increased risk of congenitalmalformations (32, 39, 81, 89, 90). An increasedrisk of left outflow tract heart defects has beeninconsistently demonstrated in association withbupropion. Overall, the limited studies have shownreassuring, but not definitive data regarding thereproductive safety of venlafaxine, trazodone,mirtazapine, and bupropion.

Bupropion. Bupropion has efficacy for smokingcessation, and tobacco use is associated with birthcomplications. Understanding the safety of bupro-pion in pregnancy is important as it may be apotential treatment option for women with depres-sion and nicotine dependence. In 1997, Glaxo-SmithKline established a Bupropion PregnancyRegistry and by March 2008, 3.6% and 1.3% ofinfants exposed to bupropion were reported tohave congenital abnormalities and congenital heartdefects, respectively. Congenital heart defects werefound in both retrospective and prospectivereports (91), raising concern that first-trimester bu-propion exposure might increase the risk of con-genital heart defects. The first prospective study onbupropion use in pregnancy did not demonstratean increased risk of major malformation with bu-propion exposure; however, the sample was smallwith only enough power to detect a five-foldincreased risk (37). A retrospective case–controlstudy that examined the risk of bupropion expo-sure 1 month prior to conception until 3 monthsafter conception found that exposed infants weremore likely to have left outflow tract heart defects,but not other defects (OR = 2.6; 95% CI 1.2–5.7)(92). Another case–control study did not find anincreased risk of congenital malformations whenthey compared first-trimester bupropion exposureto (1) first-trimester exposure to other antidepres-sants and (2) bupropion exposure outside the firsttrimester (93). Other studies (37) (92) are reassur-ing as they do not demonstrate an increased risk ofcongenital malformations following exposure tobupropion during pregnancy. Even with the possi-ble increased risk of congenital heart defects (91,92), the absolute risk of a congenital heart defectremains low at 2.1/1000 births in exposed infants(92) when compared with the estimated prevalenceof 0.82/1000 births in the general population (49).

SNRIs and other non-SSRI antidepressants. Thereare a very limited number of studies examining

101


SNRIs (such as venlafaxine and duloxetine).A large prospective cohort study that included theSNRI venlafaxine and other non-SSRI antidepres-sants – mirtazapine, nefazadone, bupropion, andtrazodone – found that the prevalence of cardiacmalformations was well below the prevalence rateat 0.6% in the antidepressants as a group (81).Data obtained from the Swedish Medical BirthRegistry also do not suggest an increased risk ofcongenital malformations after exposure to SNRI/NRIs. However, because of small sample size, itonly would have detected a marked teratogeniceffect (89).

Mirtazapine. A prospective, comparative studythat examined whether exposure to mirtazapineduring organogenesis increased the rate of majormalformations found that mirtazapine wasnot associated with an increased risk of major mal-formation (39).

Trazodone/nefazodone/vilazodone. Data on trazo-done and nefazodone are limited with the excep-tion of a multicenter prospective controlled study,which found that trazodone and nefazadone didnot increase the rates of major malformationabove the baseline (90). A literature review did notreveal any data on vilazodone.

Summary. Recently, the safety of SSRIs in preg-nancy has been challenged by data from large pop-ulation-based studies. Reports are difficult tointerpret because of the lack of consistent findingsand the inability to assess cause and effect fromassociation studies. Most reports do not take intoaccount the underlying psychiatric condition andvariables that may not be controlled for that woulddiffer between groups being compared. While someindividual studies suggest associations betweenSSRIs and some specific major malformations, thefindings are inconsistently observed; therefore, theabsolute risks appear small. While the limited avail-able data suggest a possible association between bu-propion and congenital heart defects (91, 92), theabsolute risk appears low. Although the very lim-ited studies examining SNRIs have been reassuring,further investigation is needed before the risksassociated with their use may be fully understood.

Later pregnancy controversies

Postnatal adaptation syndrome (PNAS). All SSRIscross the placenta, carrying the potential toincrease serotonin concentrations in the developingfetus. Increased serotonin concentrations mayimpact fetal cardiovascular, respiratory, and neu-

rological development, which all involve serotonin.Premature neonates may be more susceptible toPNAS given their immature lung and central ner-vous systems.

Since PNAS was first noted in 1973 (94), expo-sure to antidepressants during late pregnancy hasbeen associated with infant irritability, abnormalcrying, tremor, lethargy, hypoactivity, decreasedfeeding, tachypnea, and respiratory distress (95–99). As data emerge, this cluster of symptoms isincreasingly referred to as PNAS. It has also beenreferred to as ‘neonatal behavioural syndrome’ or‘poor neonatal adaptation syndrome’ with studiesfocusing on a collection of symptoms includingirritability, tachypnea, hypothermia, and hypogly-cemia (96, 100–102). Clinical signs and symptomsusually develop from birth to days after deliveryand are time limited. While they usually resolvewithin days or weeks of delivery (95), symptomshave been reported to last as long as 6 weeks(103). Severity and length are impacted by multiplefactors including dose, timing and duration ofexposure, and SSRI pharmacology including half-life, presence of active metabolites, and maternaland infant hepatic cytochrome P450 isoenzymegenotype, among others (104).

As shown in Table 2, Different methodologieshave been used to examine the relationshipbetween PNAS and antidepressants. Databases ofadverse drug event reports have the advantage ofbeing able to detect effects too rare to be detectedin clinical trials. Similar to case reports, however,databases of adverse drug reaction reports are lim-ited by lack of incidence rate determination, und-erreporting and reporter bias (95). Theidentification of PNAS symptoms related to anti-depressant exposure is also complicated by thechallenge of determining whether the symptomsare due to maternal illness or medication exposure(105). Important considerations in evaluating thedata include the following: i) whether systematicassessments of infant were conducted, ii) whetherappropriate control groups were included in thestudy, iii) whether raters of the infants wereblinded to antidepressant exposure, iv) whethermaternal diagnosis or symptoms were taken intoconsideration, and v) whether other confoundingvariables may contribute to neonatal symptoms.

Numerous mechanisms have been proposed forPNAS including serotonin toxicity (104), oversti-mulation of serotonin (101), and infant genotype(106). Many PNAS symptoms overlap those foundin adult SSRI discontinuation syndrome, choliner-gic overdrive, and serotonin syndrome. Severalcase reports note infant toxicity after in uteroexposure to paroxetine (106) and fluoxetine (97,

102

Byatt et al.

Table 2. Maternal use of antidepressants and the risk of postnatal adaptation syndrome (PNAS)

Study Design Antidepressant studied N Findings

Chambers et al. (1996) (35) Prospective, controlled Fluoxetine 73 infants withthird-trimesterantidepressantexposure vs. 101infants with first- andsecond-trimesterantidepressantexposure

PNAS associated with lateexposure only comparedwith early exposure(aRR = 8.7)Late pregnancy exposureassociated with NICUadmission (RR = 2.6)

Oberlander, et al. (2004) (104) Prospective, controlledfollow-up

Paroxetine, fluoxetine, sertralineor citalopram alone or incombination with clonazepam

28 infants with latepregnancy SSRIexposure vs. 18infants with SSRIand clonazepamexposure vs. 23non-exposed infants

PNAS symptoms in 39%of infants with SSRI andclonazepam exposure vs.25% exposed to SSRI and9% of controls(unadjusted RR = 3.5)

Costei, et al. (2002) (102) Prospective, controlled Paroxetine 55 with late exposureto paroxetine, 27infants with earlyexposure, and 27with no exposure

Third-trimester paroxetineexposure was associatedwith PNAs symptoms in22% of exposed comparedwith 11% controls(unadjusted RR = 4.0)

Zeskind and Stephens (2004) (156) Prospective, controlled Fluoxetine, citalopram, paroxetine,sertraline, fluvoxamine

17 SSRI-exposed vs.17 non-exposedinfants

SSRI-exposed infantsexhibited a wide rangeof neurobehaviouraloutcomes (p>0.05)

Laine, et al. (2003) (101) Prospective, controlled Citalopram, fluoxetine 20 mothers and infantswith late pregnancyantidepressantexposure vs. 20mothers and infantswithout exposure

Exposed infants had lowerApgar scores and a four-foldincrease in serotonergicsymptom score in first 4days of life (P = 0.008)As serotonergic symptomsincreased, cord blood5-H1AA levels decreased(P = 0.007)

Galbally, et al. (2009) (118) Prospective, controlled Fluoxetine, citalopram, paroxetine,sertraline, fluvoxamine, mianserin,mirtazapine, escitalopram

27 women exposedto medication vsmatched controls

Third-trimester antidepressantexposure associated withincreased risk of PNAS,increased rate of admissionto the special care nurseryand higher rates of jaundiceno difference betweenspecific antidepressants

Maschi, et al. (2008) (120) Prospective, controlled Fluoxetine, citalopram, paroxetine,sertraline, fluvoxamine

200 neonates withantidepressantexposure vs. 1200controls

No difference betweenantidepressant exposureand PNAS

Levinson-Castiel, et al. (2006) (116) Matched control SSRIs, venlafaxine 120 infants; 60 withprolongedantidepressantexposure vs. 60controls

PNAS occurred in 30% ofinfants with SSRI exposurevs. none in non-exposedgroup13% met criteria for severeneonatal dose–responseeffect.

Cohen, et al. (115) Retrospective, cohort study Fluoxetine 64 mother–infantpairs

Increased risk of specialcare nursery admissionsafter exposure to fluoxetinein late trimester whencompared with early trimesterexposure (18.9% vs. 9.1%)

103


Table 2. (Continued)


Rampono, et al. (2009) (157) Prospective, observational Fluoxetine, citalopram, paroxetine,sertraline, escitalopram,fluvoxamine, venlafaxine

56 mother–infantpairs; 27 exposedto SSRI vs. 11 tovenlafaxine vs.18 controls

Neonatal abstinence scoreswere higher (p < 0.05) on day1 in exposed infants comparedwith controlsExposed infants had higherserotonin scores and BrazeltonNeonatal Behavioral AssessmentScale (BNBAS) scores for motor andautonomic clusters, habituation,and social interactive (P<0.05)

Suri, et al. (2007) (44) Prospective, naturalisticstudy

Sertraline, fluoxetine, paroxetine,bupropion, nortriptyline

90 women comprisedof 49 with MDDtaking antidepressantvs. 22 with MDDeither not takingantidepressant orlimited exposurevs. 19 healthy controls

Infants of women with MDDand exposed toantidepressants hadgreater rates of admissionto the special care nurserythen women with MDD whowere not treated withantidepressants andhealthy women(21%, 9%, and 0%,respectively)

Suri et al. (2011) (158) Prospective, naturalisticstudy

Sertraline, fluoxetine, paroxetine,bupropion, nortriptyline

64 women; 33 with MDDand antidepressants vs.16 with a history ofMDD who were eithernot treated withantidepressant or hadlimited exposure vs. 15healthy controls

No differences betweengroups regarding Apgarscores, special nurseryadmissions or on theBNBAS

Hendrick et al. (2003) (55) Prospective case series Fluoxetine, citalopram, paroxetine,sertraline, fluvoxamine, venlafaxine

131 infants exposedto SSRIs

10.5% of infantsexhibited PNAS

Sit et al. (2011) (159) Prospective case series Fluoxetine, citalopram, paroxetine,sertraline, fluvoxamine, nortriptyline

21 mother–infant pairswith antidepressantexposure

No association betweencord-to-maternalconcentration ratiosand perinatal events

Ferreira et al. (2007) (117) Retrospective chart review Fluoxetine, citalopram, paroxetine,sertraline

66 neonates with SSRIexposure vs. 90 withoutexposure

Behavioural signs in 77.6%of SSRI-exposed neonatescompared with 41%non-exposedTremors, agitation,spasms, hypotonia,irritability, andsleep disturbances werereported in 63.2% ofexposed infants andrespiratory effects in 40.8%

Kallen (2004) (40) Prospective Swedish BirthRegistry

Paroxetine, fluoxetine, sertraline,citalopram

555 infants with lateSSRI exposure vs. 728controls

Increased risk for respiratorydistress (OR = 2.21),hypoglycemia (OR = 1.62),convulsions (OR = 1.9)low Apgar score (OR = 2.33)with maternal use ofantidepressantsEffects were not specific to any SSRI

Warburton et al. (2010) (52) Retrospective register study Fluoxetine, citalopram, paroxetine,sertraline, fluvoxamine

Infants exposed toantidepressants inthe last 14 days ofpregnancy vs. infantsexposed earlier inpregnancy

No difference in neonatalsymptoms among womenexposed to antidepressantin the last 14 days ofpregnancy when comparedwith those who were not

Sanz et al. (2005) (100) WHO database case seriesreview

Paroxetine, fluoxetine, sertraline,citalopram

93 infants with lateSSRI exposure

69% of cases with neonatalbehavioural symptomswere associated withparoxetine (n = 64), 14 withfluoxetine, 9 with sertraline,and 7 with citalopram

104

Byatt et al.

107–109). Several of those reports note elevatedinfant serum levels, supporting toxicity as thecause (97, 107, 108, 110). Other reports documentdiscontinuation symptoms following in utero anti-depressant exposure (110), specifically with sertra-line (111), paroxetine (98–100, 112, 113), andvenlafaxine (114).

In 1996, Chambers et al. (35) published the firstcohort study examining PNAS and found that latepregnancy exposure to fluoxetine was associatedwith an increased special care nursery admissionrate when compared with exposure earlier in preg-nancy. A similar study that retrospectively com-pared exposure with fluoxetine early and late inpregnancy found an increased risk of special carenursery admissions after late pregnancy exposureto fluoxetine (115).

Another study that prospectively compared neo-natal complications in infants found that third-tri-mester paroxetine exposure had a high rate ofneonatal complications compared with controls(22% vs. 5.5%, respectively) (102). Using the samedefinition as Chambers et al., Oberlander et al.found that thirty per cent of infants exposed toSSRI alone or in combination with clonazepamshowed symptoms of poor neonatal adaptation,25% and 39%, respectively (104). Another hospi-tal-based cohort study found PNAS in 30% ofinfants exposed to SSRIs (116). This rate of 30% ishigher than found by Costei et al. (22%) (102) andHendrick et al. (10.5%) (55), but very similar tothat found by Chambers et al. (31.5%) (35) andOberlander et al. (30%) (104). The data collectedby Costei may not represent the true rate as datawere collected later after delivery and cases mayhave been missed. A retrospective chart reviewstudy reported a higher rate of behavioural signs(77.6%) in SSRI-exposed infants compared with41% of the non-exposed (117).

In a prospective comparison study, using cordblood levels of 5-hydroxyindoleacetic acid(5-H1AA) and a modified Serotonin SyndromeScale, infants exposed to citalopram or fluoxetinein late pregnancy had lower Apgar scores andmore serotonergic symptoms than infants notexposed (101). Other prospective studies have alsofound that third-trimester exposure to antidepres-sants is associated with PNAS symptoms (118) andgreater special care nursery admission rates (119).While it lacked statistical significance, a prospec-tive controlled cohort noted a trend for increasedrisk of PNAS symptoms in infants exposed to an-tidepressants in the second and third trimester.Mild symptoms may have been underreportedbecause of recall bias during data collection inter-views with mothers (120).

SSRIs and SNRIs may both cause PNAS symp-toms. A prospective observational study compar-ing placental transfer and neonatal effects of SSRIand SNRI (venlafaxine) exposure in pregnancy tonon-exposed matched controls found that bothSSRIs and venlafaxine transferred across the pla-centa and were associated with PNAS symptoms(121). An analysis of the World Health Organiza-tion adverse events database reported 94 cases ofPNAS after in utero exposure to SSRIs and venla-faxine. PNAS symptoms in infants were notedafter maternal fluoxetine, citalopram, or paroxe-tine exposure (100). However, the total number ofwomen using these medications was not reported,so the incidence of neonatal symptoms was notpossible to ascertain.

In 2004, the FDA suggested (122) that providersconsider tapering antidepressants in the third tri-mester. While discontinuation is intuitive if antide-pressants are associated with neonatal symptoms,this recommendation did not receive formal clini-cal study prior to its release. Since this recommen-dation, Warburton (2010) and colleagues assessedbabies of mothers who were not exposed to antide-pressants in the last 14 days of pregnancy com-pared with those who were not exposed andfactored in maternal psychiatric symptoms andother possible cofounding variables into their anal-ysis. After accounting for confounding variables,there was no difference in PNAS among womenexposed to antidepressant in the last 14 days ofpregnancy when compared with those who werenot. However, the total number of women usingthese medications was not reported, so the inci-dence of neonatal symptoms was not possible toascertain (52). This study was also limited by theinclusion of subjects on fluoxetine, which may havebeen in the subjects’ system given its long half-lifeof 2 weeks.

PNAS appears to be multifactorial in nature,with late pregnancy antidepressant use accounting,in part, for neonatal symptoms. It is important toconsider that maternal anxiety has also been asso-ciated with changes in infant behaviour and self-regulation (123). Exposure to antidepressants inpregnancy, regardless of timing, has been associ-ated with PNAS. While the available evidence isconflicting, the overall data suggest that PNAS canoccur in neonates exposed to SSRIs and SNRIs,yet have most often been reported after exposure toparoxetine, fluoxetine, and venlafaxine (84, 120).

Persistent pulmonary hypertension of the newborn(PPHN). Pulmonary hypertension is a normaland required state for the fetus in utero becausethe placenta, as opposed to the lung, is responsible

105


for gas exchange. At birth, the lung replaces theplacenta as the primary site of gas exchange, andthere is a rapid drop in pulmonary vascular resis-tance and a resultant increase in pulmonary bloodflow. Multiple chemical pathways are responsiblefor this cardiopulmonary transition (124).

PPHN can result whenever cardiopulmonarytransition does not occur. PPHN is a rare disorderthat occurs in approximately 1–2 per 1000 births(125). Reduced length of gestation and prematurebirth has been associated with increased risk ofPPHN (121). Infants with PPHN present withintwelve hours of birth with cyanosis and mild respi-ratory distress and can develop severe respiratoryfailure requiring intubation and mechanical venti-lation (126). Even with therapy, PPHN can be fatalin approximately 10–20% of cases (127), depend-ing upon the etiology (128). Approximately 25%of infants with moderate-to-severe PPHN willdemonstrate significant neurodevelopmentalimpairment at 12–24 months (129).

Respiratory insufficiency is one symptom ofPNAS and may represent the presence of a mildform of PPHN and not PNAS, per se (130, 131). Itis not certain that SSRIs are associated with thedevelopment of PPHN, but there is some evidencethat longer periods of in utero SSRI exposure maybe associated with increasing risk, and severity, ofneonatal respiratory complications (132). HowSSRIs may affect neonatal respiratory complica-tions is under investigation. The accumulation ofSSRIs in the lungs may result in high circulatinglevels of serotonin which, through its vasoconstric-tive effects, increases pulmonary vascularresistance and may cause proliferation of smoothmuscle cells in the fetal lung (133), but not all stud-ies have found elevated serotonin levels (134).Another possible mechanism may involve theinhibitory effect of SSRIs on nitric oxide synthesis,an essential vasodilator that regulates vasculartone (135), but other studies do not support thathypothesis (134). Importantly, through unidenti-fied mechanisms, depression and the use of SSRISduring pregnancy have been associated with areduced length of gestation and increased risk ofpremature birth (84) that itself is associated withan increased risk of PPHN. Additionally, geneticfactors contribute to the risk of developing PPHN(128). Functional polymorphisms in the serotonintransporter promoter region may modulate therisk of PPHN in both adults (136) and infants within utero exposure to SSRIs (128, 137).

In 1996, Chambers et al. (35) first reported thatlate in utero exposure to fluoxetine was associatedwith an increased risk of PPHN when comparedwith first-trimester exposure (2.7% vs. 0%), espe-

cially when compared with the prevalence found inthe general population (0.07–0.10%). A subse-quent case–control study found that SSRI use afterthe 20th week of pregnancy was significantly asso-ciated with PPHN (adjusted odds ratio(AOR) = 6.1), but use of SSRIs or other antide-pressants prior to 20-week gestation was not (138).A retrospective analysis of data from the SwedishMedical Birth Register also found an associationbetween PPHN and maternal SSRI use duringearly pregnancy [relative risk (RR) = 2.4] and latepregnancy (RR = 3.6); though, the absolute riskwas small (139). This group’s most recent analysisthat also included tricyclics, monoamine oxidaseinhibitors, SNRIs, and other antidepressants dem-onstrated an increased RR of PPHN for antide-pressant exposure in early pregnancy (RR = 2.30),for later exposure (RR = 2.56), and for both earlyand later exposure (RR = 3.44) (41).

Most of the aforementioned studies (41, 140,141) restricted their analyses to infants deliveredafter 34 completed weeks of gestation becauseshorter gestation is associated with an increasedrisk of PPHN. A recent population-based cohortstudy used national health register data demon-strated an increased risk of PPHN associated withSSRI prescription after 20-week gestation andbefore 8-week gestation (142). The risk of PPHNassociated with exposure to individual SSRIs wasof a similar magnitude, suggesting a class effect.This study restricted their analyses to infants deliv-ered after 33-week gestation and was the largestcompleted study of the relationship between in ute-ro SSRI exposure and PPHN.

As shown in Table 3, other studies have sug-gested no association between antidepressant useduring pregnancy and PPHN. Two studies (143,144) compared the prevalence of PPHN amonginfants whose mothers were exposed to antidepres-sants in the third trimester of pregnancy comparedwith infants not exposed and did not find any dif-ference. The Wichman et al. study (144) is limitedby a lack of delineation between women treated inlate pregnancy and during the first trimester.Because late trimester use has been identified as apossible risk factor for PPHN, the inclusion ofwomen who were treated in the first trimester mayhave contributed to the negative finding. Addition-ally, the small size of both of these studies makes itlikely that a possible association would have beenmissed. Most recently, a case–controlled study of11 923 births, including 20 cases of PPHN, demon-strated an increased risk of PPHN with cesareandelivery prior to the onset of labor (OR = 4.9) butnot with SSRI use during the second half of preg-nancy (145).

106

Byatt et al.

In 2006, based on data from the Chamberset al. study, the FDA published a Public HealthAdvisory regarding an increased risk of PPHNassociated with the use of SSRIs after the 20th week

of pregnancy. This advisory resulted in changes todrug labeling to include a risk of PPHN with theuse of antidepressants during late pregnancy. InDecember 2011, the FDA released a Drug Safety

Table 3. Maternal use of antidepressants and the risk of persistent pulmonary hypertension of the newborn (PPHN)


Chambers CD et al. (1996) (35) Prospective observationalcohort

Fluoxetine 228 exposed women vs.254 controls

Late in utero exposureassociated with increasedrisk of PPHN as comparedwith first-trimesterexposure (2.7% vs. 0%)

Chambers et al. (2006) (138) Multicenter case control Citalopram, fluoxetine,paroxetine, sertraline,TCA, bupropion, venlafaxine,trazodone

377 women whose infantshad PPHN vs. 836 matchedcontrols

After the 20th week ofpregnancy, antidepressantuse was associated withPPHN (AOR = 6.1), but useof antidepressants prior to20-week gestation was not

Kallen and Olausson (2008) (139) Population-based retrospectivecohort

Citalopram, sertraline,fluoxetine, mirtazapine,paroxetine

504 infants with PPHN of831 324 births; 11 of whichhad antidepressant exposure

Early pregnancy SSRI use(RR = 2.4) and latepregnancy use (after 34 weeks)(RR = 3.6) associatedwith PPHN

Andrade et al. (2009) (143) Retrospective review SSRI, TCA, miscellaneous 1104 exposed infants vs.1104 matched controls

Prevalence of PPHN amonginfants with anythird-trimester antidepressantexposure = 1.81 per 1000infantsNo association among thoseinfants exposed to SSRIs inthird trimester (2.14 per 1000)vs. unexposed infants(2.72 per 1000)

Wichman et al. (2009) (144) Retrospective review Citalopram, venlafaxine,escitalopram, paroxetine,fluoxetine, sertraline,more than 1 SSRI

24 406 women with no SSRIuse vs. 808 women with SSRIexposure

16 newborns diagnosed withPPHN, but none of whomhad exposure to SSRI(0.07% vs. 0.0% p>0.99)

Wilson, et al. (2010) (160) Prospective database casecontrol

SSRI 11 923 births Use of SSRIs in the secondhalf of pregnancy wasidentified in 5% of thecontrols but none of thecases (OR = 0)

Reis and Kallen (2010) (41) Population-based, prospectivecohort

TCA, SSRIs, MAOIs,SNRIs (other antidepressant)

12 914 women with earlyexposure vs. 5987 with laterexposure vs. 4080 with bothearly and late exposure vs.1 062 190 women withoutexposure

Increased relative risk ofPPHN for antidepressantexposure in early pregnancy(RR = 2.30), for later exposure(RR = 2.56) and for both earlyand later exposure (RR = 3.44)

Kieler et al. (2011) (142) Population-based, prospectivecohort; national healthregisters

SSRIs, other antidepressant 28 067 women filled aprescription for SSRI vs. 1 588140 women without

Increased risk of PPHN for SSRIprescription in late pregnancy(AOR = 2.1; 3 per 1000 liveborninfants compared with thebackground incidence of 1.2per 1000) and before 8-weekgestation (AOR = 1.4)Women without SSRI use andwith prior hospitalization fora psychiatric disorder wereat increased risk of havinginfant with PPHN (AOR = 1.3)Women with a priorhospitalization for a psychiatricdisorder and late gestationSSRI prescription were atgreater risk (AOR = 3.1)

TCA, tricyclic; AOR, adjusted odds ratio; SSRI, selective serotonin reuptake inhibitor; RR, relative risk; OR, odds ratio; MAOI, monoamine oxidase inhibitor; SNRI, serotonin–norepinephrine reuptake inhibitor.

107


Communication (146) which stated that there isinsufficient evidence that antidepressant exposureduring pregnancy causes PPHN. This recent state-ment is an accurate reflection of the current litera-ture that has reported either a small associationbetween PPHN and maternal antidepressant useduring pregnancy or no association.

Although studies have also reported an associa-tion between mode of delivery and PPHN (140,141, 147–149), several were small and lacked con-trol groups. Studies that have investigated the roleof cesarean delivery and the risk of PPHN are lim-ited because it is not clear whether the risk ofPPHN is increased secondary to the mode of deliv-ery or intrauterine fetal distress.

Clinical implications and discussion

The treatment of women during pregnancy is com-plex, and clinical decisions should be based on therisks, benefits, and alternatives to psychopharma-cological treatment. All risks need to be consid-ered, including those of untreated maternalpsychiatric illness and the known and unknownpotential risks of psychotropic medication. To pro-vide optimal clinical care to women and theirdeveloping child, it is imperative to consider risksof treatment in the context of illness severity, con-sequences of no treatment and under-treatmentand individual treatment preferences.

Interpreting a conflicting evidence base

Clinicians face the challenge of interpreting anexpanding and sometimes controversial evidencebase that is summarized in Table 4. Comparing theavailable studies is difficult because of methodo-logical weaknesses and differences in study design,outcome measures, and exposure (72). This under-

lines the inherent and varying difficulties conduct-ing epidemiological studies of this nature. In sucha complicated area of study, no individual study isdefinitive. Statistical significance does not necessar-ily translate into a valuable clinical or epidemio-logical finding. For example, an OR of 1.2compared with 1.7 may be statistically significant,yet not important from an epidemiological or clini-cal perspective.

The current evidence for malformations is lim-ited because of inconsistent findings and limitedmethodology of the published studies (150). Fewstudies have controlled for maternal illness andtherefore do not take into account whether repro-ductive outcomes are due to maternal illness orantidepressant exposure. Many studies also groupmalformation types together to detect a differencein risk. For example, some studies have groupedtogether all septal defects or congenital heart dis-ease, encompassing a variety of birth defects anda range of severity. As a result, it is not knownwhether or not the reported increased risk for car-diac defects is for minor, moderate, or severeforms, which each carries varying medical risks tothe infant. Larger sample sizes are required toimprove the identification of particular terato-genic patterns, so that specific birth defects associ-ated with antidepressants can be isolatedconsistently and reproduced across studies. Whilethe large studies that do not show evidence of ter-atogenicity are reassuring, the literature also con-tains a number of studies that suggest concerns.

The current evidence base for PNAS also haslimitations in that it does not: i) systematicallyassess infants, ii) use appropriate control groups,iii) use blind raters of the neonates, and iv) takeinto account maternal diagnosis or symptoms orother confounding variables. Despite these limita-tions, these study findings vary less than those ofthe teratogenicity or PPHN studies and thereforemore strongly suggest an association betweenantidepressant use in pregnancy and PNAS.

Similarly, the PPHN literature is limited bysmall and/or uncontrolled studies. There are otherreported risk factors, including race, method ofdelivery, obesity, asthma, and diabetes (141) thatmany studies do not take into account. While thePPHN literature is inconclusive, the available evi-dence reports either a small association betweenPPHN and maternal antidepressant use duringpregnancy or no association.

Clinical importance of results

Given the inconclusive evidence, it is vital to havea careful discussion tailored to each patient that

Table 4. Results summary

TeratogenicityWhile individual studies suggest associations between selective serotoninreuptake inhibitors (SSRIs) and some specific major malformations, the findings areinconsistent; therefore, the absolute risks appear smallSSRIs remain one of the best-studied classes of medications used in pregnancyLess data are available for serotonin–norepinephrine reuptake inhibitors,mirtazapine, nefazadone, trazodone, and vilazodone

While an increased risk of left outflow tract heart defects has been inconsistentlydemonstrated in association with bupropion, the absolute risk of a congenitalheart defect remains low

Postnatal Adaptation Syndrome (PNAS)PNAS has been reported to occur in up to 30% of neonates exposed toantidepressants in late pregnancy and has most often been reported afterexposure to paroxetine, fluoxetine, and venlafaxine

Persistent pulmonary hypertension (PPHN)The available evidence reports either a small association between PPHN andmaternal antidepressant use during pregnancy or no association

108

Byatt et al.

incorporates the evidence to date on the risks andbenefits of antidepressant use in pregnancy. Werecommend educating women about the risks ofexposure to antidepressants throughout preg-nancy, which should include the US Food andDrug Administration categorization. Unfortu-nately, the US FDA antidepressant risk categori-zation is limited and does not adequately informthe decision-making process. The limitations ofthis system include lack of a requirement for sys-tematic human data, lack of clear differentiationbetween pregnancy categories, lack of incorpora-tion of risks of the maternal illness, and potentialbenefits of the medication. Newer drugs are usuallymuch more poorly studied in human pregnancy, aslittle human data are required before a drug comesto market. Therefore, healthcare providers andpatients who rely on the US FDA categories mayreceive an oversimplified and often inaccurateassessment of the knowledge base regarding a spe-cific medication in human pregnancy. Despitenumerous studies, information regarding possibleteratogenicity of antidepressants has not beenupdated since an FDA public health advisory in2005 was released concerning paroxetine and thepossible associated risk of increased cardiac mal-formations. The FDA is currently working on riskcategorization that will include more meaningfuland useful information to clinicians (151). How-ever, with the current limitations of the FDA cate-gories, it is crucial to incorporate the currentresearch literature into the decision-making andinformed consent process.

Translating results into clinical practice

As summarized in Table 5, we recommend weigh-ing the risks and benefits of treatment with antide-

pressants during pregnancy while carefullyconsidering the risk of untreated illness. Whatposes a greater risk: exposure to untreated illnessor the antidepressant? If the benefits of treatmentoutweigh the risks, then the medication should beprescribed based on an individualized risk/benefitassessment and discussion. Past medication trialsand previous success with symptom remission andwomen’s preference should guide treatment deci-sions. To avoid exposure to more than one antide-pressant or under-treated illness, one shouldchoose a medication with known efficacy for indi-vidual women. The goal of treatment should be tomaximize non-medication evidence-based treat-ments, such as specific forms of psychotherapy,and remission of the maternal symptoms, withjudicious use of pharmacotherapy when indicated.

Unless there is a reason to use another class ofantidepressant, SSRIs are generally consideredfirst-line in pregnancy. SSRIs are well character-ized, and even though risks have been reported,the preponderance of data is reassuring. It makesless sense to preferentially use a medication withless available human data. When selecting an anti-depressant for a pregnant woman who has not hadpast medication trials, many providers prefer fluo-xetine because of the amount of data available andlack of long-term developmental sequela in chil-dren (152). A current response or history of a posi-tive response to medication should help determinewhich medication to continue or initiate. The bene-fits of discontinuing an effective medication oftendo not outweigh the risks of relapse or of exposingmother and fetus to a second antidepressant medi-cation during pregnancy.

To maximize the treatment of depression andminimize risks of maternal and fetal exposure toantidepressants and untreated depression, womenshould receive the minimal effective dose of anantidepressant. The increased dose requirementsacross gestation (153, 154) should be consideredand weighed against the risks when determiningthe minimal effective dose. It is also important toavoid under-treatment as residual depression andmedication exposure represent dual exposures forthe fetus.

Polypharmacy with multiple psychotropic medi-cations should also be avoided, unless there is aclear indication for the use of multiple pharmaco-therapies. Some studies suggest that the use ofSSRIs in combination with benzodiazepines mayincrease the risk of congenital heart malformations(77) and PNAS (104). Another study did not dem-onstrate an increased risk of congenital malforma-tions after exposure to multiple antidepressants(82). It is important to consider that approximately

Table 5. Clinical points of emphasis

Unless there is a reason to use another class of antidepressant, selective serotoninreuptake inhibitors are generally considered first-line in pregnancyA current response or history of a positive response to medication should helpdetermine which medication to continue or initiate

Strongly consider using an antidepressant that the woman has responded to in thepast, to avoid unnecessary exposures during pregnancy

Maximize non-medication evidence-based treatmentsTo avoid exposure to both illness and medication, use lowest possible dose whilealso avoiding under-treatment

Avoid polypharmacy with multiple psychotropic medications, unless there is aclear indication for the use of multiple pharmacotherapies

Tapering antidepressants in the third trimester has not been shown the decreasein the incidence of postnatal adaptation syndrome or improve infant outcomes,and it carries the risk of precipitating relapse of depression

Exposure to untreated illness can be mitigated by preconception counseling,psychoeducation regarding risks and benefits of treatment and no treatment,close clinical monitoring, and a careful treatment plan tailored to the eachwoman

109


50% of pregnancies are unplanned and manywomen enter the first trimester on several medica-tions. For example, a positive response to takingtwo antidepressants concurrently may indicate thatthe risk of relapse with discontinuation of eitheroutweighs the risk of polypharmacy.

Despite the FDA’s suggestion in 2004 (122) thatproviders consider tapering antidepressants in thethird trimester, there is no evidence suggesting thisapproach reduces the incidence of PNAS orimproves infant outcomes. It also carries the riskof precipitating relapse or postpartum depression,particularly in high-risk individuals (52, 95).

Individualized treatment recommendations orplans should aim to diminish both the risk ofexposure to untreated illness and the antidepres-sant. Exposure to untreated illness can bemitigated by preconception counseling, psychoed-ucation regarding risks and benefits of treatmentand no treatment, close clinical monitoring, and acareful treatment plan tailored to the each woman(155). The risks associated with antidepressant usecan be mitigated using antidepressants with reas-suring human data, using the minimal effectivedose, and avoidance of polypharmacy. Outcomesfor mother and child can be optimized by the utili-zation of multidisciplinary approach that takesinto account risks of treatment and no treatmentand each woman’s preferences for treatment. Thiscan be accomplished by a careful discussion, tai-lored to each patient, which incorporates the evi-dence to date and considers methodological andstatistical limitations. Past medication trials, previ-ous success with symptom remission, and women’spreference should guide treatment decisions.

Declaration of interests

The authors declare that they have no conflict of interest.

References

1. Vesga-Lopez O, Blanco C, Keyes K, Olfson M, GrantBF, Hasin DS. Psychiatric disorders in pregnant andpostpartum women in the United States. Arch Gen Psy-chiatry 2008;65:805–815.

2. Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S,Gartlehner G, Swinson T. Perinatal depression: a system-atic review of prevalence and incidence. Obstet Gynecol2005;106:1071–1083.

3. Borri C, Mauri M, Oppo A et al. Axis I psychopathologyand functional impairment at the third month of preg-nancy: results from the perinatal depression-researchand screening unit (PND-ReScU) study. J Clin Psychia-try 2008;69:1617–1624.

4. Reck C, Struben K, Backenstrass M et al. Prevalence,onset and comorbidity of postpartum anxiety anddepressive disorders. Acta Psychiatr Scand 2008;118:459–468.

5. Bodnar LM, Wisner KL, Moses-Kolko E, Sit DK,Hanusa BH. Prepregnancy body mass index, gestationalweight gain, and the likelihood of major depressivedisorder during pregnancy. J Clin Psychiatry2009;70:1290–1296.

6. Flynn HA, Chermack ST. Prenatal alcohol use: the roleof lifetime problems with alcohol, drugs, depression, andviolence. J Stud Alcohol Drugs 2008;69:500–509.

7. Cripe SM, Frederick IO, Qiu C, Williams MA. Risk ofpreterm delivery and hypertensive disorders of preg-nancy in relation to maternal co-morbid mood andmigraine disorders during pregnancy. Paediatr PerinatEpidemiol 2011;25:116–123.

8. Wisner KL, Zarin DA, Holmboe ES et al. Risk-benefitdecision making for treatment of depression during preg-nancy. Am J Psychiatry 2000;157:1933–1940.

9. Wadhwa PD, Sandman CA, Porto M, Dunkel-Schetter C,Garite TJ. The association between prenatal stress andinfant birth weight and gestational age at birth: a pro-spective investigation. Am J Obstet Gynecol1993;169:858–865.

10. Istvan J. Stress, anxiety, and birth outcomes: a criticalreview of the evidence. Psychol Bull 1986;100:331–348.

11. Grote NK, Bridge JA, Gavin AR, Melville JL, IyengarS, Katon WJ. A meta-analysis of depression during preg-nancy and the risk of preterm birth, low birth weight,and intrauterine growth restriction. Arch Gen Psychia-try 2010;67:1012–1024.

12. Suri R, Altshuler LA, Mintz J. Depression and the deci-sion to abort. Am J Psychiatry 2004;161:1502.

13. Gotlib IH, Whiffen VE, Wallace PM, Mount JH. Pro-spective investigation of postpartum depression: factorsinvolved in onset and recovery. J Abnorm Psychol1991;100:122–132.

14. Jablensky AV, Morgan V, Zubrick SR, Bower C, Yella-chich LA. Pregnancy, delivery, and neonatal complica-tions in a population cohort of women withschizophrenia and major affective disorders. Am J Psy-chiatry 2005;162:79–91.

15. Chung TK, Lau TK, Yip AS, Chiu HF, Lee DT. Antepar-tum depressive symptomatology is associated withadverse obstetric and neonatal outcomes. PsychosomMed 2001;63:830–834.

16. Forman DR, O’hara MW, Stuart S, Gorman LL, LarsenKE, Coy KC. Effective treatment for postpartum depres-sion is not sufficient to improve the developing mother-child relationship. Dev Psychopathol 2007;19:585–602.

17. Britton JR. Infant temperament and maternal anxietyand depressed mood in the early postpartum period.Women Health 2011;51:55–71.

18. Sohr-Preston SL, Scaramella LV. Implications of timingof maternal depressive symptoms for early cognitive andlanguage development. Clin Child Fam Psychol Rev2006;9:65–83.

19. Downey G, Coyne JC. Children of depressed parents: anintegrative review. Psychol Bull 1990;108:50–76.

20. Deave T, Heron J, Evans J, Emond A. The impact ofmaternal depression in pregnancy on early child devel-opment. BJOG 2008;115:1043–1051.

21. Paulson JF, Keefe HA, Leiferman JA. Early parentaldepression and child language development. J Child Psy-chol Psychiatry 2009;50:254–262.

22. Pilowsky DJ, Wickramaratne PJ, Rush AJ et al. Childrenof currently depressed mothers: a STAR*D ancillarystudy. J Clin Psychiatry 2006;67:126–136.

23. Weissman MM, Pilowsky DJ, Wickramaratne PJ et al.Remissions in maternal depression and child psychopa-

110

Byatt et al.

thology: a STAR*D-child report. JAMA 2006;295:1389–1398.

24. Lindahl V, Pearson JL, Colpe L. Prevalence of suicidalityduring pregnancy and the postpartum. Arch WomensMent Health 2005;8:77–87.

25. Lobel M, Cannella DL, Graham JE, Devincent C, Schnei-der J, Meyer BA. Pregnancy-specific stress, prenatalhealth behaviors, and birth outcomes. Health Psychol2008;27:604–615.

26. Beydoun H, Saftlas AF. Physical and mental health out-comes of prenatal maternal stress in human and animalstudies: a review of recent evidence. Paediatr PerinatEpidemiol 2008;22:438–466.

27. Buss C, Davis EP, Muftuler LT, Head K, Sandman CA.High pregnancy anxiety during mid-gestation is associ-ated with decreased gray matter density in 6-9-year-oldchildren. Psychoneuroendocrinology 2010;35:141–153.

28. Cohen LS, Altshuler LL, Harlow BL et al. Relapse ofmajor depression during pregnancy in women whomaintain or discontinue antidepressant treatment.JAMA 2006;295:499–507.

29. Bennett IM, Marcus SC, Palmer SC, Coyne JC. Preg-nancy-related discontinuation of antidepressants anddepression care visits among Medicaid recipients. Psy-chiatr Serv 2010;61:386–391.

30. Hemels ME, Einarson A, Koren G, Lanctot KL, EinarsonTR. Antidepressant use during pregnancy and the ratesof spontaneous abortions: a meta-analysis. Ann Phar-macother 2005;39:803–809.

31. Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomesfollowing exposure to serotonin reuptake inhibitors: ameta-analysis of clinical trials. Reprod Toxicol2006;22:571–575.

32. Einarson A, Fatoye B, Sarkar M et al. Pregnancy out-come following gestational exposure to venlafaxine: amulticenter prospective controlled study. Am J Psychia-try 2001;158:1728–1730.

33. Einarson A, Choi J, Einarson TR, Koren G. Rates ofspontaneous and therapeutic abortions following use ofantidepressants in pregnancy: results from a large pro-spective database. J Obstet Gynaecol Can 2009;31:452–456.

34. Nakhai-Pour HR, Broy P, Berard A. Use of antidepres-sants during pregnancy and the risk of spontaneousabortion. CMAJ 2010;182:1031–1037.

35. Chambers CD, Johnson KA, Dick LM, Felix RJ, JonesKL. Birth outcomes in pregnant women taking fluoxe-tine. N Engl J Med 1996;335:1010–1015.

36. Kulin NA, Pastuszak A, Sage SR et al. Pregnancy out-come following maternal use of the new selective seroto-nin reuptake inhibitors: a prospective controlledmulticenter study. JAMA 1998;279:609–610.

37. Chun-Fai-Chan B, Koren G, Fayez I et al. Pregnancy out-come of women exposed to bupropion during preg-nancy: a prospective comparative study. Am J ObstetGynecol 2005;192:932–936.

38. Yaris F, Kadioglu M, Kesim M et al. Newer antidepres-sants in pregnancy: prospective outcome of a case series.Reprod Toxicol 2004;19:235–238.

39. Djulus J, Koren G, Einarson TR et al. Exposure to mirt-azapine during pregnancy: a prospective, comparativestudy of birth outcomes. J Clin Psychiatry 2006;67:1280–1284.

40. Kallen B. Neonate characteristics after maternal use ofantidepressants in late pregnancy. Arch Pediatr AdolescMed 2004;158:312–316.

41. Reis M, Kallen B. Delivery outcome after maternal useof antidepressant drugs in pregnancy: an update usingSwedish data. Psychol Med 2010;40:1723–1733.

42. Lund N, Pedersen LH, Henriksen TB. Selective serotoninreuptake inhibitor exposure in utero and pregnancy out-comes. Arch Pediatr Adolesc Med 2009;163:949–954.

43. Simon GE, Cunningham ML, Davis RL. Outcomes of pre-natal antidepressant exposure. Am J Psychiatry2002;159:2055–2061.

44. Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A,Mintz J. Effects of antenatal depression and anti-depressant treatment on gestational age at birth andrisk of preterm birth. Am J Psychiatry 2007;164:1206–1213.

45. Croen LA, Grether JK, Yoshida CK, Odouli R, HendrickV. Antidepressant use during pregnancy and childhoodautism spectrum disorders. Arch Gen Psychiatry2011;68:1104–1112.

46. Gentile S, Galbally M. Prenatal exposure to antidepres-sant medications and neurodevelopmental outcomes: asystematic review. J Affect Disord 2011;128:1–9.

47. Rynn L, Cragan J, Correa A. Update on overall preva-lence of major birth defects–Atlanta, Georgia, 1978–2005. MMWR Morb Mortal Wkly Rep 2008;57:1–5.

48. Hoffman JI, Kaplan S. The incidence of congenital heartdisease. J Am Coll Cardiol 2002;39:1890–1900.

49. Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle

WT, Correa A. Prevalence of congenital heart defects inmetropolitan Atlanta, 1998-2005. J Pediatr 2008;153:807–813.

50. Kallen B, Nilsson E, Olausson PO. Antidepressant useduring pregnancy: comparison of data obtained from aprescription register and from antenatal care records.Eur J Clin Pharmacol 2011;67:839–845.

51. Kallen BA, Otterblad Olausson P. Maternal use of selec-tive serotonin re-uptake inhibitors in early pregnancyand infant congenital malformations. Birth Defects ResA Clin Mol Teratol 2007;79:301–308.

52. Warburton W, Hertzman C, Oberlander TF. A registerstudy of the impact of stopping third trimester selectiveserotonin reuptake inhibitor exposure on neonatalhealth. Acta Psychiatr Scand 2010;121:471–479.

53. Malm H, Klaukka T, Neuvonen PJ. Risks associated withselective serotonin reuptake inhibitors in pregnancy.Obstet Gynecol 2005;106:1289–1296.

54. Pastuszak A, Schick-Boschetto B, Zuber C et al. Preg-nancy outcome following first-trimester exposure to flu-oxetine (Prozac). JAMA 1993;269:2246–2248.

55. Hendrick V, Smith LM, Suri R, Hwang S, Haynes D,Altshuler L. Birth outcomes after prenatal exposure toantidepressant medication. Am J Obstet Gynecol2003;188:812–815.

56. Goldstein DJ, Corbin LA, Sundell KL. Effects of first-trimester fluoxetine exposure on the newborn. ObstetGynecol 1997;89:713–718.

57. Ericson A, Kallen B, Wiholm B. Delivery outcome afterthe use of antidepressants in early pregnancy. Eur J ClinPharmacol 1999;55:503–508.

58. Sivojelezova A, Shuhaiber S, Sarkissian L, Einarson A,Koren G. Citalopram use in pregnancy: prospectivecomparative evaluation of pregnancy and fetal outcome.Am J Obstet Gynecol 2005;193:2004–2009.

59. Hallberg P, Sjoblom V. The use of selective serotoninreuptake inhibitors during pregnancy and breast-feed-ing: a review and clinical aspects. J Clin Psychopharma-col 2005;25:59–73.

111


60. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, FriedmanJM. Use of selective serotonin-reuptake inhibitors inpregnancy and the risk of birth defects. N Engl J Med2007;356:2684–2692.

61. Merlob P, Birk E, Sirota L et al. Are selective serotoninreuptake inhibitors cardiac teratogens? Echocardio-graphic screening of newborns with persistent heartmurmur. Birth Defects Res A Clin Mol Teratol2009;85:837–841.

62. Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitch-

ell AA. First-trimester use of selective serotonin-reup-take inhibitors and the risk of birth defects. N Engl JMed 2007;356:2675–2683.

63. Birndorf CA, Madden A, Portera L, Leon AC. Psychiat-ric symptoms, functional impairment, and receptivitytoward mental health treatment among obstetricalpatients. Int J Psychiatry Med 2001;31:355–365.

64. Wogelius P, Norgaard M, Gislum M et al. Maternal useof selective serotonin reuptake inhibitors and risk ofcongenital malformations. Epidemiology 2006;17:701–704.

65. Diav-Citrin O, Shechtman S, Weinbaum D et al. Paroxe-tine and fluoxetine in pregnancy: a prospective, multi-centre, controlled, observational study. Br J ClinPharmacol 2008;66:695–705.

66. Cole JA, Ephross SA, Cosmatos IS, Walker AM. Paroxe-tine in the first trimester and the prevalence of congenitalmalformations. Pharmacoepidemiol Drug Saf2007;16:1075–1085.

67. Williams M, Wooltorton E. Paroxetine (Paxil) and con-genital malformations. CMAJ 2005;173:1320–1321.

68. Einarson A, Koren G. Counseling pregnant women trea-ted with paroxetine. Concern about cardiac malforma-tions. Can Fam Physician 2006;52:593–594.

69. Berard A, Ramos E, Rey E, Blais L, St-Andre M, OraichiD. First trimester exposure to paroxetine and risk of car-diac malformations in infants: the importance of dosage.Birth Defects Res B Dev Reprod Toxicol 2007;80:18–27.

70. Wurst KE, Poole C, Ephross SA, Olshan AF. First tri-mester paroxetine use and the prevalence of congenital,specifically cardiac, defects: a meta-analysis of epidemio-logical studies. Birth Defects Res A Clin Mol Teratol2010;88:159–170.

71. Bar-Oz B, Einarson T, Einarson A et al. Paroxetine andcongenital malformations: meta-Analysis and consider-ation of potential confounding factors. Clin Ther2007;29:918–926.

72. Bakker MK, Kerstjens-Frederikse WS, Buys CH, De

Walle HE, De Jong-Van Den Berg LT. First-trimesteruse of paroxetine and congenital heart defects: a popula-tion-based case-control study. Birth Defects Res A ClinMol Teratol 2010;88:94–100.

73. Malm H, Artama M, Gissler M, Ritvanen A. Selectiveserotonin reuptake inhibitors and risk for major congen-ital anomalies. Obstet Gynecol 2011;118:111–120.

74. Einarson A, Pistelli A, Desantis M et al. Evaluation ofthe risk of congenital cardiovascular defects associatedwith use of paroxetine during pregnancy. Am J Psychia-try 2008;165:749–752.

75. Gentile S, Bellantuono C. Selective serotonin reuptakeinhibitor exposure during early pregnancy and the riskof fetal major malformations: focus on paroxetine.J Clin Psychiatry 2009;70:414–422.

76. Bakker MK, De Walle HE, Wilffert B, De Jong-Van

Den Berg LT. Fluoxetine and infantile hypertrophicpylorus stenosis: a signal from a birth defects-drug expo-

sure surveillance study. Pharmacoepidemiol Drug Saf2010;19:808–813.

77. Oberlander TF,Warburton W,Misri S, RiggsW, Aghaja-nian J, Hertzman C. Major congenital malformations fol-lowing prenatal exposure to serotonin reuptakeinhibitors and benzodiazepines using population-basedhealth data. Birth Defects Res B Dev Reprod Toxicol2008;83:68–76.

78. Kornum JB, Nielsen RB, Pedersen L, Mortensen PB,Norgaard M. Use of selective serotonin-reuptake inhibi-tors during early pregnancy and risk of congenitalmalformations: updated analysis. Clin Epidemiol2010;2:29–36.

79. Pedersen LH, Henriksen TB, Vestergaard M, Olsen J,Bech BH. Selective serotonin reuptake inhibitors in preg-nancy and congenital malformations: population basedcohort study. BMJ 2009;339:b3569.

80. Wen SW, Yang Q, Garner P et al. Selective serotonin re-uptake inhibitors and adverse pregnancy outcomes. AmJ Obstet Gynecol 2006;194:961–966.

81. Einarson A, Choi J, Einarson TR, Koren G. Incidence ofmajor malformations in infants following antidepressantexposure in pregnancy: results of a large prospectivecohort study. Can J Psychiatry 2009;54:242–246.

82. Einarson A, Choi J, Koren G, Einarson T. Outcomes ofinfants exposed to multiple antidepressants during preg-nancy: results of a cohort study. J Popul Ther Clin Phar-macol 2011;18:e390–e396.

83. Ramos E, St-Andre M, Rey E, Oraichi D, Berard A.Duration of antidepressant use during pregnancy andrisk of major congenital malformations. Br J Psychiatry2008;192:344–350.

84. Wisner KL, Sit DK, Hanusa BH et al. Major depres-sion and antidepressant treatment: impact on pregnancyand neonatal outcomes. Am J Psychiatry 2009;166:557–566.

85. Klieger-Grossmann C, Weitzner B, Panchaud A et al.Pregnancy outcomes following use of escitalopram: aprospective comparative cohort study. J Clin Pharmacol2011;52:766–70.

86. Addis A, Koren G. Safety of fluoxetine during the firsttrimester of pregnancy: a meta-analytical review of epi-demiological studies. Psychol Med 2000;30:89–94.

87. Einarson TR, Einarson A. Newer antidepressants in preg-nancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharma-coepidemiol Drug Saf 2005;14:823–827.

88. O’brien L, Einarson TR, Sarkar M, Einarson A, KorenG. Does paroxetine cause cardiac malformations?J Obstet Gynaecol Can 2008;30:696–701.

89. Lennestal R, Kallen B. Delivery outcome in relation tomaternal use of some recently introduced antidepres-sants. J Clin Psychopharmacol 2007;27:607–613.

90. Einarson A, Bonari L, Voyer-Lavigne S et al. A multicen-tre prospective controlled study to determine the safetyof trazodone and nefazodone use during pregnancy. CanJ Psychiatry 2003;48:106–110.

91. GlaxoSmithKline. The Bupropion Pregnancy RegistryFinal Report. 2008; Available from: http://pregnancy-registry.gsk.com/documents/bup_report_final_2008.pdf

92. Alwan S, Reefhuis J, Botto LD, Rasmussen SA, CorreaA, Friedman JM. Maternal use of bupropion and risk forcongenital heart defects. Am J Obstet Gynecol2010;203:52.e1–6.

93. Cole JA, Modell JG, Haight BR, Cosmatos IS, StolerJM, Walker AM. Bupropion in pregnancy and the

112

Byatt et al.

prevalence of congenital malformations. Pharmacoepi-demiol Drug Saf 2007;16:474–484.

94. Webster PA. Withdrawal symptoms in neonates associ-ated with maternal antidepressant therapy. Lancet1973;2:318–319.

95. Moses-Kolko EL, Bogen D, Perel J et al. Neonatal signsafter late in utero exposure to serotonin reuptake inhibi-tors: literature review and implications for clinical appli-cations. JAMA 2005;293:2372–2383.

96. Nordeng H, Ystrom E, Einarson A. Perception of riskregarding the use of medications and other exposuresduring pregnancy. Eur J Clin Pharmacol 2010;66:207–214.

97. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicityin a neonate. Pediatrics 1993;92:721–722.

98. Dahl ML, Olhager E, Ahlner J. Paroxetine withdrawalsyndrome in a neonate. Br J Psychiatry 1997;171:391–392.

99. Nijhuis IJ, Kok-Van Rooij GW, Bosschaart AN. With-drawal reactions of a premature neonate after maternaluse of paroxetine. Arch Dis Child Fetal Neonatal Ed2001;84:F77.

100. Sanz EJ, De-Las-Cuevas C, Kiuru A, Bate A, Edwards R.Selective serotonin reuptake inhibitors in pregnantwomen and neonatal withdrawal syndrome: a databaseanalysis. Lancet 2005;365:482–487.

101. Laine K, Heikkinen T, Ekblad U, Kero P. Effects of expo-sure to selective serotonin reuptake inhibitors duringpregnancy on serotonergic symptoms in newborns andcord blood monoamine and prolactin concentrations.Arch Gen Psychiatry 2003;60:720–726.

102. Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinataloutcome following third trimester exposure to paroxe-tine. Arch Pediatr Adolesc Med 2002;156:1129–1132.

103. Alehan F, Saygi S, Tarcan A, Gurakan B. Prolongedneonatal complications after in utero exposure tofluoxetine. J Matern Fetal Neonatal Med. 2008;21:921–923.

104. Oberlander TF, Misri S, Fitzgerald CE, Kostaras X,Rurak D, Riggs W. Pharmacologic factors associatedwith transient neonatal symptoms following prenatalpsychotropic medication exposure. J Clin Psychiatry2004;65:230–237.

105. Oberlander TF, Warburton W, Misri S, Aghajanian J,Hertzman C. Neonatal outcomes after prenatal exposureto selective serotonin reuptake inhibitor antidepressantsand maternal depression using population-based linkedhealth data. Arch Gen Psychiatry 2006;63:898–906.

106. Knoppert DC, Nimkar R, Principi T, Yuen D. Paroxetinetoxicity in a newborn after in utero exposure: clinicalsymptoms correlate with serum levels. Ther Drug Monit2006;28:5–7.

107. Kwon P, Lefkowitz W. Poor neonatal adaptation in terminfant. Fluoxetine toxicity. Pediatr Ann 2008;37:131–133.

108. Mhanna MJ, Bennet JB II, Izatt SD. Potential fluoxetinechloride (Prozac) toxicity in a newborn. Pediatrics1997;100:158–159.

109. Mohan CG, Moore JJ. Fluoxetine toxicity in a preterminfant. J Perinatol 2000;20:445–446.

110. Anbu AT, Theodore A. Fluoxetine withdrawal syndromein the newborn. Indian Pediatr 2006;43:66–69.

111. Kent LS, Laidlaw JD. Suspected congenital sertralinedependence. Br J Psychiatry 1995;167:412–413.

112. Boucher N, Bairam A, Beaulac-Baillargeon L. A newlook at the neonate’s clinical presentation after in uteroexposure to antidepressants in late pregnancy. J ClinPsychopharmacol 2008;28:334–339.

113. Herbst F, Gortner L. [Paroxetine withdrawal syndromeas differential diagnosis of acute neonatal encephalopa-thy?]. Z Geburtshilfe Neonatol 2003;207:232–234.

114. De Moor RA, Mourad L, Ter Haar J, Egberts AC. [With-drawal symptoms in a neonate following exposure tovenlafaxine during pregnancy]. Ned Tijdschr Geneeskd2003;147:1370–1372.

115. Cohen LS, Heller VL, Bailey JW, Grush L, Ablon JS,Bouffard SM. Birth outcomes following prenatal expo-sure to fluoxetine. Biol Psychiatry 2000;48:996–1000.

116. Levinson-Castiel R, Merlob P, Linder N, Sirota L,Klinger G. Neonatal abstinence syndrome after in uteroexposure to selective serotonin reuptake inhibitors interm infants. Arch Pediatr Adolesc Med 2006;160:173–176.

117. Ferreira E, Carceller AM, Agogue C et al. Effects ofselective serotonin reuptake inhibitors and venlafaxineduring pregnancy in term and preterm neonates. Pediat-rics 2007;119:52–59.

118. Galbally M, Lewis AJ, Lum J, Buist A. Serotonin discon-tinuation syndrome following in utero exposure to anti-depressant medication: prospective controlled study.Aust N Z J Psychiatry 2009;43:846–854.

119. Suri R, Altshuler L, Hendrick V, Rasgon N, Lee E, Mintz

J. The impact of depression and fluoxetine treatment onobstetrical outcome. Arch Womens Ment Health2004;7:193–200.

120. Maschi S, Clavenna A, Campi R, Schiavetti B, Bernat M,Bonati M. Neonatal outcome following pregnancy expo-sure to antidepressants: a prospective controlled cohortstudy. BJOG 2008;115:283–289.

121. Hibbard JU, Wilkins I, Sun L et al. Respiratory morbid-ity in late preterm births. JAMA 2010;304:419–425.

122. Administration US Food and Drug Administration.FDA Medwatch Drug Alert on Effexor (venlafaxineHCL) and Effexor XR (venlafaxine HCL) 2004 [cited2011 12/22/11]; Available from: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm154975.htm.

123. Hernandez-Martinez C, Arija V, Balaguer A, Cavalle P,Canals J. Do the emotional states of pregnant womenaffect neonatal behaviour? Early Hum Dev [ResearchSupport, Non-U.S. Govt]. 2008;84:745–750.

124. Steinhorn RH. Neonatal pulmonary hypertension. Pedi-atr Crit Care Med 2010;11:S79–S84.

125. The Neonatal Inhaled Nitric Oxide Study Group.Inhaled nitric oxide in term and near-term infants: neu-rodevelopmental follow-up of the neonatal inhaled nitricoxide study group (NINOS). J Pediatr 2000;136:611–617.

126. Davidson D, Barefield ES, Kattwinkel J et al. Inhalednitric oxide for the early treatment of persistent pulmo-nary hypertension of the term newborn: a randomized,double-masked, placebo-controlled, dose-response, mul-ticenter study. The I-NO/PPHN Study Group. Pediat-rics 1998;101:325–334.

127. Greenough A, Khetriwal B. Pulmonary hypertension inthe newborn. Paediatr Respir Rev 2005;6:111–116.

128. Occhiogrosso M, Omran SS, Altemus M. Persistent pul-monary hypertension of the newborn and selective sero-tonin reuptake inhibitors: lessons from clinical andtranslational studies. Am J Psychiatry 2012;169:134–40.

129. Group NINOS. Inhaled nitric oxide in term andnear-term infants: neurodevelopmental follow-up of theneonatal inhaled nitric oxide study group (NINOS).J Pediatr 2000;136:611–617.

113


130. Koren G, Boucher N. Adverse effects in neonatesexposed to SSRIs and SNRI in late gestation–MotheriskUpdate 2008. Can J Clin Pharmacol 2009;16:e66–e67.

131. Boucher N, Koren G, Beaulac-Baillargeon L. Maternaluse of venlafaxine near term: correlation between neona-tal effects and plasma concentrations. Ther Drug Monit2009;31:404–409.

132. Oberlander TF, Warburton W, Misri S, Aghajanian J,Hertzman C. Effects of timing and duration of gesta-tional exposure to serotonin reuptake inhibitor antide-pressants: population-based study. Br J Psychiatry2008;192:338–343.

133. Eddahibi S, Raffestin B, Hamon M, Adnot S. Is the seroto-nin transporter involved in the pathogenesis of pulmo-nary hypertension? J Lab Clin Med 2002;139:194–201.

134. Fornaro E, Li D, Pan J, Belik J. Prenatal exposure to flu-oxetine induces fetal pulmonary hypertension in the rat.Am J Respir Crit Care Med 2007;176:1035–1040.

135. Dakshinamurti S. Pathophysiologic mechanisms of per-sistent pulmonary hypertension of the newborn. PediatrPulmonol 2005;39:492–503.

136. Eddahibi S, Humbert M, Fadel E et al. Serotonin trans-porter overexpression is responsible for pulmonaryartery smooth muscle hyperplasia in primary pulmonaryhypertension. J Clin Invest 2001;108:1141–1150.

137. Oberlander TF, Bonaguro RJ, Misri S, Papsdorf M, RossCJ, Simpson EM. Infant serotonin transporter (SLC6A4)promoter genotype is associated with adverse neonataloutcomes after prenatal exposure to serotonin reuptakeinhibitor medications. Mol Psychiatry 2008;13:65–73.

138. Chambers CD, Hernandez-Diaz S, Van Marter LJ et al.Selective serotonin-reuptake inhibitors and risk of per-sistent pulmonary hypertension of the newborn. N EnglJ Med 2006;354:579–587.

139. Kallen B, Olausson PO. Maternal use of selective seroto-nin re-uptake inhibitors and persistent pulmonaryhypertension of the newborn. Pharmacoepidemiol DrugSaf 2008;17:801–806.

140. Heritage CK, Cunningham MD. Association of electiverepeat cesarean delivery and persistent pulmonaryhypertension of the newborn. Am J Obstet Gynecol1985;152:627–629.

141. Hernandez-Diaz S, Van Marter LJ, Werler MM, LouikC, Mitchell AA. Risk factors for persistent pulmonaryhypertension of the newborn. Pediatrics 2007;120:e272–e282.

142. Kieler H, Artama M, Engeland A et al. Selective seroto-nin reuptake inhibitors during pregnancy and risk ofpersistent pulmonary hypertension in the newborn: pop-ulation based cohort study from the five Nordic coun-tries. BMJ 2011;344:d8012.

143. Andrade SE, Mcphillips H, Loren D et al. Antidepressantmedication use and risk of persistent pulmonary hyper-tension of the newborn. Pharmacoepidemiol Drug Saf2009;18:246–252.

144. Wichman CL, Moore KM, Lang TR, St Sauver JL, HeiseRH Jr, Watson WJ. Congenital heart disease associatedwith selective serotonin reuptake inhibitor use duringpregnancy. Mayo Clin Proc 2009;84:23–27.

145. Wilson KL, Zelig CM, Harvey JP, Cunningham BS,Dolinsky BM, Napolitano PG. Persistent pulmonaryhypertension of the newborn is associated with mode ofdelivery and not with maternal use of selective serotoninreuptake inhibitors. Am J Perinatol 2010;28:19–24.

146. Administration USFAD. FDA Drug Safety Communi-cation: Selective serotonin reuptake inhibitor (SSRI)antidepressant use during pregnancy and reports of arare heart and lung condition in newborn babies. 12/4/11 ed2011.

147. Keszler M, Carbone MT, Cox C, Schumacher RE. Severerespiratory failure after elective repeat cesarean delivery:a potentially preventable condition leading to extracor-poreal membrane oxygenation. Pediatrics 1992;89:670–672.

148. Levine EM, Ghai V, Barton JJ, Strom CM. Mode ofdelivery and risk of respiratory diseases in newborns.Obstet Gynecol 2001;97:439–442.

149. Reece EA, Moya F, Yazigi R, Holford T, Duncan C,Ehrenkranz RA. Persistent pulmonary hypertension:assessment of perinatal risk factors. Obstet Gynecol1987;70:696–700.

150. Gentile S. Selective serotonin reuptake inhibitor expo-sure during early pregnancy and the risk of birth defects.Acta Psychiatr Scand. [Review]. 2011;123:266–275.

151. US Food and Drug Administration. Pregnancy andDrug Labeling 2008 [cited 2012 11/6/12]; Availablefrom: http://www.fda.gov/Drugs/DevelopmentAppro-valProcess/DevelopmentResources/Labeling/ucm093307.htm.

152. Nulman I, Rovet J, Stewart DE et al. Child developmentfollowing exposure to tricyclic antidepressants or fluoxe-tine throughout fetal life: a prospective, controlledstudy. Am J Psychiatry 2002;159:1889–1895.

153. Sit DK, Perel JM, Helsel JC, Wisner KL. Changes inantidepressant metabolism and dosing across pregnancyand early postpartum. J Clin Psychiatry 2008;69:652–658.

154. Hostetter A, Stowe ZN, Strader JRJR, Mclaughlin E,Llewellyn A. Dose of selective serotonin uptake inhibi-tors across pregnancy: clinical implications. DepressAnxiety 2000;11:51–57.

155. Yonkers KA, Wisner KL, Stewart DE et al. The man-agement of depression during pregnancy: a report fromthe American Psychiatric Association and the AmericanCollege of Obstetricians and Gynecologists. Gen HospPsychiatry 2009;31:403–413.

156. Zeskind PS, Stephens LE. Maternal selective serotoninreuptake inhibitor use during pregnancy and newbornneurobehavior. Pediatrics 2004;113:368–375.

157. Rampono J, Simmer K, Ilett KF et al. Placental transferof SSRI and SNRI antidepressants and effects on theneonate. Pharmacopsychiatry 2009;42:95–100.

158. Suri R, Hellemann G, Stowe ZN, Cohen LS, Aquino A,Altshuler LL. A prospective, naturalistic, blinded studyof early neurobehavioral outcomes for infants followingprenatal antidepressant exposure. J Clin Psychiatry2011;72:1002–1007.

159. Sit D, Perel JM, Wisniewski SR, Helsel JC, Luther JF,Wisner KL. Mother-infant antidepressant concentra-tions, maternal depression, and perinatal events. J ClinPsychiatry 2011;72:994–1001.

160. Wilson KL, Zelig CM, Harvey JP, Cunningham BS,Dolinsky BM, Napolitano PG. Persistent pulmonaryhypertension of the newborn is associated with mode ofdelivery and not with maternal use of selective serotoninreuptake inhibitors. Am J Perinatol 2011;28:19–24.

114

Byatt et al.

review antidepressant use in pregnancy: a critical review ... use in pregna… · maternal...

Documents