safety of ssri's in pregnancy

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Clinical Therapeutics/Volume 31, Theme Issue, 2009

Safety Concerns Associated With the Use of SerotoninReuptake Inhibitors and Other Serotonergic/NoradrenergicAntidepressants During Pregnancy: A ReviewMarco Tuccori, PharroDl-'; Arianna Testi, PharmD2,3; Luca Antonioli, PhD1;Matteo Fornai, PhD1; Sabrina Montagnani, PharruDl- ; Narcisa Ghisu, PhD1;Rocchina Colucci, PhD1; Tiberio Corona, PharmD2,3; Corrado Blandizzi, MD1,2; andMario Del Tacca, MD1,21Division ofPharmacology andChemotherapy, Department ofInternal Medicine University ofPisa, Pisa, Italy;2Tuscan Regional Centre for Pharmacovigilance, Florence Italy; and 3University Hospital ofPisa Pisa, ItalyABSTRACT

Background: There is ongoing debate about thesafety of selective serotonin reuptake inhibitors (SSRIs)and other serotonergiclnoradrenergic antidepressantswhen used during pregnancy.

Objective: This article reviews the available literature on the main safety concerns associated with theuse of SSRIs and othe r serotonergiclnoradrenergicantidepressants (serotonin-norepinephrine reuptakeinhibitors, norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants)during pregnancy.

Methods: English-language reports of analyticaland descriptive studies, including case reports, caseseries,and meta-analyses, were identified through searches of MEDLINE, EMBASE, and PsycINFO (1966April 2009). The search terms were [luoxetine, paroxetine, sertraline, citalopram, escitalopram, [luuoxamine,uenlafaxine, mirtazapine, reboxetine, duloxetine, SSRI,SNRI, NaSSA, and NRI in association with depression, pregnancy, prenatal exposure, miscarriage, spontaneous abortion, malformation, in utero exposure,and neonatal complications.

Results: Paroxetirie has been associated with significant risks of major malformation, particularlycardiac defects, when used during pregnancy. Significant associations between maternal exposure toSSRIs and both persistent pulmonary hypertension ofthe newborn and a self-limiting neonatal behavioralsyndrome have been reported in a number of recentoriginal studies and meta-analyses. Some studies havesuggested a relat ionship between the use of SSRIs orother serotonergiclnoradrenergic antidepressants andthe occurrence of miscarriage, although these studies

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had methodologic limitations that affected the strengthof the data. Evidence for a possible association betweenin utero exposure to SSRIs or other serotonergiclnoradrenergic antidepressants and alterations in neurobehavioral development, bleeding, and QTc-intervalprolongation is currently weak.

Conclusion: The available evidence suggests thatSSRIs and other serotonergiclnoradrenergic antidepressants should be used with caution during pregnancy, with careful follow-up of infants exposed tothese agents in utero. Clin Ther. 2009;31 [ThemeIssue]:1426-1453) 2009 Excerpta Medica Inc.

Key words : pregnancy, infant, antidepressants,SSRIs, malformations.

INTRODUCTIONDepression and other mood disorders are commonduring pregnancy, with an estimated prevalence ranging from 9% to 16%.1.2 Depression may be associatedwith an increased risk of preterm delivery, low birthweight, operative delivery, and admission of the newborn to the neonatal intensive care unit.v- Antidepressant treatment would appear to be an option for thesewomen, although ensuring its safety for both themother and fetus may represent a challenge. AmericanAcademy of Pediatrics guidelines for the use of psychotropic drugs in pregnancy recommend use of thelowest dose that provides adequate control of depres-

Accepted forpubltcationMay 8, 2009dotl 0.1016/J.c1lnthera.2009.07.0090149-2918/$ - see front matter 2009 Excerpta Medica Inc. All rights reserved.

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sion.> In an observational study from the Netherlandsin a cohort of 29,005 pregnant women, 2% of thesample received antidepressants during the first trimester of pregnancy, and 1.8% did so in the secondand third trimesters.f Almost 60% of women whoused antidepressants before pregnancy discontinuedthese drugs in the first trimester, and 11 % stoppedthereafter. Among women using antidepressantsduring pregnancy, one thi rd s tarted the medicationduring gestation. Paroxetine and fluoxetine were themost frequently used antidepressants (48% and 12%,respectively).

A recently published study from the Netherlandsreported that the duration of selective serotonin reuptake inhibitor (SSRI) use and total defined dailydoses (DDDs) prescribed during pregnancy in 20002004 were significantly higher than those in 19951999 (median duration of use, 99.5 vs 64.0 days, respectively [P = 0.008]; median total DDDs, 111.5 vs67.5 [P = 0.009]).7 In a study employing a database ofall pregnancies in Quebec in 1998-2002 (N = 97,680),rates of antidepressant prescribing decreased significantly from 6.6% in the prepregnancy period(12 months before gestation) to 3.7% in the first trimester (P = 0.01).8 After delivery, rates of antidepressant prescribing increased to 7.0% compared with theperiod before pregnancy (P = 0.01). Although thesedata reflect specific populations, rates of antidepressant use during pregnancy would be expected to besimilar in other Western countries.

An increasing number of antidepressants have become available for clinical use, most of them acting through blocking the reuptake o f serotonin(5-hydroxytryptamine [5-HT]) . Based on their specificity, serotonin reuptake inhibitors (SRIs) can be classified as SSRIs and serotonin-norepinephrine reuptakeinhibitors (SNRIs). The available SSRIs are fluoxetine,paroxetine, fluvoxamine, sertraline, citaloprarn, andescitalopram, and the SNRIs are venlataxine and duloxetine. Use of the noradrenergic and specific serotonergic antidepressants (NaSSAs) and norepinephrine reuptake inhibitors (NRIs) has increased in recentyears. Mirtazapine is the only available NaSSA andreboxetine the only available NRI.

Reviews of data on the safety of antidepressant useduring pregnancy are continually being published.t-l''The aim of the present art icle was to review recent evidence concerning the safety of treatment with SSRIs,SNRIs, NaSSAs, and NRIs during pregnancy.

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M. Tuccori et al.

METHODSThe English-language literature indexed on MEDLINE,EMBASE, and PsycINFO was searched from 1966through April 2009 using the terms fluoxetine, paroxetine, sertraline, citalopram, escitalopram, [luuoxamine,uenlafaxine, mirtazapine , reboxet ine, duloxet ine,SSRI, SNRI, NaSSA, and NRI in association withdepression, pregnancy, prenatal exposure, miscarriage,spontaneous abortion, malformation, in utero exposure, and neonatal complications. The reference listsof identif ied articles were examined for additionalpertinent publications.

For inclusion in the review, original observationalstudies (controlled and uncontrolled, prospective andretrospective) and meta-analyses had to evaluate neonatal or maternal outcomes after exposure to SSRIs orother serotonergic/noradrenergic antidepressants during pregnancy and repor t the frequency/risk of malformations (both major and minor), miscarriage (ie,spontaneous abortion), neonatal behavioral syndrome,persistent pulmonary hypertension, effects on neurobehavioral development (using standardized ratingscales), bleeding complications, and neonatal prolongation of the QT c interval. Case reports and case series describing adverse events ascribed to in utero exposure to selected antidepressants were considered forinclusion. Abstracts presented at national and international meetings were no t included.

Because there is no standard clinical definition ofneonatal behavioral syndrome, case reports dealingwith neonata l behavioral alterations after in uteroexposure to antidepressants were used to generateclusters of symptoms suggestive of this syndrome.These clusters were then used as search terms to identify studies reporting the frequency of neonatal outcomes associated with possible neonatal behavioralsyndrome (including single behavioral signs, poorneonatal adaptation, and admission to a special-carenursery).TERATOGENIC RISK CLASSIFICATIONSeveral systems have been proposed for classifying theteratogenic r isks of medicat ions , some of which arelimi ted by a failure to specify the doses and/or durat ions of gestational exposure that may be associatedwith teratogenic risk, making them difficult for clinicians to interpret and use in counseling patients.IAmong the major systems of teratogenic risk classification are those of the US Food and Drug Adrninistra-

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Clinical Therapeutics

t ion (FDA), the Australian Drug Evaluation Committee (ADEC), and the Swedish Catalogue of ApprovedDrugs FASS . In these systems, teratogenic risk iscategorized from class A (drugs regarded as safe foruse dur ing pregnancy) to class D or X (drugs associated with a risk of major malformation when takenduring pregnancy). Overall, these 3 regulatory agencies suggest a cautious approach to the use of SRIs and

other serotonergic/noradrenergic antidepressantsparticularly paroxetine (FDA, ADEC, FASS) andrnirtazapine (ADEC, FASS)-during pregnancy. Inthe major ity of cases, this recommendat ion is basedon a lack of data or conflicting study findings. Theteratogenic risk classifications for the availableSSRIs, SNRIs, NaSSAs, and NRIs are summarized inTable I.

Tab le I. Teratogenic risk classification of selective serotonin reuptake inhibitors and other se rotonergic/noradrenergic antidepressants.

Drug FDA* ADEet FASS*Fluoxetine C C 83Serr ral ine C C 83Paroxeti ne D D CFluvoxa mine C C 81Cita lopra m C C 83Escita lop ram C C 83Yenlafaxine C 82 83Mirraz a pine C 83 CDuloxetin e C 83Reboxetin e 81 83Source: Add is et al. '., FDA US Food and Drug Administration classification. Category C either s tudies in animals found adverse effects onth e fetus and th e r e we re no cont r olled stud ies in women , or s tud ies in women and an ima ls were no t ava ilab le; drugsshould be given onlyif the po te ntia lbenefit justifies the po tential r isk to the fetus . Category D there is positive evidenceof human feta l ris k, b ut t he b ene fits of the use in pregnan t women may be acceptab le desp i te the ri sk (eg , if the d rug isneeded in a life-th reatening situation or fo r a se rious di sease for which sa fe r d rugs cannot be used ) .

t ADEC - Austra lian Drug Evaluation Co mmittee classifi cation. Category B - dru gs that have been taken byonlya limitednum ber of pregnan t womena nd women ofchildbearing age wit hout an increase in the frequency of malforma t ion or ot herdi rec t o r ind irect harm ful e ffect s on the fetu s . As the re is limited exper ience with the ef fects of these d rugs in hum ans ,results of toxico logic s tudies to date are categorized as follows: B1 s tud ies in animals have not shown evidence of anincreased occurrence offeta l damage; B2 - s tudies in anima ls are inadequate and may be lacking, but avai lable dat a s howno evidence of an increased occurrence of feta l damage, the significance of which is considered uncerta in in humans; andB3 = stu dies in anima ls have show n evidence of an increased occurre nce of feta l dam age, the significance ofwhich is considered uncertain in humans . Ca tegory C - dru gs whose ph armacologic effects have caused or may be suspected of causing harmful effect s o n t he human fetu s o r newborn withou t caus ing mal format ions ; these effects may be revers ible.Ca tegory D = drugs tha t have caused , a re suspecte d of causing , or may be expected to caus e an increased inciden ce ofhum an feta l malformat ions or irreversib le damage; these drugs may also have adverse pharmacologic effects.

t FASS - Swedish Catalogue ofApproved Drugs classificat ion . Category B- medicinal products th at can be assumed to havebeen used in onlya limited group of pregnant women and women of childbearing age with no distu rbance of the reproductive process identif ied so far. Because there is limited experie nce with the effects of these medicinal products in humans ,evidence of rep roductive toxicity in animals is categorized as follows: B1 - reprodu ctive toxicity st udies have not found evidence of feta l da mage or other deleter ious effects on the reproductive process; B2 = reproductive toxicity stud ies are inad eq uate or lacking, but available data do not indicate an increased incidence offetal da mage or other deleterious ef fec ts onthe reprodu ctive process; a nd B3 = repr oductive toxicity studies in anima ls have found an increased inciden ce offe ta l damage or other deleteriou s effects on the reproductive process, the significance ofwhich is considered uncertain in human s.Category C = medicinal product s wit h pharmacologic effects tha t have caused or may be suspec ted of causing d istu rba nces in the reproductive process tha t may involve risk to the fetus without being directly tera togenic.

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RISK OF MAJOR MALFORMATIONSMajor malformations are defined as structural orfunctional abnormalities that have substantial medicalor social consequences, and usually require medical orsurgical treatment. 12 Because serotonergic drugs haveexhibited potential biological activity on developingembryos in animal studies, there may be an increasedrisk of birth defects in humans. 13,14 Early evaluationsindicated that 5-HT is p resen t in the oocyte, where itappears to function as a regulator of cell cleavage.Later, it plays an important role in gastrulation, withsubstan tia l areas of 5-HT uptake in the primitivestreak. Subsequently, 5-HT uptake occurs in the floorplate of the developing neural tube in association withneurulation, and 5-HT has been found to facilitate cellmigration and stimulate cell differentiation duringformation of the neural crest and branchial arch. Atthe time of morphogenesis of craniofacial structures,5-HT promotes dental development and may aid incusp formation. 13,14

Most commonly prescribed antidepressants enhance5-HT activity and could theoretically promote teratogenic effects through this mechanism. However, redundancy within the serotonergic system may allowreceptor and uptake pathways to funct ion normallyeven in the presence of abnormal levels of circulating5-HT. In line with this concept, 5-HT-binding proteins, which are expressed in most craniofacial regionsat critical times during development, may exert a buffering action that maintains adequate 5-HT tissue levelsover a wide range of 5-HT serum concentrations. 15,16

The findings of investigations that assessed the riskof major malformations associated with exposure toSSRIs, SNRIs, NRIs, and NaSSAs during pregnancyare summarized in Table 11.12,17--42 Some studies, particularly those conducted before 2000, found no evidence of a risk for major congenital malformationswith SSRIs.12,17-28,35,37-3 9 A recent s tudy by Einarsonet a128 compared 928 pregnant women exposed toantidepressant medications (bupropion, citaloprarn,escitalopram, fluvoxamine, nefazodone, paroxetine,rnirtazapine, fluoxetine, trazodone, venlafaxine, andsertraline) during the first trimester of pregnancy with928 pregnant women who were no t exposed to knownteratogens. The odds ra tio (OR) for major malformations was 0 .90 (95% CI, 0.50-1.61). However, thisstudy did no t estimate drug-specific ORs.

A retrospective epidemiologic investigation of datafrom 2 US managed care databases conducted by the

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manufacturer of paroxetine found a higher risk ofmajor malformation in paroxetine users (n = 704)compared with users of other antidepressants (n =3547).43 Compared with infants born to women whoreceived other ant idepressants in the first tr imester ,those born to women receiving paroxetine had increased risks of overall malformations (adjusted OR[AOR] = 1.84; 95% CI, 1.16-2.91) and cardiac malformations (AOR = 2.26; 95% CI, 1.17-4.33). Thefindings of this study led US and Canadian regulatoryagencies to issue a warning that use of paroxetine during pregnancy may increase the risk of major congenital malformations.vvi Studies in mouse embryos suggested that these effects might be ascribed toalterations in 5-HT concentrations, which were mostpronounced when exposure began at day 9 of embryonic development, before cushion formation.w

A recent study of behavioral abnormalities in micefound that prenatal exposure to fluoxetine, but notfluvoxamine, had a dose-dependent effect on the likelihood of affective disorders.i ? Differences in thematernal-fetal pharmacokinetics of fluoxetine andfluvoxamine (ie, rate of placental crossing and distribution to fetal tissues) were hypothesized, suggestingthat drug-specific pharrnacokinetic profiles may playa primary role in the teratogenic potential of SSRIs.

Using the same databases as in a previously mentioned study,43 Cole et a129 analyzed data on paroxetine from 1020 infants born to 989 mothers who usedpa roxetirie monotherapy or combination therapy during the first t rimester of pregnancy, including815 infants born to 791 women who used rnonotherapy. The controls were 4936 infants born to 4767 mothers exposed to monotherapy or combination therapywi th o ther antidepressants, including 4196 infantsborn to 4072 mothers exposed to monotherapy, TheAOR for all congenital malformations was 1.89 for paroxetine monotherapy (95% CI, 1.20-2.98) and 1.76for paroxetirie monotherapy/cornbination therapy(95% CI, 1.18-2.64). The corresponding AORs for cardiovascular malformations were 1.46 (95% CI,0.742.88) and 1.68 (95% CI, 0.95-2.97), suggesting amoderate risk of congenital malformation associatedwith first-trimester exposure to paroxetine comparedwith other antidepressants.

Because these observations were inconsistent withthe general perception of the safety profile of antidepressants (and of paroxetine in particular) whenused during pregnancy, subsequent studies assessed

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Tab le II. Studies of major malformations and o the r physical abno rma lities of th e newborn assoc iated withfirst-trimester exposure to selective serotonin reuptake inhibitors (SSRls) and oth er seroton ergic/noradrenergic antidepressants.

Authors/D escription Active(Data Source) Drugs Controls Main FindingsKulin et a J 2 Fluvoxamine, No expos ure to Inciden ce of major malformations: 4 1%Prosp ective cohort paroxetine, a nd known terato gens fluvo xam ine, paroxet ine, and sertraline;stu dy, Can ad a and sert raline (n = 267 ) (n = 267 ) 3.8% no expos ure (RR = 1.06; 95% CI,United Stat es 0.43-2.62)(TISdat a)Nu lman e t a J 7 Fluoxetin e (n = 80), No expos ure to Inciden ce of major malformation s: 3.63%Prosp ective co ho rt TCAs (n = 55 ) known teratogens fluoxetin e, 3.75%TCAs, 2.38% nostudy, Can ad a (n = 84) exposure P = NS)(TIS dat a)McElhatton et ailS Non-TCAs (n = 416), None No . of majo r ma lform ations: 7 ca ses each,Prospective case TCAs (n = 330) non -TCAs and TCAsseries, Europe andIsrael (TIS data)Ericson et aJ19 SSRls (n = 531), All births in Congenital anomalies (actua l/expectedProsp ect ive co ho rt non-SSRls (n = 423), populati on cases): 39/ 34.3 SSRls non-SSRls, 21/ 18.7study, Sweden SSRls non -SSRls SSRls, 18/15.7 non -SSRls P = NS)(NMR data) (n = 15)Chamb ers et a l20 Fluoxet ine No expo sure to Inciden ce of majo r malfo rmatio ns: 5%Prospective co ho rt (n = 228) known te ra togens fluoxetine , 4% no exposure P = 0.63)study, United St ates (n = 254)(TIS dat a)Pastuszak et a l21 Fluoxetine (n = 128), No exposure to Inciden ce of majo r malformations ttestProspect ive co ho rt TCAs (age mat ch ed ) known te ra toge ns, fo r pair ed data : 2 .0% f1u oxetin e, 1.8% nostudy, Can ad a (n = 74) age mat ched exposure P = 0.38); analysis of varian ce:(TIS dat a) (n = 128) 3.4% fluoxetine, 0%TCAs, 3.0% no

exposure P = 0.8)Gold stein et a l22 Fluoxetin e (n = 796)Retrospective co hortstu dy, United States(CPR data)Sivojelezova et al23 Citalopram (n = 132)Prospective cohortstudy, Canada(TIS dat a)

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Data on newbornsfrom the NationalHospitalDischarge SurveyDisease-mat chedg roup (n = 132),no exposure toknown teratogens(n = 132)

Incidence of major malformations: 5%,cons idered to be within the range ofhistorical report s (no sta tistica l a nalysisprovided )Incidence of major malforma tions: 0.9%cita lopra m, 2.6%disease-matched groupP = 0.64), 0.8% no exposure P = 0.52)

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Tabl e II (cont inued).Autho rs/D escription(Data Source)l.enn est al andKallen24Retros pective coho rtstu dy, Sweden(NMRdata)

Masch i et a l25Prosp ective cohortstudy, Italy(TISdata)

Ramos et a l26Ret rospect ive casecon tro l study,Canada(NMRdata)

Wichm an et a l27Retros pective cohortstu dy, United States(hosp ita l records)

2009

ActiveDrugs

Mian serin (n 61);mirtazapine (n 145);venlafaxine (n 505);reboxetin e (n = 14);com bina tions ofrruan serin ,mirtazap ine, an dreboxetine withvenlafaxine (n = 12)

Antidepressants(n = 200, includ ingparoxetine [58],fluoxeti ne [32], andamitriptyline [26))

Birt h defects(n = 189)

SSRls: citalopram(n = 122), venlafaxine(n = 53), escita lopram(n 8), paroxetine(n = 134 ), fluo xetine(n = 184), sert raline(n = 296), >1 SSRI(n = 11 )

Contro lsAll deliveries inthe po pulation(n 860 ,215),deliveries inmothers usingSSRls (n = 6481)30

No exposure toknown te ratogens(n = 1200)

No birth defects(n = 2140)

All recordeddeliveries in whicht he mother hadnot used SSRls(n 25,214)

M. Tuccori et al.

Main FindingsRisk of malfor ma tions- SNRls/NRls vs a llde liveries: AOR = 0.85 (95% CI, 0.58- 1.24);SSRls vs a ll deliveries: AOR = 0.89(95% CI, 0.79-1.07 )

Incidence of major malformations:0.5% antidepressants , 1 .3% no exposureP 0.05)

Exposure to SSRls other newerantide pressants: 73.9%Risk for major co ngenita l mal format ionswit h 1st-trimes te r exposure to an yantide pressant, byd uration of exposure 1-3 0 d: AOR = 1.23 (95% CI, 0.77-1.98) ;31-60 d: AOR = 1.03 (95% CI, 0.63-1.69);>61 d: AOR 0.92 (95% CI, 0.50-1.69)Risk for major co ngenita l mal formationswit h exposure to any ant ide pressant ,byt iming of exposure l st trimester:AOR = 1.10 (95% CI, 0.75-1.62); 2ndtrimester: AOR = 1.13 (95% CI, 0.59217); 3rd trimester: AOR = 0.86(95% CI, 0.45- 1.65)

Incidence of co ngenital hear t defects :0.4% SSRls, 0.8% no SSRls P = 0.23)

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Tabl e II (conti nued).Auth ors/D escription(Data Source)Eina rso n et a l2sProsp ective coho rtstu dy, Can ad a(T IS data)

Col e et a l29Ret rosp ective co ho rtstu dy, United Sta te s( insurance database)

Kallen a ndOtt erbl adOlausson ?Retrospective co ho rtstudy, Sweden(NMRdata)

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ActiveDrugs

1st-Trimes te rexposure tocita lopram (n = 184),venlafaxine (n = 154),paroxetine (n = 148),bupropi on (n = 113),mirtazap ine (n = 68),fluoxetine (n = 61),sert raline (n = 61),f luvoxamine (n = 52),nefazodone (n = 49),escita lopram (n = 21),and trazodone (n = 17)Paroxetinemonotherapy(n = 791) ormon otherapy/co mb ination th erapy(n = 989)

SSRls (n = 6481)

Con tro lsMatched controlswith no expos ureto knownteratogens(n = 928

Otherantidepress antmono therapy(n = 4072) o rmono thera py/combinationth erapy (n = 4767)

All births inpopu lation(n = 866,696)

Main FindingsRisk of majo r ma lformations,a ntidep ressa nts vs no exposure:OR = 0.90 (95% CI, 0.50 -1.61)

Risk of all conge nita l malformationspa roxetine mon otherapy vs otherantidep ressant monotherapy: AOR =1.89 (95% CI, 1.20 -2 .98); paroxetinemon otherapy/combinati on therapy vsother antidepress ant mon otherapy/combination th erapy: AOR = 1.76(95% CI, 1.18-2.64)Risk of cardiovascular malformat ionsparoxetin e monotherapy vs otherantidepressant monotherapy: AOR =1.46 (95% CI, 0.74-2.88); paroxetinemon otherapy/combination th erapy vsother antidepressant monotherapy/combination th erapy: AOR = 1.68(95% CI, 0.95-2 .97)

Risk of malformations-any SSRI: RR = 0.89(95% CI, 0.79 -1.07); f1uoxetine: RR =0.85 (95% CI, 0.61-1.19); citalo pra m:RR = 0.94 (95% CI, 0.78-1.13);paroxetine: RR = 1.03 (95% CI,0.76 -1.38) ; sertraline : RR = 0.78 (95%CI, 0.61-1.00); fluvoxam ine: RR = 0.50(95%CI, 0.13-3 .80); escita lopram: RR=0.91 (95% CI, 019-2.66)Risk of cyst ic kidney, SSRls vs all births:RR = 3.50 (95% CI, 1.60 -6 .65)Risk of any cardiac malformation, paroxetinevs all births: RR = 1.63 (95%CI, 1.05-2.53)Risk of anyca rd iac defect , paroxetine vsall bir ths: RR = 2.63 (95%CI, 1.40 -4 .50)Risk of atrial septa l defect s + ventricularse pt a l defect s, paroxetine vs a ll births:RR = 3.07 (95% CI, 1.32- 6.04)(continued)



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Table II (cont inued) .Aut hors/ Descripti on(Data Source)Berard et a l31Retr ospect ive casecontrol study,Canada(NMR data)

Louik et a J32Retr ospect ive case control study, Canadaand United States(Slone EpidemiologyCenter Birth DefectsStudy)

Alwan et a l33Retrospective casecontrol stu dy, UnitedSta tes(Nat ional BirthDefects PreventionStudy)

2009

ActiveDrugsMajor malformations(n = 101), includ ingcardiac malformations(n = 24)

Birth defects(n = 9849)

Birth defe cts(n = 9622)

ControlsNo major or minormalformations(n = 1270)

No birth defects(n = 5860)

No birt h defect s(n = 4092)

M. Tuccori et al.

Main Findi ngsRisk of cardiac malformati ons- paroxetin e

vs non-SSRls: AOR = 1.38 (95% CI,0.49 -3.92); other SSRls vs no n-SSRls:AOR = 0.89 (95% CI, 0.28-2 .84)1st-Trimester exposure to paroxetine >25 mg/dvs non -SSRls-risk of major congenitalmalformations:AOR = 2.23 (95%CI , 1194.17); riskofmajor cardiac malformations:AOR = 3.07 (95% CI, 1.00-9.42)

Risk of ompha locele ser tra line: AOR =5.7 (95% CI, 1.6-20.7)Risk of cardiac sept a l defects ser traline:AOR = 2.0 (95% CI, 1.2-4 .0)

Risk of right ventricular outf low tractobstruction defects-SSRl s: AOR = 2.0(95% CI, 11- 3.6); paroxetine:AOR = 3.3(95% CI, 1.3-8 .8)

Risk of major birt h defects wit h SSRlsanencepha ly: AOR = 2.4 (95%CI, 11-5 1);craniosynostosis:AOR = 2.4 (95%CI, 1.5-4.0);omphalocele:AOR = 2.8 (95%CI, 1.3-5.7)Risk of major birth de fects with f1 uoxetinecra niosynostosis (10 exposed infants):AOR = 2.8 (95% CI, 1.3- 61)Risk of majo r birth defects with sertralineanencephaly(4 exposed infants):AOR = 3.2(95%CI, 11-9.3)Risk of major birth defects with paroxetineanencephaly(5 exposed infants):AOR = 5.1(95%CI, 1.7-15.3); right ventricular outflow

tract obstruct ion (7 exposed infants):AOR = 2.5 (95%CI, 1.0- 6.0); omphalocele(6 exposed infants): AOR = 8.1 (95% CI,31-20.8); gastroschisis (5 exposed infants):AOR = 2.9 (95% CI, 1.0-8.4)No significant risk of other co ngenitalanoma lies or co ngenital heart defects

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Tabl e II (conti nued) .Authors/D escription Active(Data Source) Drugs Con tro ls Main Find ingsDavis et aJ34 SSRls (n = 1047), No exposure to Risk of malfor ma tions, SSRls vs noRet rosp ective coho rt TCAs (n = 221), antide pressants expos ure: RR = 0.97 (95% CI, 0.81-1 16)study, United St ates o th er a ntide pressa nts (n = 49,654) Risk of congenita l abnorma lit ies of the(insurance datab ase) (n = 173) eye, paroxetine vs no exposure: RR = 2.36(95% CI, 1.20-4 .66)

Risk of co ngenital a bnorma lities of t heheart, paroxetine vs no exposure: RR= 1.98(95% CI, 0.64- 6.15)

Ob erland er et a J35 SRls (n = 2625), No expo sure to Risk of co ngenita l hear t defects-SRls/BDZsRetrospec tive coho rt BDZs (n = 968), known teratogens vs no exposure:ARD = 118 (95%CI, 0.18-stu dy, Can ad a SRls+ BDZs (n = 107,320) 2.18); citalopram vs no exposure:ARD = 2.28(NMR data) (n = 359) (95% CI, 0.19-4 .36)Risk of atria l sep ta l defects-SRl s vs no

exposu re:ARD = 0.21 (95%CI, 0.05-0 .36)Risk of major congenita l anomalies-

f1uoxetine/BDZs vs no exposure:ARD = 5.18(95% CI, 0.30 -10 .07)

Diav-Citrin et a J 6 Fluoxetine (n = 314), No exposure to Incidence of major abnormalities (includingProspective coho rt paroxetine (n = 410) known teratogens elective termination of pregnancy due tos tudy, Germany, (n = 1467) potential ab normalities): 5.2% paroxet ine,Israel , and Italy 6.3% f1uoxetine, 2.9%no exposure P< 0.05)(TIS data) Risk of cardiovascular a bnorma lities

paroxetine:AOR = 2.66 (95%CI, 0.80- 8.90);f1uoxetine:AOR = 4.47 (95%CI, 1.31-15.27)

Einarson et a l37 Venlafaxine (n = 150), No expo sure to Incidence of major malformat ions (expectedProspective co ho rt SSRls (n = 150) known teratogens baseline rate, 1%-3%): 1.6%venlafaxine,study, Canad a and (n = 150) 2.4%SSRls, 0.7% no expo sure P = 0.89)United Stat es(TIS data)Djulus e t a l38 Mirtazapine (n = 104), No expo sure to Incidence of major malformat ions (expectedProspective co ho rt ot her antid epr essants known teratogens baseline rat e , 1%-3%): 1.9% mirtazapinestudy, Austral ia , (n = 104) (n = 104) (95%CI, 0.5-2.7), 1.0%other an tidepressantsCan ada , Israel, It aly, (95% CI, 0.2-2.7) , 1.9% no exposureand United Sta tes (95% CI, 0.5- 3.6)(TISdata)Simon et a J39 SSRls (n = 185), Match ed co ho rt Risk of major ma lform ations, SSRls vs noRetrospective coho rt TCAs (n = 209) with no SSRI exposure: OR = 1.36 (95% CI, 0.56- 3.30)stu dy, United St ates exposure (n = 185),(insurance databases) ma tched cohort

with no TCAexposure (n = 209)

(continued )



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M. Tuccori et al.

Table II (co ntinued).Autho rs/D escription(Data Source)Maim et a l40Retrospective co hortstudy, Finland(NMR da t a )

Eina rso n et a l41Retrospective co hortstudy, Australi a andCa nada(TIS da ta )

Wogeliu s et a l42Co ho rt study,Denm ark(NMR da t a )

Acti veDrugs

SSRI purchasedur ing pregnan cy(n = 1782), SSRIpu rch a s e in 1stt rimes te r (n = 1398),

SSRI purchase in2 nd t rimester(n = 548), SSRIpurchase in 3 rdt rimes te r (n = 597),

SSRI purchase ineac h t rimeste r(n = 229)Paroxetineunpublished co ho rt(n = 1174), paroxetinehis tori cal co ho rt(n = 2061)

SSRI prescrip tion sfro m 1 mo befo reco ncept io n to endof 1st trim ester(n = 1051), SSRIprescriptions in 2ndo r 3 rd mo (n = 453)

Co nt ro lsMatched pregnantcontro ls with noreimbursed drugpu rchases(n = 1782)

No exposu re t oknown te ra toge ns(n = 3379)

Non -SSRIprescription s(n = 150,780 )

Main FindingsIncidence of major malforma tion s: 4. 2%

SSRI pu rch a se in any peri o d , 3 .5% nopu rchase P = 0.6)

Risk of major malformat ion s w it h I sttr imester purchase- all SSRls : AOR =1.0 (95%CI, 0.6-1.7); cita lopra m (n = 554):AOR = 0.4 (95% CI, 0.1-1.4); flu oxet ine(n = 525): AOR = 1.7 (95% CI, 0.9-3 .3);paroxetine (n = 152): AOR = 0.4 (95% CI,0.1-3 .3); sert ra line (n = 118): AOR = 0.7(95% CI, 0.1-5.3); f luvoxamine (n = 65):AOR = 1.0 (95% CI, 0 .1-7.8 )

Incidence of ca rd iac malform at ion s,paroxetine (unpub lished + histo r icalco ho r ts) vs no exposure: 1.2%(OR = 1.7;95% CI, 1.1-2 .1)

Risk of ca rd iac malform at ion s, paroxet ine(unpublished co ho r t) vs no exposu re :O R = 1.1 (95% CI, 0.36-2.78)

Risk of co nge nita l mal format ion s- SSRIprescription s from 1 mo before concept ionto end of 1st tr imester : ARR = 1.34(95% CI, 1.00-1.79); SSRI prescrip tion s in2nd o r 3 rd mo: ARR = 1.84 (95% CI, 1.252.71)

T IS teratology informat ion service; RR risk ratio; TCAs tricyclic antidepressants; NMR national medical registr y(including national birth registries, registries of congenital malformations, hospital discharge registries, prescriptionregistries); CPR company pregnancy registry; SNRls serotonin- norepinephrine reuptake inhibito rs; NRls norepinephrine reuptake inhibitors; AOR adjusted odds ratio; OR odds rat io; SRls seroto nin reuptake inhibitors; BDZsbenzodiazepines; ARD adjusted risk difference; ARR adjusted risk ratio.

this matt er using different methodologies in o therpopulations. Using data from the Swedish nat ionalmedical registry, Killen and Otterblad Olausson-?found that women who received paroxetine in earlypregnancy had an ~ f o l d increase in risk for delivering an infant with cardiac defects compared withbirths in the entire population (risk ratio [RR] = 2.63;95% CI, 1.40-4.50). Berard et a13l performed a6-year, population-based, case-control analysis ofdata from the Canadian Medication and Pregnancy

2009

Registry to quantify the aSSOCIatIOn between firsttrimester exposure to paroxetine and congenital cardiac malformations, as well as to evaluate the potential dose-response relat ionship between paroxetineuse and cardiac defects. Among 1403 pregnant women, they identified 101 infants with major congenitalmalformations, including 24 cardiac defects. Exposure to paroxetine at a dose >25 mg/d dur ing the firsttrimester was associated with increased risks of majorcongenital malformations (AOR = 2.23; 95% CI,

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1.19-4.17) and major cardiac malformations (AOR =3.07; 95% CI,1.00-9.42).

To assess the potential association between firsttrimester exposure to SSRIs and the risk of birth defects, Louik et a132 performed a case-control analysis ofdata from the Slone Epidemiology Center Birth DefectsStudy involving 9849 infants with bir th defects and5860 without such defects. SSRIswere associated withright ventricular outflow tract obstruction defects in15 exposed infants (AOR = 2.0; 95% CI, 1.1-3.6).Among individual SSRIs, significant associations werefound between sertraline and ornphalocele in 3 exposedinfants (AOR = 5.7; 95% CI, 1.6-20.7), sertraline andcardiac septal defects in 13 exposed infants (AOR =2.0; 95% CI, 1.2-4.0), and paroxetine and right ventricular outflow tract obstruction defects in 6 exposedinfants (AOR = 3.3; 95% CI,1.3-8.8).

Another case-control analysis compared 9622 casesof major malformation in the National Birth DefectsPrevention Study with 4092 controls residing in thesame geographic areas.v-' A significant association wasfound between gestational exposure to SSRIs and anencephaly (AOR = 2.4; 95% CI, 1.1-5.1), craniosynostosis (AOR = 2.4; 95% CI, 1 .5-4.0) , andornphalocele (AOR = 2.8; 95% CI, 1.3-5.7); no association was found between SSRI exposure and congenital heart defects or other birth defects. Significantassociations were found between individual SSRIs (paroxetine, sertraline, and fluoxetine) and specific majormalformations (P < 0.05), but the small number ofexposed cases limited the strength of the findings.Furthermore, SSRI exposure was determined using astandardized telephone interview of the mothers, whichmay have introduced recall bias.

Using data from 5 health maintenance organizationdatabases in the United States, Davis et a134 conducteda retrospective cohort study comparing 1441 infants exposed to antidepressants during gestation and 49,654 unexposed controls. Exposure to SSRIs during pregnancywas not associated with a significant risk of congenital malformations compared with unexposed controls(RR = 0.97; 95% CI, 0.81-1.16). Paroxetine exposure(n = 182) was not found to be significantly associatedwith the risk of congenital heart defects comparedwith no paroxetine exposure (RR = 1.98; 95% CI,0.64-6.15). However, there was a significant risk forcongenital abnormalities of the eye in infants exposedto paroxetine compared with unexposed infants (RR =2.36; 95% CI, 1.20-4.66).

436

Einarson et a141 compared outcomes in 1174 infants from 8 teratology information services and ahistorical cohort of 2061 infants exposed to paroxetine during the first trimester of pregnancy from5 previously published database studies wi th outcomes in 3379 infants from the same informationservices with no exposure to known teratogens. In theteratology information services cohort, rates of cardiovascular defects were 0.7% in the exposed groupand 0.7% in the unexposed group (OR = 1.1; 95% CI,0.36-2.78). When the data from the teratology information services and database studies were pooled, themean rate of cardiovascular defects in the paroxetineexposed group was 1.2% (OR = 1.7; 95% CI, 1.12.1). The authors concluded that first-trimester exposure to paroxe tine did not appear to be associatedwith an increased risk of cardiac defects, as they considered the est imated incidence well within the incidence in the general populat ion ~ %). They did notcomment on the significant results obtained when the2 exposed groups were combined; however, the heterogeneity of the data would appear to render thisfinding of limited relevance. The role of chance in atleast some of the study findings cannot be ruled ou t,and additional research is warranted to assess the actual degree of risk for cardiovascular malformationsassociated with the use of paroxetine during pregnancy.

In a retrospective cohort study that employed datafrom the Canadian nat ional medical registry, Oberlander et a135 assessed the potential association between congenital abnormalities and prenatal exposureto SRIs (paroxetine, sertraline, fluoxetine, venlataxine, fluvoxamine, and citalopram], alone or in combination with benzodiazepines (BDZs). After adjustment for several maternal clinical features that wereused as a proxy for the severity of depression, combined SRIIBDZ exposure was associated with an increased risk of congenital heart defects compared withno exposure (adjusted risk difference [ARD] = 1.18;95% CI, 0.18-2.18), and exposure to SRIs was associated with an increased risk of atrial septal defects compared with no exposure (ARD = 0.21; 95%CI, 0.05-0.36). In analyses of individual antidepressants , citalopram was associated with a significantrisk for congenital heart defects (ARD = 2.28; 95%CI, 0.19-4.36), and the combination of fluoxetinelBDZ was associated with an increased risk for majorcongenital abnormalities (ARD = 5.18; 95% CI,0.3010.07).



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Diav-Citrin et a136 conducted a prospective cohortstudy comparing the outcomes of 410 pregnancies involving first-trimester exposure to paroxetine, 314 pregnancies involving first-trimester exposure to fluoxetine, and 1467 control pregnancies with no exposureto known teratogens. There were significant risks forcardiovascular abnormalities with both paroxetine(OR = 3.47; 95% CI, 1.13-10.58) and fluoxetine (OR =4.81; 95% CI, 1.56-5.71). After logistic regressionanalysis with adjustment for a maternal smoking habitof >10 cigarettes/d. the association remained significant only in the fluoxetine group (AOR = 4.47; 95%CI,1.13-15.27).

Einarson et a137 conducted a prospective s tudy ofdata from 150 women exposed to venlataxine duringthe first trimester of pregnancy, 150 exposed to SSRIs,and 150 who received nonteratogenic drugs. Theyfound no significant increase in the incidence of majormalformations between venlafaxine, SSRIs,and nonteratogenic drugs (1.6%,2.4%, and 0.7%, respectively).

The findings of animal studies suggest that exposure to duloxetine during pregnancy may have negatively affected birth weight and survival, but was no tassociated with teratogenic risk. 48However, no clinical data concerning the risks of duloxetine exposureduring pregnancy were identified.

Little information was identified regarding the safetyof gestational use of NaSSAs and NRIs. After examining the outcomes of 104 pregnancies from 5 teratology information services, Djulus et a138 reported thatthe incidence of major malformations did no t differsignificantly between infants born to women whoreceived mirtazapine, other antidepressants (SSRIs,SNRIs, or tricyclic antidepressants [TCAs]), or nonteratogenic drugs during pregnancy (1.9%, 1 .0%, and1.9%, respectively).

In the only study identified that reported on the useof reboxetine (although in combination with other antidepressants), Lennestal and Killen24 found no evidenceof an increased risk for congenital defects with the gestational use of SNRIs/NRIs (venlataxine, rnianserin,reboxetine, rnirtazapine, and their combinations) compared with all deliveries in the population (AOR =0.85; 95% CI, 0.58-1.24). Further specific investigations are needed to ascertain the potential risks formajor malformations associated with gestational exposure to rnirtazapine, reboxetine, and duloxetine.

Five meta-analyses have evaluated the risk for major malformations in association with use of SSRIs

9

M. Tuccori et al.

and other serotonergic/noradrenergic antidepressantsduring pregnancy (Table III).49-53 Four of these analyses found no increase in the risk of major malformations with exposure to SSRIs in the first tr imester ofpregnancy,49-51,53 although 3 of these had methodologic limitations that may have resulted in underestimation of the risks.49-51

The meta-analysis by Addis and Koren49 evaluatedthe overall occurrence of major malformations in 4 studies of pregnancy outcomes in women exposed to fluoxetine during pregnancy, only 2 of which included acontrol population. The small population (367 pregnancies) and low specificity may have limited the abilityof this analysis to detect increases in the risk of specificmalformations, such as congenital heart defects.

The meta-analysis by Einarson and Einarson-? investigated exposure to a group of drugs (SSRIs, venlafaxine, rnirtazapine, reboxetine, bupropion, trazodone,and nefazodone) rather than to specific antidepressants. Because the included drugs have differentmechanisms of action, it was no t possible to evaluatepotential class effects. Moreover, specific malformat ions were no t investigated, and 5 of the 7 includedstudies involved women who were no t representativeof the general population or comparable to patientsfrom the other studies, as they were participants in theMotherisk Program in Toronto, Canada, and hadbeen specifically educated to follow teratology information service instructions.

The meta-analysis by Rahimi et a151 is valuable forits inclusion of the specific end point of congenitalheart defects. However, it assessed exposure to a groupof drugs (citaloprarn, fluoxetine, fluvoxamine, paroxetine, and sertraline) rather than to specific antidepressants. Moreover, exposure to this group of drugs waslimited to the first trimester in 6 of 9 studies, whilethe remainder considered exposure at different timesduring gestation. This is an important limitation, aswomen who are first exposed to potential teratogensin the second or third trimester have a lower risk ofdelivering infants with major malformations comparedwith those with first-trimester exposure.54

The remaining 2 meta-analyses were performed bythe same research group and had conflicting findings.Bar-Oz et a152 found a signif icant increase in the riskof cardiac malformations in infants exposed to paroxet ine in the first t rimester (OR = 1.72; 95% CI, 1.222.42). This was a well-designed meta-analysis, evaluating specific end point s in a large number of patients

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Tab le II I. Meta-analyses of studies including data on major malformations a ssocia t ed with maternal use ofselective seroton in reuptake inhibitors (SSRls) a nd other serotonergic/norad renergic ant idepressan ts during pregnancy.

Authors/ DescriptionAddis and Koren ?4 Stud ies (N = 36 7) , 2 co ntrol leda nd 2 un contro lled

Einarson and Einarson-?7 Stud ies (N = 1774)

Rah imi e t alS19 Stud ies (N = 2699)

Bar-Oz et a ls2Meta-ana lysis of majormalformations (7 studies, n = 17,226)Meta -analysis of cardiacmalformations (6 studies, n = 16,789)

O' Brien et a ls3Case-control ana lysis (3 stu dies,n = 30 ,247)

Cohort analysis (6 stud ies,n = 66,4 09)

Main Selectio n Criteriaand Comparato rsProsp ect ive co ntro lled anduncon tro lled stud ie s with dataon exposure to fluoxe tine in 1s tt rimes te r vs no expos ure toknown te ra togensProspect ive co ho rt s tu dies withdata on exposu re t o SSRls ,SNRls, NRls, NaSSAs,bup rop ion , trazod on e, ornefazod on e in 1st tr imes te r vsco nt ro l swit h no exposu re t oknown terat ogensCohort s tu d ies wit h data o nexposure to SRls (cita lopra m,fluoxe tine, fluvoxamine,paroxetine, or sertra line) in 1stt rimeste r o r t h roughou tpregnan cy vs no exposureCase-cont ro l and coho r ts tud ies with data o n exposureto paroxet ine in 1st trimes ter vsno exposureExposure to paroxetine in 1stt rimester vs no exposure (casecontro l a nalysis) or vs exposureto other antide pressa nts in 1sttr imester (co ho rt a na lysis)

Main FindingsSum ma r y OR for pooled relative riskof major malformations: 1.33 (95% CI,0.49 -3 .58)

Sum mary RR fo r majo r structu ra l o rfunction a l ma lfo rmat ions: 1.01(95% CI, 0 .57- 1.80 )

Su mmar y OR, major ma lforma tion s:1.39 (95% CI, 0.91- 2.15)

Summary OR, ca rdiac malformat ions:119 (95% CI , 0 .53-2 .68)

Sum mar y OR, major ma lforma tion s:1.31 (95%C I, 1.03-1 .67)

Su mmary OR, ca rdiac malformations:1 .72 (95% CI, 1 .22-2.42)Risk of co ngen ita l malforma tion s,

case-co nt rol analysis : OR = 118(95% CI, 0.88-1 .59)

Risk of ca rdiac malformations, co horta nalysis: WAD = 0.3% (95% CI,- 0 .1 to 0.7 ); P = 0.19

O R = odd s ra t io ; SN Rls = sero to nin-norepinephr ine reuptake inhib itors ; NRls = norepineph r ine reupt ake inhibi tors ;NaSS As = noradrenergic and specific sero tonergic ant ide pressants ; RR = risk ra t io; SRls = sero t oni n reuptake inhib ito rs ;WAD = weighted ave rage di fference.

(n = 2621) exposed to a single drug (paroxetine) andincluding a control group consisting of women exposed to antidepressants other than paroxetine (n =14,774), thus controlling for potential indication bias.In the same publication, the authors reported a separate analysis using a large population-based administrative database from Quebec (N = 24,947) to exam-

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ine access to diagnostic testing as a potential confounder for congenital malformation. They found thatusers of paroxetine, other SSRIs, and non-SSRI antidepressants had significantly higher mean numbers ofdiagnostic tests (ultrasound, echocardiography, andamniocentesis) during pregnancy compared with thosewho used no antidepressants (2.4,2.5, 2.3, and 1.9,



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respectively; P < 0.001). Based on this finding, allwomen who use antidepressants during pregnancymight be expected to have a higher r isk of exposure topotential teratogenic procedures. However, the authorssuggested that the higher risk associated with paroxetine may relate to its more frequent prescription forpatients with anxiety, whose anxie ty might promptthem to seek more diagnostic testing and resul t inmore exposure to poten tial teratogens. In the metaanalysis by O'Brien et al,53 which extended the analysis by Bar-Oz et al by including 2 additional studies,the significant association between gestational exposure to paroxetine and the r isk of cardiac malformations was lost (OR = 1.18; 95% CI,0.88-1.59).

In summary, data published mainly before 2000 andobtained from small teratology information servicedatabases supported the lack of an association betweenuse of SSRIs during pregnancy and an increased risk fordevelopment of major malformations. However, morerecent data from large population-based studies usingmore appropriate pharrnacoepidemiologic approacheshave challenged this assumption. Recent guidelines andupdated teratogenic classifications recommend cautious use of SSRIs during pregnancy and avoidance ofparoxetine.55-57Paroxetine was the first SSRIto be associated with an enhanced risk of birth defects, particularly cardiac defects. Similar concerns do not appear toapply to other SSRIs, despite recent findings suggestinga certain degree of risk with other SSRIs, particularlyfluoxetine. The possible channeling of paroxetineprescriptions toward women with anxiety disorders,who are characterized by more frequent exposure topotentially teratogenic diagnostic procedures, mayhave biased the findings of studies that reported a significant associat ion between paroxet ine use duringpregnancy and the occurrence of congenital malformations. This hypothesis warrants further investigation.MINOR MALFORMATIONS ANDMILD STRUCTURAL ANOMALIESMinor malformations are considered of limited clinical relevance, do no t general ly require medical orsurgical treatment, and do no t greatly affect the infant's appearance. Examples include ear abnormalities, mongoloid eyes, overriding toes, absence of a hairwhorl, extra nipples, frontal bossing, iris freckles, tapered fingers, and cleft uvula.58

In a study in 228 women exposed to fluoxetine in thefirst trimester of pregnancy compared with 254 wom-

9

M. Tuccori et al.

en who were no t exposed to known teratogens,Chambers et aIlo reported that significantly more infants exposed to fluoxetine were born with ::::3 minordefects compared with controls (15.5% vs 6.5%, respectively; P = 0.03). A study by Casper et a159 foundno significant increase in the incidence of minor malformations in infants born to 31 mothers with depression who were exposed to SSRIs (sertraline, fluoxetine, paroxetine, and fluvoxamine) throughoutgestation compared with infants born to 13 motherswith depression and no exposure to SSRIs (76% and54%, respectively). Both studies were included in ameta-analysis that found no increase in the risk ofminor malformations in users of SSRIs compared withnonusers (OR = 0.97; 95% CI,0.14-6.93).51

There are few available data on the risk for minormalformations and mild structural abnormalities associated with SSRI exposure during pregnancy. Accurate prospective evaluations of these risks in pregnant women exposed to SSRIs and other serotonergiclnoradrenergic antidepressants are required.MISCARRIAGEIn studies that have evaluated the risk of miscarriagein women using SSRIs or SNRIs during pregnancy,crude estimates of the incidence of pregnancy loss didno t differ significantly from controls or did no t exceedexpected rates in the overall population for fluoxetine(10.0%_13.8%),18,20-22,36 paroxetine (9.1%),36 fluvoxarnine (9.0%),18 citaloprarn (11.0%),23 venlataxine (12.0%),37 and rnirtazapine (19.0%).38 Table IVsummarizes the main findings of studies that reportedmiscarriage rates.

A pooled analysis by Kulin et al12 reported an 11.2 %incidence of pregnancy loss among 267 users of fluvoxamine, paroxetine, or sertraline, compared with a 7.9%incidence in 267 nonusers of these antidepressants (P =NS). In contrast, a meta-analysis of 9 studies involvinga total of 2699 pregnancies reported a significant associat ion between SSRI use and spontaneous abortion(OR = 1.7%; 95% CI, 1.28-2.24; P < 0.001).51 Basedon the findings of Bassiouni and Rafei,60 who reportedthat blood concentrat ions of 5-HT were higher inwomen with spontaneous abortion in early pregnancycompared with those with a normal course of earlypregnancy, the authors of the meta-analysis suggested apossible serotonergic mechanism for pregnancy loss.

A meta-analys is by Hemels et a161 compared ratesof spontaneous abortion in women taking antidepres-

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Tab le IV. Studies eva luat ing rat es of miscarriage assoc ia ted with th e use of selective serotonin reuptake inhibitors (SSRls) or other serotonergic/norad ren ergic ant ide pressa nts du ring pregnan cy.Authors/D escription Active(Data Source) Drugs Cont ro ls Main FindingsKulin et a J 2 Fluvoxamine, No expos ure to known Inc ide nce o f miscarri age: 11.2%Prospectiv e coho rt stu dy, paroxetine , and te ra togens (n = 267 ) fluvoxamine, paroxetine, or sertraline;Canada and Unit ed se rt ra line 7.9% no expos ure P = 0.24)States (TIS da ta ) (n = 267)McElhatton et a J 8 TCA expos ure Non e Incidence of miscarriage: 11.0%TCAProspective case series , (n = 33 0), non - monotherapy, 13.2%TCA otherEurope and Israel TCA expos ure drugs, 13.0% non -TCA mon otherapy,(TIS data) (n = 416) 10.6% no n-TCA other drugs , 13.5%fluoxetine, 9.0% fluvoxamine (no

stat istica l a nalysis provided)Chambers et a l20 Fluoxetin e No expos ure to Incidence of miscarriage: 10.0%Prosp ective study, (n = 228) known teratogens fluoxetine, 8.5%no exposureUnited States (TIS data) (n = 254) P=0.59Pastuszak et a l21 Fluoxetin e TCAs (n = 74), no Incid en ce of miscarriag e: 13.5%Prosp ective co hort study, (n = 128) exposure to known fluoxetine, 12.2%TCAs, 6.8% noCanada (TIS data) teratogens (n = 128) expo sure P=0.31

RR, fluoxetine vs no exposure: 1.9(95% CI, 0.92-3 .92)

Golds tein e t a l22 Fluoxetine Rates o f miscarriag e Incide nce of miscarriage: 13.8%Retrospective cohort (n = 796) from the National (no difference reported vs his toricstu dy, United St ates Hospital Discharge newbo rn surveys, a lthough no(CPR dat a) Survey sta t ist ica l analysis provided )Sivojelezova et al23 Citalopram Disease-matched Incidence of misca rriage: 11%Prospect ive cohort study, (n = 132) group (n = 132), no cit alo pra m, 10% d isease-matchedCanada exposure to known group , 10% no exposure (no

teratogens (n = 132) s tat is t ica l ana lysis provided)Diav-Citrin et al36 Fluoxetin e No expos ure to Incidence of miscarriage: 11.8%Prospective coho rt study, (n = 314) , known teratogen s f luoxe t ine P < 0.05 vs no exposure),Germany, Israel, and Italy paroxetine (n = 1467) 91% paroxetine P= NSvs no exposure),(TIS data) (n = 419) 6.6% no exposureEinarson et a l37 Venlafaxine No expos ure to Incid ence of miscarriage: 12.0%Prospective cohort study, (n = 150), SSRls known teratogens ven lafaxine, 10.7%SSRls, 7.3% noCanada and United States (n = 150) (n = 150) exposure P = 0.38)(TIS data)Djulus et aP8 Mirtaz apin e No expos ure to Incidence of miscarriage: 19%Prosp ect ive co ho rt st ud y, (n = 104), known teratogens mirtazapine P = 0.86 vs otherAustra lia , Canada , Israe l, o t her (n = 104) a ntide pressa nts; P = 0.12 vs noIta ly, and United Sta te s antidepressants exposure), 17%other a ntide pressants,(TISdata) (n = 104) 11% no exposureTIS = terato logy information service; TCA= tricyclic antidepressant; RR = relative risk; CPR= company pregnancy registry.



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sants during pregnancy (n = 1534) and women withou t depression (n = 2033) from 6 cohort studies. Thebaseline ra te of spontaneous abortion was 8.7%(95% CI, 7.5-9.9), compared with 12.4% in thewomen exposed to antidepressants (95% CI, 10.814.1). This represented a 3.9% increase (95% CI,1.9-6.0), with a relative risk of 1.45 (95% CI, 1.191.77). Although there was no heterogeneity amongstudies and the quality score for all studies was adequa te (>50%), it should be noted that the results ofthis meta-analysis may have been biased by indication.

The conclusions of some of the preceding analyseswere based on crude comparisons that do not supportan increased rate of miscarriage in association withmaternal use of SSRIs.18-20,22,23,28,36,37 Several factorsmay have influenced these observations (eg, time ofcontact with a teratogen information service, rate ofinduced abortion, maternal age, severity of depression).When calculating the incidence of spontaneous abortion, the majority of the reviewed studies used the totalnumber of pregnancies as a denominator, which is aninappropriate procedure, given that an early inducedabortion would rule out a later spontaneous abortionand an early spontaneous abort ion would rule out alater induced abortion. Thus, the rate of miscarriageshould be analyzed in terms of fetal survival on a weekby-week basis. Based on the literature search, no published study has applied such an approach to SSRIs orother serotonergidnoradrenergic antidepressants. Finally, the inclusion of untreated control populations in theidentified studies suggests a potential for bias by indication. Studies that employ this type of control populat ion should include an adjustment for disease severity when investigating the potential for miscarriageassociated with the use of SSRIs or other serotonergidnoradrenergic antidepressants.NEONATAL BEHAVIORAL SYNDROMEA variety of behavioral and neurologic symptoms,including irritability, persistent crying, shivering, tremor, restlessness, feeding difficulties, sleep disturbances,and seizures, have been reported in infants born towomen who used SSRIs dur ing pregnancy.v- Mildcentral nervous system (CNS), motor, respiratory, andgastrointestinal signs and metabolic dysfunction areusually present but disappear during the second weekafter birth. This clinical picture has been interpretedas representing a neonatal withdrawal syndrome or adirect toxic effect of antidepressants on the newborn.

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M. Tuccori et a

Because the withdrawal mechanism has no t been established, the designation neonatal behavioral syndrome is preferred. Medical management of this syndrome consists mainly of support ive treatment in aspecial-care nursery. This syndrome may be severe,with symptoms ranging from seizures to dehydration,excessive weight loss, and hyperpyrexia, and even aneed for intubation.v-

With regard to SSRIs and SNRIs, 18 case reportswere identified describing 25 cases of abnormal neonatal behavior-11 involving paroxetine.v-'< 7 fluoxetine,68-73 2 sertraline,74,75 2 citalopram,63,76 1 venlafaxine,77 1 mirtazapine. and 1 duloxetine.t An analysisof spontaneous reports of neonatal behavioral abnormalities associated with SSRIs in the World HealthOrganization adverse drug reac tion da tabase up tothe second quarter of 2003 identified 93 cases from11 countries that involved maternal SSRI use associated with either neonatal convulsions or behavioralalterations.s'' Paroxetine was implicated in nearly twothirds of suspected cases, and the remaining cases occurred in association with exposure to fluoxetine,sertraline, or citaloprarn.

Nineteen studies were identified that described adverse neonatal outcomes in relation to maternal exposure to SSRIs and other serotonergic/noradrenergicantidepressants from the last trimester through delivery (Table V .20,24,25,34,40,81-94 Overall, these studiesindicated the potential for symptoms consistent witha neonata l behaviora l syndrome or a high risk of admission to a special-care nursery in relat ion to maternal exposure to antidepressants, mainly SSRIs, duringthe third trimester of pregnancy.

The potential impact of maternal psychiatric disorders on the occurrence of neonatal behavioral alterations has been the subject of much discussion, andmothers with untreated depression have occasionallybeen enrolled in studies to adjust for possible confounding by indication.V However, women with untreated disease are generally likely to have less severepsychiatric problems than women with treated psychiatric disease. Therefore, Oberlander et a189 used propensity score matching to compare outcomes in newborns whose mothers received SSRIs for depressionduring pregnancy and those whose mothers did notreceive SSRIs for depression, thus controlling for potential confounders such as disease severity, maternalpsychotropic medication use, and concurrent illness.The incidence of symptoms of behavioral syndrome in

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Tab le V. Studies evaluating the occurrence of neonatal behavioral syndrome associated with maternal use ofselective serotonin reuptake inhibitors (SSRls) or other serotonergic/noradrenergic antidepressantsdu r ing pregnancy.

Authors/ Descript ionChambers et a l20Prospective/retrospective maternalreports and infantmed ical record review,United States

l.enn estal a ndKiillen24Ret rospective cohortstudy using recordlinkage methodo logy,Sweden

Maschi et a l25Prospective cohortstu dy, Italy

Davis et aJ34Retrospectiveinsurance databas eana lysis, United States

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ComparatorsEarlyexposure 25 wk) to fluoxetine(MDO, 28 mg) (n = 101), late exposure

wk) to fluoxet ine (MOD, 25 mg)(n = 73)

Exposure (early pregnan cy-delivery) toSNRls/NRls/NaSSAs (n = 737) (mianserin[611, mirtazapine [1 45], venlafaxine [505],reboxeti ne [14], mianserin venlafaxine[2], mirtazapine venlafaxine [9],reboxetine venlafaxine [1]) or SSRls(n = 6481); alldeliveries in population(n = 873,876)

Exposure (befo re conception todelivery) to unspecified a ntidepressants(n = 200), paroxetine (n = 58), fluoxetine(n = 32), or other antidepressants (n = 90);no exposure (n = 1200)

Exposure (3rd trimeste r) toantidepressa nts (SSRls, TCAs, ot hers)(n = 220 1), no exposure (n = 75,833)

Main FindingsRisk of poor neonatal ada ptation , la te vsea rly exposure: RR = 3.5 (95%CI, 1.7-7.2)Risk of special-ca re nursery ad mission

(excluding prema tu re infants), late vsearly expos ure: RR = 2.7 (95% CI, 1.4 -5.0)

Earlyexposure (before wk 12 in 90%of women)to SNRls/ NRls/ NaSSAs not associatedwith a significant increase in risk for an youtcome vs a ll deliveries

Early exposure to SSRls- risk of respiratoryprob lems: RR= 1.17 (95%CI, 1.03- 1.23); riskof low Apgar score 7 at 5 min): RR = 1.35(95% CI, 1.08-1.68); risk of hypoglycemia:RR = 1.17 (95% CI, 1.02-1 .33)

Late exposure to SNRls/NRl s/N aSSAs risk ofhypoglycemia: RR = 2.11 (95%CI, 1.10-3 .89)Lat e exposure to SSRls - risk of respirato ryproblems: RR= 1.72 (95%CI, 1.41-211); riskof low Apgar score 7 at 5 min): RR = 2.22(95% CI, 1.58-3 12); risk of hypoglycemia:RR= 1.32 (95%CI, 1.05-1.68); risk of neonatalconvulsions: RR= 2.94 (95%CI, 1.34-5.58)

Incidence of poo r neonatal adaptat ion:7.0% exposed, 4.2% no exposure P = NS)

Risk of z l perinatal event : RR = 116 (95% CI,1.06-1. 26); risk offeta l distress: RR = 6.00(95%CI, 1.88-1918); risk of respiratory distresssyndrome: RR = 1.97 (95%CI, 1.65-2 .35);risk of endo crine/metabolic disturbance:RR = 1.61 (95% CI, 1.15-2.27); risk oftemperature regulation disorders: RR = 1.56(95%CI, 1.06-2 .31); risk of convulsions: RR =2.60 (95% CI, 116-5.84)

(continued)



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Table V (continued) .Aut hors/ DescriptionMaim et a l40Retr ospect ive cohortstudy using recordlinkage meth odology,Finlan d

Costei et a l81Prospective matern alreport (inte rview),Ca nada

Lain e et a l82Pros pect ivepediatrician evaluationof newbo rns, Finland

Cohen et a l83Retr ospective chartreview, United States

Gold stein 'Compa ny registr y ofoutco mes ofpregna ncies wit hfluoxetine exposure(pros pecti ve andretrospective),United StatesOber lande r et a l85Prosp ective cohortstu dy wit h infa ntmed ical recordreview, Can ad a

2009

Comparato rsSSRI pur chase during pregnancy (n =1782), SSRI purchase in 1st trimester

(n = 1398), SSRI purchase in 2ndt rimeste r (n = 548), SSRI purchasein 3rd trimes ter (n = 597), SSRIpurc hase in each tri mester (n = 229);matched pregnant co ntrols wit h noreimbursed drug purchase (n = 1782)Earlyexposure (1 wk-6 mo) to paroxetine(MOD, 20 mg) (n = 27), late exposure(3rd tr imeste r) to paroxetine (MOD,20 mg ) (n = 65), no exposure (n = 27 )

Exposu re (mean, 38 wk before delivery)to cita lo p ram 20 mg (n = 10) orfluoxetine 20 mg (n = 10), no expos ure(n = 20)

Exposure to fluoxetine (MOD, 27 mg)in firs t 2 t rimesters (n = 11), exposureto fluoxe t ine (MOD, 27 mg) from 3rdt rimeste r to delivery (n = 53)Exposure (3rd trimester to de livery) tofluoxetine (MOD, 20 mg) (n = 112),historical co nt rols from NationalHospital Discharge Summary(n = 3,888,000)

Exposure (1st t rimeste r to delivery) toan SSRI (n = 28) (pa roxetine [MOD,22.2 mg] [17], fluoxetine [MOD,21.3 mg] [7], and sertra line [MOD,81 mg] [4]) o r a n SSRI clonazepa m(n = 18) (pa roxetine [MOD , 21.6 mg][16] and fluoxetine [MOD, 15 mg][2]) ; no exposu re (n = 23)

M. Tuccori et al.

Main Findings3rd- vs 1st-Trimes ter purchase risk of lowApgar sco re 7 at 1 min): AOR = 1.6(95% CI, 1.0 -2.4); risk of specia l-ca renursery or intensive ca re unit admission:AOR = 1.6 (95% CI, 1.1-2.2)

Lat e exposure vs early and no exposure-riskof neonatal complications (respiratory distress,hypoglycemia, bradycardi a, sucking problems,prolonged hospitalization ): RR = 4.0 (95% CI,1.2-131); risk of respiratory difficulties: RR =4.4 (95% CI, 1.0-19.5)Sum of Serotonin Syndrom e Scale scores on

days 1-4 : 121 citalopra m or fluoxetine,3 0 no exposure P = 0.008)

Risk of z l serotonergic s ign o n days 1- 4,cita lo pram or fluoxetine vs no exposure:OR = 6.9 (95% CI, 1.6-29.2)Exposure in 3rd trimester vsfirst 2 trimestersrisk for poor neonatal ada pta t ion: RR = 3.3(95%CI,0.5-22 .5); risk for special-care nurseryad mission: RR = 2.1 (95% CI, 0.3-14.6)3rd -Trimes te r exposure to fluoxetineincidence of poor neonat al adaptation: 13.4%(no stat ist ical analysis provided ); risk ofrespirato ry signs: RR = 0.6 (95% CI, 0.1-2 .2);risk of sleep problems: RR = 1.7 (95% CI,0.4-6.6)

Incidence of special-ca re nursery ad missio n:2% SSRls , 0% no exposure (no sta tisticalanalysis provid ed)

Risk of poor neo natal adaptatio n (jitteriness,respiratory difficulties, hypoglycemia): RR =3.5 (95% CI, 0.9-14 1)

(co ntinued)

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linic l Therapeutics

Table V (continued).Aut hors/ Descript ionKallen86Prospective cohortstudy wit h review ofant enatal and pediatricregistry, Swed enZeskind andStep hen s'i/Prospect ive cohortstudy wit h materna lmedical record review,United States

Hendrick et al88Uncontrolled ,prospective review ofpsychiatric, obstet ric,and pediatric records,United StatesOber lande r et a l89Retr ospective record linkage stu dy withprop ensity sco rematchin g, Canada

Ferreira et al90Retrospective co ho rtstudy, Canada

Pearso n et al9 1Retr ospective co ho rtstudy, United States

444

Comparato rsExposure to SSRls (n = 558) (mostfrequent: citalopram [285], paroxetine[106], fluoxetine [61], sertra line [77]);a llwomen giving bir th (n = 573,728)Expos ure to SSRls at any time duringpregnan cy (n = 17) (cita lop ram [MOD,24 mgJ [5],fluoxetine [MOD, 30 mgJ [1],paroxetine [MOD, 17.4 mg] [3], sertra line[MOD, 56 mgJ [5], SSRI mon otherapyfollowed by SSRI + bupropio n [2], andSSRI + bupropi on [1]); no exposure(n = 17)Exposure (late pregnan cy) to cita lop ram(MOD, 20 mg) (n = 4), fluoxetine (MOD,20 mg) (n = 15), paroxetine (MOD,20 mg) (n = 8), a nd se rtra line (MOD,75 mg) (n = 11)Main study: depression with exposure(1st trimester to delivery) to SSRls(n = 1451); depression with no exposure(n = 14,234); no depression, no exposure(n = 92,192)Propensity sco re- matched study:depression with exposure (1st trimeste rto delivery) to SSRls (n = 817);depression with no exposure (n = 805)Expos ure (3rd trimeste r to delivery) toSSRI+ venlafaxine (n = 76), cita lo pram(n = 6), fluoxetin e (n = 10), fluvoxamine(n = 2), paroxetine (n = 46), sertra line(n = 3), and venlafaxine (n = 9) ; noexpos ure (unmatched) (n = 90)

Expos ure (early pregnan cy to delivery)to ant ide pressant s (n = 84) (SRls [42],TCAs [37], others [5]); no exposure(n = 168)

Main FindingsRisk of respirato ry distress: RR = 2.0 (95% CI,1.4-2 .8); risk of low Apgar sco re: RR = 2.4(95% CI, 1.3- 4.2); risk of convulsions: RR =4 1 (95%CI, 1.5-10.9)Difference in measures of neurobehavioraldevelopment, exposed vs no expos uretremulousness: +29%P = 0.08); motor activity:+49 P = 016) ; no. of different behavio ra lsta tes: - 32% P = 0.02); no. of changes inbehavioral states: -57% P = 0.01); no. ofbouts of act ive sleep: -49% P < 0.001);no. of sta rtles: +49% P = 0.26)Incidence of admission to special-care nurseryin exposed infants: 10.5%(statistical ana lysisnot provided)

Main stu dy- difference in incidence ofhospital stay >3 d, exposed vs nonexposedinfants: 5.0% P < 0.001); difference inincidence of respirato ry dist ress, exposed vsnon expo sed infa nts: 6.3% P < 0.001)Prop ensity score-matched study- differencein incidence of respirator y dist ress,exposed vs non exposed infa nts: 4.4%P = 0.006)Incidence of all neo nata l behavioral signs:77.6% exposed vs 411% no exposure P


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M. Tuccori et al.

Tab le V (co nt inued).Authors/D escription

Suri et a l92Prospective natura listics tudy, United St ates

Bou cher et a l93Ret rosp ect ive co ho rtstudy, Cana da

Jordan et a l94Ret rosp ect ive co ho rts tudy, United Sta tes

Co mpa rato rs

Group 1: major dep ressive disord ertreated with ant ide pressants , mainlySSRls (n = 49; 40 in 1st tr imester)

Gr oup 2 : majo r dep ressive disorder nottreated with ant ide pressants o r wit hlimited antidepressant exposure (n = 22)

Gr oup 3: s ubjects with out depression(n = 19)Exposure ( la te pregnan cy) toa ntide pressants , mainly SSRls (n = 73);no exposu re (n = 73)

Exposure (last month to delivery) toSRls (n = 49) (cita lopram [33], sertra line[11], venlafaxine [3], escita lopram [2]) ;no exposu re (n = 59)

Main Findings

Spec ia l-care nursery adm ission : 26.7% gro up1,1 7.1% group 2, 7.1% group 3 P = 0.36)

Increase in risk , exposed vs no exposurealte ra t io n in a lert ness: OR = 37 (95% CI,8- 174); altered muscu lar to ne: OR = 20(95% CI, 5-71); feedin g and gast rointestinalprob lems : OR = 3.8 (95% CI, 1.7-8.1);ta chyp nea : OR = 2.5 (95% CI, 11-5 .3)

No. o f infan ts with neuro logic prob lems: 8/ 73exposed vs 0/73 non exposed P< 0.00 6)

Neonatal behavioral syndro me (anyco mpo nent), exposed vs non exposed : 28% vs17%, resp ectively; neu rologic events: 20% vs12%; respira to ry even ts: 7%vs 7%;gastrointest ina l events: 6% vs 8% (all, P = NS)

MDD - median daily dose; RR- relative risk; SNRls - serotonin- norepinephrine reuptake inhibitors; NRls - norepinephrine reuptake inhibitors; NaSSAs = noradrenergic and specific serotonergic antidepressa nts; TeAs = tr icyclic ant idepressants; AOR = adjusted odds ratio; SRls = serotonin reuptake inhibitors ;OR = odds ratio.

infants born to depressed mothers who had not beenexposed to SSRIs was similar to that in infants bornto depressed mothers who were exposed to SSRIs,with the exception of respiratory distress (differencein incidence, 4.4%; P = 0.006). Thus, it appeared thatprevious studies had not controlled for the severity ofdepression and that the use of SSRIs during pregnancymay no t be associated with an increased ri sk for neonatal behavioral syndrome.

In a subsequent study, Oberlander et a195 used thepropensity score approach to assess whether lategestational exposure to SRIs (n = 1925) was associated with an increased r isk of adve rse neonatal outcomes compared with early exposure (n = 1575). Lateversus early exposure was associated with significantrisks of lower birth weight, respiratory distress, andgestational age


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of 5-HT at presynaptic sites,96 all increase centralsynaptic 5-HT concentrations' and can cross theplacenta, ? potentially inhibiting 5-HT reuptake in thedeveloping fetus. During gestation, 5-HT regulatescardiovascular and respiratory function'f and circadian rhythm, ? and acts as a trophic signal regulat ingthe development of serotonergic and other monoaminergic pathways in the brain. 1 Moreover, in animalmodels, 5-HT was found to playa direct role in thedevelopment of pulmonary artery smooth muscle inthe fetal lung and the pathogenesis of pulmonary hypertension.l'' Thus, alterations in levels of 5-HT during crucial periods of development might impair respiratory maturation or adaptation to the extrauterineenvironment, leading to neonatal respiratory distressand behavioral alterations.

Oberlander et a185 analyzed 2 groups of infants7 with symptoms of transient poor neonatal adaptation and 9 without such symptoms-whose mothershad similar mean (SD) levels of exposure to paroxetineduring pregnancy (22.5 [10.3] and 17.9 [7.6] mg/d,respectively) and at delivery (22.5 [10.3] and 20.0[7.7] mg/d). Paroxetine concentrations were significantly higher in paroxetine-exposed infants with symptoms compared with those without symptoms (30.6[15.2] vs 14.9 [15.6] ng/mL, respectively), at delivery(33.3 [31.3] vs 9.1 [8.6] ng/mL) and on day 2 of life(7.0 [5.3] vs 1.5 [1.6] ng/mL) (all, P < 0.05).

In summary, the available evidence supports an association between the use of several ant idepressantsduring the third trimester of pregnancy and symptomsof neonatal behavioral syndrome. However, most ofthe evidence concerns SSRIs and, to a lesser extent,venlataxine. There is a need for additional studies evaluating the risk of this syndrome with duloxetine, reboxetine, and rnirtazapine, for which only weak evidence is available.OTHER ADVERSE EVENTSPersistent Pulmonary Hypertension

Persistent pulmonary hypertension of the newborn(PPHN) is a rare and potentially fatal condition thatoccurs in an estimated 1 or 2 infants per 1000 livebirths. 102.103 The hypothesis that maternal use of SSRIs,particularly fluoxetine, in late pregnancy may be a riskfactor for PPHN arose from a cohort study in which2 of 73 infants (2.7%) exposed to fluoxetine in thethird trimester developed the condition, compared withan expected frequency in the general population rang-

446

ing from 0.07% to 0.1 %.20 The potential mechanismfor this adverse effect remains undetermined, althoughit may involve a direct action of SSRIs in the lungs. Inparticular, it has been suggested that high circulatinglevels of 5-HT in the fetus and accumulation of 5-HTin the fetal lungs may lead to vasoconstrict ion of pulmonary vessels or to proliferation of pulmonarysmooth muscle, with consequent increases in pulmonary vascular resistance.l' Consistent with this hypothesis, a ra t study found that after in utero exposureto low concentrations of fluoxetine (10 mg/kg/d), therate of proliferation of pulmonary arterial smooth muscle was significantly increased in fetal cells (P < 0.01),but not adult cells. 1 5 Another potential mechanismmight involve the inhibitory effect of SSRIs on thesynthesis of nitric oxide, a potent vasodilator that playsa role in the regulat ion of vascular tone and reactivity,both in utero and during early postnatal life. 1 6

A case-control study (377 cases, 836 controls) ofrisk factors for PPHN, with a focus on exposure toNSAIDs and SSRIs after the twentieth week of gestation, found an association between maternal exposureto particular SSRIs (fluoxetine, paroxetine, and sertraline) during late pregnancy and the occurrence ofPPHN (AOR = 6.1; 95% CI, 2.2-16.8; P = 0.001).107In contrast, no association was found between the riskof PPHN and use of SSRIs (ci talopram, fluoxetine,paroxetine, and sertraline) before the twentieth weekof gestation (AOR = 0.3; 95% CI, 0.1-1.2) or the useof non-SSRI antidepressants (amitriptyline, imipramine,nortriptyline, bupropion, venlafaxine, and trazodone)throughout pregnancy (AOR = 0.8; 95% CI,0.2-2.7).

A retrospective evaluation of data from the Swedish Medical Birth Registry (N = 831,324) found anassociation between maternal use of SSRIs in earlypregnancy (n = 7587) and PPHN in full-term infants(RR = 2.4; 95% CI, 1.2-4.3).108 A subgroup analysisthat included only data f rom mothers taking SSRIsduring late gestation (n = 2350) indicated an increasein the risk for development of PPHN (RR = 3.6; 95%CI, 1.2-8.3). Andrade et aP09 conducted a retrospective cohort study of US hospital registry data involving 1104 infants exposed to SSRIs dur ing the thirdtrimester of pregnancy and 1104 control infants withno exposure to antidepressants during gestation. Only5 cases of PPHN were identif ied in the entire cohort,with no difference in prevalence between cases (2.14per 1000 births; 95% CI, 0.26-7.74) and controls(2.72 per 1000 births; 95% CI, 0.56-7.93). A retro-



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spective cohort analysis of pregnancy records fromthe Mayo Clinic (N = 25,214) found no cases ofPPHN in the group that used SSRIs or venlataxine atany point during pregnancy (n = 808), whereas therewere 16 cases of PPHN in the group that had no exposure to SSRIs or venlataxine (n = 24,406) (no statistical analysis provided)Y

Although it is important to acknowledge the limitations (retrospect ive design, potential for inaccuraterecall or recall bias) of the case-control study byChambers et al,107 the high OR for development ofPPHN in that study was confirmed, at least in part, bythe findings of Killen and Olausson.l- Furthermore,given its small sample size and difficulty of determining past recorded cases of PPHN, the s tudy by Andrade et a1 1 9 neither rules out nor minimizes the risk.The findings of Wichman et al27 may also have beenaffected by methodologic limitations, predominantlythe retrospective design, which made it difficult toretrieve information on exposure to potential teratogens in both s tudy groups. Nonetheless , even if anassociat ion between SSRI intake dur ing pregnancyand development of PPHN were eventually confirmed,the absolute risk would not be substantially differentfrom that observed in the general populat ion. Addit ional evidence is needed to determine the true risk ofPPHN associated with SSRI use during pregnancy.Effects on Neurobehavioral Development

Five studies were identified that evaluated longterm developmental effects after exposure to SSRIsand other serotonergic/noradrenergic antidepressantsduring pregnancy.17,59,110- 112 Nulrnan et all 7 compared cognitive, language, and behavioral development in infants whose mothers had used fluoxetine(n = 55) or TCAs (n = 80) during pregnancy and acontrol group of infants born to 84 women who hadbeen exposed to nonteratogens (ie, acetaminophen,oral penicillins, and dental radiography). At the age of16 to 86 months, exposed children did not differ significantly from unexposed controls in terms of cognitive, language, or behavioral development , as measured on the Bailey Mental Development Index (riskdifference = 2.1; 95% CI, -5.0 to 9.2).

Nulman et all 1 used several scales to assess neurologic development in infants (age range, 15-71 months)born to mother s exposed to fluoxetine (n = 40) orTCAs (n = 46) during pregnancy compared with infants born to 36 nondepressed women with no expo-

9

M. Tuccori et al.

sure to these drugs. There were no significant differences between either group of exposed children andcontrols in mean IQ scores (obtained using the BaileyMental Development Index or the McCarthy Scales ofChildren's Abilities) or mean scores for temperament,behavior, reactivity, or mood (obtained using theReynell Developmental Language Scales and the ChildBehavior Checklist).

Oberlander et all 11 prospectively evaluated externalizing behaviors in -l-year-old children with prolongedprenatal exposure (mean [SD], 181.5 [75.0] days) toSSRIs (n = 22) compared with nonexposed controls(n = 14). The main study measures included maternalmood, duration of SSRI exposure, drug levels in umbilical cord blood, history of poor neonatal adaptation, and direct observation of attention, activity, andimpulsiveness. No significant differences were foundbetween groups. Significant predictors of externalizing behavior at 4 years of age were maternal mood atthe time of observation (measured using the HamiltonRating Scale for Depression, the Hamilton AnxietyScale, and a symptom questionnaire) and parenta lstress at the time of observat ion (measured using theParenting Stress Index) (both, P < 0.05), regardless ofmaternal mood before delivery or SSRI treatment during pregnancy. In contrast, Casper et a159 found thatmaternal exposure to SSRIs (fluoxetine, sertraline,paroxetine, and fluvoxamine) (n = 31) was associatedwith lower scores on the psychomotor and behavioraldevelopment subscales of the Bayley Scales of InfantDevelopment at 6 to 40 months compared with infants born to unt reated depressed mothers (n = 13)(Mental Development Index: 94.3 and 91.0, respectively [P = NS]; Psychomotor Development Index:98.2 vs 90.0 [P = 0.03]; Behavioral Rating Scale: 89.5vs 76.0 [P = 0.04]). Drug-specific evaluations wereno t performed, probably because of the small samplesize.

Mortensen et al 112 performed a follow-up analysisusing data from a regional prescription registry inDenmark and identified 340 children born to womenwith prescriptions for CNS drugs, including 50 bornto women with prescriptions for unspecified antidepressants. This cohort was compared with a randomlyselected control population of 755 children born towomen who were pregnant during the same periodbut had no prescript ions for CNS drugs. The BOELtest was performed when children were 7 to 10 monthsold. Abnormal scores on this test were recorded in

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16% (n = 8) of children exposed to antidepressantsand 4% (n = 31) of the control population; the AORfor abnormal BOEL scores in children exposed toantidepressants was 5.9 (95% CI, 1.1-31.0).Althoughthis study had l imitat ions (eg, testing of a select groupof chi ldren, possible role of the mother's underlyingdisease, lack of information on postnatal medical andsocial factors), it raised concerns that should be addressed in well-designed studies.Bleeding Complications

Because bleeding may be associated with the use ofSRIs,l13 a variety of blood-related clinical conditionshave been investigated in infants born to mothers receiving serotonergic antidepressants during pregnancy.Intracranial hemorrhage is regarded as an uncommoncondition, at least in newborns who are no t extremelyprernature.U Predisposing factors for intracranialhemorrhage in newborns include preterm delivery,respiratory distress syndrome, hypoxic injuries, reperfusion damage, increased or decreased cerebral bloodflow, and large fetal head size in relation to the maternal pelvic outlet. 114

There have been 4 case reports describing neonatalsubarachnoid and/or intraventricular hemorrhage after exposure to SSRIs in late pregnancy.llS-11S Threeof the mothers received paroxetine and 1 receivedfluoxetine. However, intracranial hemorrhage represents a possible complication of delivery.U and therefore the causal relationship between these adverseevents and drug exposure remains uncertain.

Maayan-Metzger et al 120 evaluated platelet function in 27 infants born to mothers who had beentreated with SSRIs (paroxetine, fluoxetine, or citalopram) f rom the last month of gestation to deliverycompared with 27 nonexposed controls. No correlat ion was found between SSRI exposure in newbornsor mothers and 2 indexes of p latelet funct ion, themean (SD) surface coverage (10.44% [3.7%] exposed,9.34% [3.3%] unexposed) and mean size of plateletaggregates (27.9 [9] and 23.9 [6] urn , respectively).The authors concluded that maternal treatment withSSRIs did no t impair whole-blood platelet function inthese healthy full-term newborns.

More recently, in a population-based, nested casecontrol s tudy f rom Ontario, Salkeld et al 121 examined whether use of SSRIs in late pregnancy was associated with an increased risk of hemorrhagiccomplications compared with use of non-SSRI anti-

448

depressants (2460 cases of postpartum bleeding complications and 23,943 matched controls). The AORfor the association between postpartum hemorrhageand exposure to SSRIs within 90 days before deliverywas 1.30 (95% CI, 0.98-1.72), compared with anAOR of 1.12 for exposure to non-SSRI medications(95% CI, 0.62-2.01), indicating lack of statist icalsignificance to support the study hypothesis.QTc lnterval Prolongation

Of the SSRIs, f luoxet ine has been suspected of inducing torsades de pointes in humans,l22 whereascitaloprarn appears to have the potential to alter cardiac repolarization.L'v Following publication of a report of QTc-interval prolongation in a newborn afterin utero exposure to fluoxetine.P a retrospective cohort study assessed the proarrhythmic potential ofSRIs (paroxetine, citaloprarn, fluoxetine, fluvoxamine,and venlafaxine) in 52 exposed newborns comparedwith 52 unexposed controls matched by gestationalage. 12SThe newborns exposed to antidepressants hada longer mean (SD) QTc interval compared with unexposed controls (409 [42] vs 392 [29] msec, respectively; P = 0.02), bu t there were no cases of arrhythmia. Although this study did no t include drug-specificevaluations or measurement of serum electrolytes, itsfindings sparked debate about possible alterations incardiac electrophysiology associated with gestationaluse of the studied antidepressants. Therefore, furtherwell-designed studies are warranted to investigatethese preliminary observations, establish their clinicalrelevance, and assess whether specific drugs may carrya major risk compared with other drugs of the sameclass.DISCUSSIONComplications have been reported in newborns after maternal use of SSRIs and other serotonergidnoradrenergicantidepressants during pregnancy. Risks of major malformations, particularly cardiac malformations, haveemerged in regard to paroxetine. However, the causalrelationship between exposure to antidepressants andthese adverse events is subject to debate, and the conflicting findings of the available studies make it difficul t to quantify the risk. The teratogenic potential ofparoxetine is unlikely to represent a class effect ofSSRIs, although the results of recent studies suggestthat other drugs in this class should be used with caution. Therefore, some regulatory agencies and scientific



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societies advise cautious use or avoidance of paroxetinefor the treatment of depression during pregnancy.55-57

Several studies found a moderately increased risk formiscarriage with the use of SSRIsand other serotonergic/nor adrenergic antidepressants. However, studies of fetalsurvival on a week-by-week basis are warranted tofurther assess the extent of this risk.

In utero exposure to SSRIs from the last tr imesterto delivery has been associated with a self-limitingneonatal behavioral syndrome. The apparent increasein this syndrome may reflect a grea te r frequency ofgestational SSRI use, although this remains to be determined. All infants with neonatal behavioral syndrome should be monitored carefully in the first daysof life for the clinical evolution of specific symptoms.Better understanding of the pharmacodynamics andpharmacokinetics of SSRIs and potential withdrawalconsequences is necessary, and there is a need for further research focusing on the safety of SSRI use duringthe last trimester of pregnancy.

The potential for SSRI exposure to induce alterations in neurobehavioral development remains undefined, and further invest igat ions are required. Evidence supporting the risk of bleeding complicat ions(eg, intracranial hemorrhage) in association with useof SSRIs and other serotonergic/noradrenergic antidepressants during pregnancy is inconsistent. The possibility of QT c-interval prolongation in newborns exposed to SRIs in late pregnancy requires further study.

Most available data on the use of antidepressantsduring pregnancy involve SSRIs, with limited information on other antidepressants. Therefore, there is aneed for more data on the safety of gestational use ofnewer antidepressants such as escitalopram, rnirtazapine, and venlataxine. In addit ion, there is a need forsubstantial improvement in the methodology used toanalyze antidepressant safety in pregnant women, aswell as to assess a drug's teratogenic potential. Forexample, the potential contribution of the severity ofdepression to neonatal outcomes cannot be overlooked.Use of propens ity score matching, as in the study byOberlander et al,89 represents a potentially useful approach to this matter.

This review has some limitations. Articles were no tselected for review using quali ty-based assessment,which may have led to possible overest

safety of ssri's in pregnancy

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