Clinical Therapeutics/Volume 31, Theme Issue, 2009

Safety Concerns Associated With the Use of Serotonin Reuptake Inhibitors and Other Serotonergic/Noradrenergic Antidepressants During Pregnancy: A Review
Marco 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; and Mario Del Tacca, MD1,2

Department of Internal Medicine) University of Pisa, Pisa, Italy; 2Tuscan Regional Centre for Pharmacovigilance, Florence) Italy; and 3 University Hospital ofPisa) Pisa, Italy
1Division

of Pharmacology and Chemotherapy,

ABSTRACT Background: There is ongoing debate about the safety of selective serotonin reuptake inhibitors (SSRIs) and other serotonergiclnoradrenergic antidepressants when used during pregnancy. Objective: This article reviews the available literature on the main safety concerns associated with the use of SSRIs and other serotonergiclnoradrenergic antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants) during pregnancy. Methods: English-language reports of analytical and descriptive studies, including case reports, case series, 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, particularly cardiac defects, when used during pregnancy. Significant associations between maternal exposure to SSRIs and both persistent pulmonary hypertension of the newborn and a self-limiting neonatal behavioral syndrome have been reported in a number of recent original studies and meta-analyses. Some studies have suggested a relationship between the use of SSRIs or other serotonergiclnoradrenergic antidepressants and the occurrence of miscarriage, although these studies
1426

had methodologic limitations that affected the strength of the data. Evidence for a possible association between in utero exposure to SSRIs or other serotonergicl noradrenergic antidepressants and alterations in neurobehavioral development, bleeding, and QTc-interval prolongation is currently weak. Conclusion: The available evidence suggests that SSRIs and other serotonergiclnoradrenergic antidepressants should be used with caution during pregnancy, with careful follow-up of infants exposed to these agents in utero. (Clin Ther. 2009;31 [Theme Issue]:1426-1453) 2009 Excerpta Medica Inc. Key words: pregnancy, infant, antidepressants, SSRIs, malformations.

INTRODUCTION Depression and other mood disorders are common during pregnancy, with an estimated prevalence ranging from 9% to 16%.1.2 Depression may be associated with an increased risk of preterm delivery, low birth weight, operative delivery, and admission of the newborn to the neonatal intensive care unit.v-" Antidepressant treatment would appear to be an option for these women, although ensuring its safety for both the mother and fetus may represent a challenge. American Academy of Pediatrics guidelines for the use of psychotropic drugs in pregnancy recommend use of the lowest dose that provides adequate control of depresAccepted for publtcation May 8, 2009 dotl 0.1 016/J.c1lnthera.2009.07.009 0149-2918/$ - see front matter

2009 Excerpta Medica Inc. All rights reserved.

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M. Tuccori et al.

sion.> In an observational study from the Netherlands in a cohort of 29,005 pregnant women, 2 % of the sample received antidepressants during the first trimester of pregnancy, and ~ 1.8 % did so in the second and third trimesters.f Almost 60% of women who used antidepressants before pregnancy discontinued these drugs in the first trimester, and 11 % stopped thereafter. Among women using antidepressants during pregnancy, one third started the medication during gestation. Paroxetine and fluoxetine were the most frequently used antidepressants (48% and 12%, respectively). A recently published study from the Netherlands reported that the duration of selective serotonin reuptake inhibitor (SSRI) use and total defined daily doses (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 vs 67.5 [P = 0.009]).7 In a study employing a database of all 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 the period before pregnancy (P = 0.01). Although these data reflect specific populations, rates of antidepressant use during pregnancy would be expected to be similar in other Western countries. An increasing number of antidepressants have become available for clinical use, most of them acting through blocking the reuptake of serotonin (5-hydroxytryptamine [5-HT]). Based on their specificity, serotonin reuptake inhibitors (SRIs) can be classified as SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs). The available SSRIs are fluoxetine, paroxetine, fluvoxamine, sertraline, citaloprarn, and escitalopram, and the SNRIs are venlataxine and duloxetine. Use of the noradrenergic and specific serotonergic antidepressants (NaSSAs) and norepinephrine reuptake inhibitors (NRIs) has increased in recent years. Mirtazapine is the only available NaSSA and reboxetine the only available NRI. Reviews of data on the safety of antidepressant use during pregnancy are continually being published.t-l'' The aim of the present article was to review recent evidence concerning the safety of treatment with SSRIs, SNRIs, NaSSAs, and NRIs during pregnancy.
2009

METHODS The English-language literature indexed on MEDLINE, EMBASE, and PsycINFO was searched from 1966 through April 2009 using the terms fluoxetine, 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. The reference lists of identified articles were examined for additional pertinent publications. For inclusion in the review, original observational studies (controlled and uncontrolled, prospective and retrospective) and meta-analyses had to evaluate neonatal or maternal outcomes after exposure to SSRIs or other serotonergic/noradrenergic antidepressants during pregnancy and report 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 rating scales), 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 for inclusion. Abstracts presented at national and international meetings were not included. Because there is no standard clinical definition of neonatal behavioral syndrome, case reports dealing with neonatal behavioral alterations after in utero exposure to antidepressants were used to generate clusters 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 behavioral syndrome (including single behavioral signs, poor neonatal adaptation, and admission to a special-care nursery). TERATOGENIC RISK CLASSIFICATION Several systems have been proposed for classifying the teratogenic risks of medications, some of which are limited by a failure to specify the doses and/or durations of gestational exposure that may be associated with teratogenic risk, making them difficult for clinicians to interpret and use in counseling patients.I! Among the major systems of teratogenic risk classification are those of the US Food and Drug Adrninistra1427

Clinical Therapeutics

tion (FDA), the Australian Drug Evaluation Committee (ADEC), and the Swedish Catalogue of Approved Drugs (FASS). In these systems, teratogenic risk is categorized from class A (drugs regarded as safe for use during pregnancy) to class D or X (drugs associated with a risk of major malformation when taken during pregnancy). Overall, these 3 regulatory agencies suggest a cautious approach to the use of SRIs and

other serotonergic/noradrenergic antidepressantsparticularly paroxetine (FDA, ADEC, FASS) and rnirtazapine (ADEC, FASS)-during pregnancy. In the majority of cases, this recommendation is based on a lack of data or conflicting study findings. The teratogenic risk classifications for the available SSRIs, SNRIs, NaSSAs, and NRIs are summarized in Table I.

Tab le I. Teratoge nic risk classification of selective serotonin reuptake inhibitors a nd other se rotonergic/ noradrenergic antidepressants. Drug Fluoxet ine Serr ral ine Paroxeti ne Fluvoxa mine Cita lo pra m Escita lop ram Yen lafa xine Mirraz a pin e Duloxetin e Re boxetin e FDA* C C D C C C C C C ADEet C C D C C C FASS*

83 83
C

82 83 81

81 83 83 83
C

83 83

So urce: Add is et a l.!' ., FDA ~ US Foo d a nd Drug Ad m inistratio n classificat ion. Ca te go ry C ~ eit he r stu d ies in a nima ls fo und adverse effec ts o n th e fetus a nd th er e were no co nt ro lled stu d ies in wo me n, or stu d ies in wo me n a nd a nima ls were not ava ilab le; dr ugs s ho uld be given o nly if th e po te ntia l benefit j ustifies t he potentia l risk to t he fetu s. Category D ~ t here is positive evide nce of hum an fetal risk, b ut t he benefits of t he use in pregn ant wo me n may be a cce ptable desp ite th e risk (eg, if t he d rug is need ed in a life-thr ea ten ing sit uatio n o r for a serio us disea se for w hich sa fer d ru gs ca nno t be used ). t AD EC - Austra lian Dru g Evalua t io n Co mm ittee classifi ca t ion. Ca tegory B - dru gs th at have bee n ta ken by o nly a limited num ber of pregn ant wo me n a nd wo me n ofchild be a ring age wit ho ut a n increase in t he frequ en cy of mal forma t io n o r ot her direct o r ind irect harm ful effect s o n th e fetu s. As th ere is lim ited expe rience wit h th e effect s of th ese d rugs in hum an s, resul t s of to xico logic stu dies to da te a re ca te go rized as fo llows: B1 ~ stu d ies in a nima ls have not sho w n evidenc e of a n increase d o ccurrence offeta l dam a ge; B2 - stu d ies in a nima ls are ina deq ua te a nd may be lackin g, bu t avai lab le d ata show no evidence of a n increas ed o ccurrence of fetal dam age, t he significa nce o f w hich is co nsidered uncertain in huma ns; a nd B3 = stu d ies in a nima ls have s how n evide nce of a n increased occurre nce of feta l dam age, th e significa nce of which is co ns idere d un certain in humans. Ca tegory C - dru gs whose ph arm acologic effect s have ca used or may be sus pected of ca using harmful effect s o n t he hum an fetus o r new born wit ho ut ca us ing malformation s; t hes e effects may be rever sible. Ca tegory D = d ru gs t ha t have ca used , a re sus pecte d of ca us ing , or may be expe cted to ca use a n incr eased inciden ce of hum an feta l malformation s o r irreversib le dam age; t hese dr ugs may a lso have adverse ph a rm a col ogic effec ts. t FASS - Swedis h Ca ta log ue of Ap prov ed Drugs cla ssificat ion . Ca tego ry B - med icinal produ ct s th at ca n be a ssumed to have be en used in o nly a limited gro up of pregn an t wo me n a nd wo men of child be a ring age wit h no d istu rba nce o f th e repro du ctive pro cess ide nti fied so far. Beca us e th ere is limited experie nce wit h th e effect s of th ese med icinal prod ucts in hum an s, evidence of rep rodu ct ive toxicity in anim als is ca tego rized as follows: B1 - repro du ctive toxicity st udies ha ve no t found eviden ce of fet al da mage o r o t her deleter iou s effects o n t he re prod uct ive process; B2 = reprodu ctive to xicity stud ies a re inad eq uate o r lacking, b ut avai lab le d ata d o no t indica te a n increased inc ide nce offetal da mage or o ther delet erio us effects o n th e repr odu ct ive pro cess; a nd B3 = repr oduct ive toxicity stud ies in a nima ls have found an increase d inciden ce offeta l damage or o t her deleteriou s effects o n th e reproducti ve process, t he significa nce of w hich is co ns ide red un cer ta in in human s. Category C = medi cinal produ ct s wit h pharma co logic effect s that have ca use d or may be sus pected of ca using d istu rba nces in t he repro du ct ive pro cess t hat may involve risk to t he fetu s wit ho ut being directly teratogenic.

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RISK OF MAJOR MALFORMATIONS Major malformations are defined as structural or functional abnormalities that have substantial medical or social consequences, and usually require medical or surgical treatment. 12 Because serotonergic drugs have exhibited potential biological activity on developing embryos in animal studies, there may be an increased risk of birth defects in humans. 13,14 Early evaluations indicated that 5-HT is present in the oocyte, where it appears to function as a regulator of cell cleavage. Later, it plays an important role in gastrulation, with substantial areas of 5-HT uptake in the primitive streak. Subsequently, 5-HT uptake occurs in the floor plate of the developing neural tube in association with neurulation, and 5-HT has been found to facilitate cell migration and stimulate cell differentiation during formation of the neural crest and branchial arch. At the time of morphogenesis of craniofacial structures, 5-HT promotes dental development and may aid in cusp formation. 13,14 Most commonly prescribed antidepressants enhance 5-HT activity and could theoretically promote teratogenic effects through this mechanism. However, redundancy within the serotonergic system may allow receptor and uptake pathways to function normally even in the presence of abnormal levels of circulating 5-HT. In line with this concept, 5-HT-binding proteins, which are expressed in most craniofacial regions at critical times during development, may exert a buffering action that maintains adequate 5-HT tissue levels over a wide range of 5-HT serum concentrations. 15,16 The findings of investigations that assessed the risk of major malformations associated with exposure to SSRIs, SNRIs, NRIs, and NaSSAs during pregnancy are summarized in Table 11. 12,17--42 Some studies, particularly those conducted before 2000, found no evidence of a risk for major congenital malformations with SSRIs.12,17-28,35,37-3 9 A recent study by Einarson et a12 8 compared 928 pregnant women exposed to antidepressant medications (bupropion, citaloprarn, escitalopram, fluvoxamine, nefazodone, paroxetine, rnirtazapine, fluoxetine, trazodone, venlafaxine, and sertraline) during the first trimester of pregnancy with 928 pregnant women who were not exposed to known teratogens. The odds ratio (OR) for major malformations was 0.90 (95% CI, 0.50-1.61). However, this study did not estimate drug-specific ORs. A retrospective epidemiologic investigation of data from 2 US managed care databases conducted by the
2009

manufacturer of paroxetine found a higher risk of major malformation in paroxetine users (n = 704) compared with users of other antidepressants (n = 3547).43 Compared with infants born to women who received other antidepressants in the first trimester, 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). The findings of this study led US and Canadian regulatory agencies 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 to alterations in 5-HT concentrations, which were most pronounced when exposure began at day 9 of embryonic development, before cushion formation.w A recent study of behavioral abnormalities in mice found that prenatal exposure to fluoxetine, but not fluvoxamine, had a dose-dependent effect on the likelihood of affective disorders.i? Differences in the maternal-fetal pharmacokinetics of fluoxetine and fluvoxamine (ie, rate of placental crossing and distribution to fetal tissues) were hypothesized, suggesting that drug-specific pharrnacokinetic profiles may play a primary role in the teratogenic potential of SSRIs. Using the same databases as in a previously mentioned study,43 Cole et a12 9 analyzed data on paroxetine from 1020 infants born to 989 mothers who used paroxetirie monotherapy or combination therapy during the first trimester of pregnancy, including 815 infants born to 791 women who used rnonotherapy. The controls were 4936 infants born to 4767 mothers exposed to monotherapy or combination therapy with other antidepressants, including 4196 infants born to 4072 mothers exposed to monotherapy, The AOR for all congenital malformations was 1.89 for paroxetine monotherapy (95% CI, 1.20-2.98) and 1.76 for 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 a moderate risk of congenital malformation associated with first-trimester exposure to paroxetine compared with other antidepressants. Because these observations were inconsistent with the general perception of the safety profile of antidepressants (and of paroxetine in particular) when used during pregnancy, subsequent studies assessed
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Tab le II. Studi es of major ma lformations a nd oth er phy sical a b no r malitie s of th e newborn ass ociated with first-trimester exposur e to sel ective serotonin re uptake inhibit ors (SSR ls) and oth er seroton ergic/ noradrenergic antid epressants. Authors/Description (Data Source) Kulin et a J1 2 Prosp ectiv e co ho rt stu dy, Can ad a and United St a t es (T IS data) Nu lma n et a J1 7 Prosp ective co ho rt stud y, Can ad a (T IS data) McElhatton et a ilS Prospective case se ries, Europe and Israel (T IS data) Ericson et aJ1 9 Prosp ective co ho rt study, Swed en (NMR data) Chamb ers et a l20 Prospectiv e co ho rt stud y, Unit ed St ates (T IS data) Pastuszak et a l21 Prosp ect ive co ho rt study, Can ad a (T IS data) Active Drugs Fluvoxamine, paroxetin e, a nd se rt ra line (n = 267 )

Controls No expos ure to kno wn t erato gens (n = 267 )

Main Findin gs Inciden ce of major malforma t ion s: 4 .1 % fluvo xam ine, paroxet ine, and se rt ra line; 3.8% no expos u re (RR = 1.0 6; 95% CI, 0.4 3-2.62)

Fluo xetin e (n = 8 0), TCAs (n = 55 )

No expos ure to known t eratogen s (n = 84)

Inciden ce of major malforma t ion s: 3.63% fluoxetin e, 3.75% TCAs, 2.38% no exposu re (P = NS)

No n-TCAs (n = 416), TCAs (n = 33 0)

Non e

No . of majo r ma lform ati on s: 7 cases each, non -TCAs a nd TCAs

SSRls (n = 531 ), non-SSRls (n = 423), SSRls + non -SSRls (n = 15) Fluoxetine (n = 228)

All births in populati on

Congen ital an omalies (a ctual/expected cases): 39/ 34 .3 SSRls + non-SSRls, 21/ 18.7 SSRls, 18/15.7 non -SSRls (P = NS)

No expo sure to known t era toge ns (n = 254)

Inciden ce of majo r ma lfo rmatio ns: 5% flu oxetin e, 4% no exposu re (P = 0.63 )

Fluo xetine (n = 128 ), TCAs (age match ed ) (n = 74)

No ex posure to known te ratoge ns, age match ed (n = 128)

Inciden ce of majo r malforma t ion s-t t est fo r pair ed data : 2.0% f1u oxetin e, 1.8% no exposu re (P = 0.38); an alysis of vari an ce: 3.4% f luoxet ine , 0% TCAs, 3 .0% no expo su re (P = 0.8) Inciden ce of major malformat ion s: 5%, co ns ide red to be within th e ran ge of histori cal rep orts (no stat ist ica l a na lysis provid ed ) Inciden ce of maj or malformat ion s: 0 .9% cita lopra m, 2.6% d isease-match ed gro u p (P = 0.64 ), 0.8 % no exposu re (P = 0.5 2)

Gold stein et a l22 Retrospective co ho rt stu d y, United St ates (CPR data) Sivojelezova et al 23 Prosp ectiv e co ho rt study, Can ad a (T IS data)

Fluoxetin e (n

796)

Data on newborns from th e Natio na l Hospital Discharge Sur vey Disea se-m a t ch ed g ro up (n = 132), no expos ure to known t er a to gen s (n = 132)

Citalopram (n

132)

(co nt inued)

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Tabl e II (co nt inue d) . Auth o rs/Descript ion (Data Source) l.enn est al and Kallen 24 Ret ros pect ive co ho rt stu dy, Swede n (NMR d a t a)
Act ive Drugs

Contro ls All delive ries in t he po pulat io n (n ~ 86 0,2 15), de liveries in moth ers using SSRls (n = 6481)30

Mai n Findi ngs Risk of malforma tion s- SNRl s/NRl s vs a ll de liveries: AOR = 0.85 (95% CI, 0.58 - 1.24) ; SSRls vs a ll de liveries: AOR = 0.89 (95% CI, 0.79-1 .07 )

Mian serin (n ~ 61); mirtazapin e (n ~ 145); venlafaxine (n ~ 505 ); reb oxetin e (n = 14); com bina tions of
rruan serin ,

mir ta zap ine, an d reb oxetin e w ith venlafaxine (n = 12)

Ma sch i et a l25 Pro sp ect ive co hort study, It aly (T IS data)

Anti depressants (n = 20 0, includ ing pa roxet ine [58 ], f luoxeti ne [32], an d a mitriptyline [26 ))

No exposure to known te ratoge ns (n = 120 0)

Inciden ce of major malforma t io ns: 0.5% a ntide pressa nts, 1.3% no expo sure
(P> 0 .05 )

Ra mos et a l26 Retros pect ive casecon tro l stu dy, Ca na da (NMR d a t a)

Birt h defects (n = 18 9)

No birth d efects (n = 214 0)

Expos ure to SSRls + othe r newe r a ntide pressa nts: 73 .9% Risk for major co ngeni ta l malforma t ions wit h 1st-t rimes te r exposure to an y a ntide pressant , by d uration of expos ure1-3 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 fo r major co nge nita l malforma t ion s wit h ex posure to any an tide pres sant, by t iming of exposure-l st t rimester: AOR = 1.10 (95% CI, 0.75-1.62); 2nd t rime ster: AOR = 1.13 (95% CI, 0.592.1 7); 3rd t rimester: AOR = 0.86 (95% CI, 0.4 5- 1.65)

W ichm an et a l27 Ret ros pect ive co hort stu dy, Unit ed States (hosp ita l reco rds)

SSRls: cita lopra m (n = 122), venlafaxine (n = 53), escitalopra m (n ~ 8), paro xeti ne (n = 134 ), flu o xet ine (n = 184), se rt ra line (n = 296), >1 SSRI

All reco rd ed de liveries in w hich t he mothe r had no t used SSRls (n ~ 25,2 14)

Inciden ce of co ngenita l heart defects : 0.4% SSRls, 0.8% no SSRls (P = 0.2 3)

(n

11 )
(contin ued)

2009

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Tabl e II (co nti nue d) . Auth ors/Descrip tion (Data Source) Eina rs o n e t a l2s Pro sp ectiv e co ho rt stu dy, Can ad a (T IS data) Active Drugs 1st-Trimeste r exposure to citalopra m (n = 184 ), ven lafa xine (n = 154), paroxetin e (n = 148), bupropi on (n = 113), mirt a zapine (n = 68), f luo xetine (n = 61), se rt ra line (n = 61), f luvoxa mine (n = 52), nefazodone (n = 49), escitalo pra m (n = 21), and trazod one (n = 17) Paroxetin e monoth er apy (n = 791) or mon oth erapy/ co mb ina t io n th erapy (n = 989 )

Con t ro ls Ma tch ed co nt ro ls with no expos ure t o kno wn t eratogen s (n = 928)

Main Find ings Risk of major ma lformations, a nt ide pressa nt s vs no exposure: OR = 0.90 (95% CI, 0.50 -1 .61)

Col e et a l29 Retrosp ective co ho rt stu dy, Un ited States (insu ra nce da tabase)

Oth er antidepress ant mon o th erapy (n = 4072) o r mon o th er a py/ co m bina t io n th erapy (n = 4767 )

Risk of a ll co nge nita l malformationsparoxetin e mon o th er apy vs o t her antidepressant monoth er ap y: AOR = 1.89 (95% CI, 1.20 -2 .98 ); paroxetin e mon oth erapy/ combinati on th er apy vs other antidepress ant mon otherapy/ co m bina t io n th er apy: AOR = 1.76 (95% CI, 1.18- 2.64) Risk of ca rdi ova sc u la r malformat ionsparoxetin e monotherapy vs oth er antidep ressant monotherapy: AOR = 1.46 (95% CI, 0.74 - 2.88) ; paroxetin e mon otherapy/combination th erapy vs other antidepressant monotherapy/ co m bina t io n th er apy: AOR = 1.68 (95% CI, 0.95 -2 .97) Risk of ma lformations-any SSRI: RR = 0.89 (95% CI, 0.79 -1 .07) ; f1uoxetin e: RR = 0.85 (95% CI, 0.61-1 .19); cit a lo pra m: RR = 0.94 (95% CI, 0.78 -1 .13); paro xetin e: RR = 1.03 (95% CI, 0.76 -1 .38) ; sertraline: RR = 0.78 (95% CI, 0.61-1.00); f luvoxam ine: RR = 0.50 (95% CI, 0.13-3 .80); escitalopra m: RR = 0.91 (95% CI, 0.1 9-2 .66) Risk of cystic kidn ey, SSRls vs all births: RR = 3.50 (95% CI, 1.60 -6.65 ) Risk of a ny ca rd iac ma lformation, paroxetin e vs all births: RR = 1.63 (95% CI, 1.05- 2.53) Risk of a ny ca rd iac defect , paro xetin e vs a ll birt hs: RR = 2.63 (95% CI, 1.40 -4.50 ) Ris k of atria l septa l d efects + ve nt ricular se pta l defects, paroxetin e vs a ll births: RR = 3.07 (95% CI, 1.32- 6.04 ) (continued)

Kal len a nd Otterbl ad

Olausson '?

SSRls (n

648 1)

All births in popu lation (n = 86 6,69 6)

Retrospectiv e co ho rt stud y, Swed en (NM R d a t a)

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Tabl e II (co nt inue d) . Aut hors/ Descripti on (Data So urce) Ber ar d et a l3 1 Retr os pect ive caseco nt ro l study, Ca nada (NMR data) Active Drugs Major malformation s (n = 101), includ ing ca rdiac malfor matio ns (n = 24)

Controls No majo r or minor malformation s (n = 1270)

Ma in Findi ngs Risk of ca rd iac malform ati on s- par oxetin e vs no n-SSRls: AOR = 1.38 (95% CI, 0.49 - 3.92 ); oth er SSRls vs no n-SSRls: AOR = 0.89 (95% CI, 0.28 - 2.84) 1st-Trimester exposure to paroxetine >25 mg/d vs non -SSRls-risk of majo r co nge nita l ma lformatio ns: AOR = 2.23 (95% CI , 1.1 94.17); risk of major ca rdiac malfor matio ns: AOR = 3 .07 (95% CI, 1.0 0- 9.42)

Lou ik et a J32 Retr os pect ive ca seco ntrol study, Canada an d United States (Slone Epide miology Center Birth Defects Study)

Birt h defects (n = 98 49)

No birt h d efects (n = 58 60 )

Ris k of omp ha locele-sertra line: AOR = 5.7 (95% CI, 1.6 -20.7) Risk of ca rd iac septa l d efects-ser trali ne: AOR = 2.0 (95% CI, 1.2- 4 .0) Ris k of right vent ricular o utflow t ra ct o bst ructio n defect s-SSRl s: AOR = 2.0 (95% CI, 1.1 - 3.6); pa roxeti ne: AOR = 3.3 (95% CI, 1.3- 8 .8)

Alwa n et a l33 Ret ros pect ive ca secontro l stu dy, United States (Nat ional Birth Defects Preventio n St udy )

Birt h defe ct s

(n = 9622)

No birt h d efects (n = 4092)

Risk of major birt h defec ts wit h SSRlsa nence pha ly: AOR = 2.4 (95% CI, 1.1 -5 .1 ); craniosynostosis: AOR = 2.4 (95% CI , 1.5- 4.0); omphalocele: AOR = 2.8 (95% CI, 1.3-5 .7) Risk of majo r birth defects with f1 uoxet inecra niosy nostosis (10 exposed infants): AOR = 2.8 (95% CI, 1.3 - 6.1 ) Risk of majo r birt h defects with sertralineanencephaly(4 exposed infants): AOR = 3.2 (95%CI, 1.1 -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 o bst ruct ion (7 exposed infan ts): AOR = 2.5 (95% CI, 1.0- 6.0); om phalocele (6 expo sed infan ts): AOR = 8 .1 (95% CI, 3.1 -20.8); gastroschisis (5 exposed infants): AOR = 2.9 (95% CI, 1.0- 8 .4) No significa nt risk of oth er co ngenita l a no ma lies o r co nge nita l hea rt defects (continued)

2009

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Clinical Therapeutics

Tabl e II (co nti nue d) . Auth ors/Descrip tion (Data Source) Davis et aJ34 Retrosp ective co ho rt stud y, Unit ed St ates (insu ra nce da t abase) Active Drugs SSRls (n = 1047), TCAs (n = 221 ), o th er a ntide pressa nts (n = 173)

Con t ro ls No exposure to a nt ide pressa nts (n = 49,654)

Main Find ings Risk of mal for ma tion s, SSRls vs no expos ure: RR = 0.97 (95% CI, 0.81-1 .1 6) Risk of conge nita l a bno rma lit ies of t he eye, paroxetin e vs no exposure: RR = 2.36 (95% CI, 1.20-4.6 6) Ris k of co nge nita l a bno rma lit ies of t he heart, paroxetine vs no exposure: RR = 1.98 (95% CI, 0.64 - 6.15) Risk of co ngenita l heart defects-SRls/B DZs vs no expos ure: ARD = 1.1 8 (95% CI, 0.182.18); citalopram vs no exposure: ARD = 2.28 (95% CI, 0.19-4.36) Risk of a t ria l septa l d efect s-SRls vs no exposu re: ARD = 0.21 (95% CI, 0.05 -0.36) Risk of maj or co nge nita l an omali esf1uoxetine/BDZs vs no exposure: ARD = 5.18 (95% CI, 0.30 -10.07) Incide nce of major abnormalities (including elective termination of pregn an cy due to potential ab normalities): 5.2% paroxet ine, 6.3% f1uoxetine, 2.9% no exposure (P < 0.05) Risk of ca rdiova sc u la r a b no rma litiesparoxetine: AOR = 2.66 (95% CI, 0.80- 8.90); f1uoxetine: AOR = 4 .47 (95% CI, 1.31-15.27) Incidence of major malformations (expect ed baseline ra t e, 1%-3%): 1.6% venlafaxine, 2.4% SSRls , 0.7 % no expo sure (P = 0.89 )

Ob erlander et a J35 Retrosp ec tive co ho rt stu dy, Can ad a (NMR d a t a)

SRls (n = 26 25), BDZs(n = 968), SRls+ BDZs (n = 359)

No expo sure to known t eratogens (n = 107,320)

Diav-Cit rin et a J36 Prosp ective co ho rt stu dy, Germany, Israel , a nd Italy (T IS data)

Fluoxetine (n = 314 ), paroxetin e (n = 410)

No ex po sure to known ter atogens (n = 1467 )

Einarson et a l37 Prospectiv e co ho rt stud y, Canad a a nd United St ates (T IS data) Djulus et a l38 Prosp ective co ho rt study, Austral ia , Can ada , Israe l, It aly, and Unit ed Stat es (T IS data) Simon et a J39 Retrospectiv e co ho rt stu d y, United St ates (insuran ce databases)

Venlafaxine (n = 150), SSRls (n = 150 )

No expo sure to known teratogens (n = 150)

Mirtazapin e (n = 104), ot her antid epressants (n = 104)

No expo sure to known teratogens (n = 104)

Incidence of major ma lformat ions (expect ed baseline rate, 1%-3%): 1.9% mirtazapin e (95% CI, 0.5-2.7), 1.0% other antidepressants (95% CI, 0.2-2.7), 1.9% no exposure (95% CI, 0.5 - 3.6) Risk of major ma lform ation s, SSRls vs no exposure: OR = 1.36 (95% CI, 0.5 6- 3 .30)

SSRls (n TCAs (n

= =

185), 209)

Match ed co ho rt with no SSRI expos ure (n = 185 ), match ed co ho rt wit h no TCA expos ure (n = 209)

(continued )

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M. Tuccori et al.

Table II (co ntin ued). Auth o rs/D esc ript ion (Data Source) Maim et a l4 0 Ret ro s pective co hort study, Finland (N M R d a t a)
~1

Acti ve Drugs SS RI purch a se during pr eg nan c y (n = 178 2), ~ 1 SS RI purch a se in 1st t rimes te r (n = 1398), ~ 1 SS RI purch a se in 2 nd t rimeste r (n = 54 8 ), ~ 1 SSRI pu rc hase in 3 rd t rimes te r (n = 59 7) , ~ 1 SSRI purch a se in eac h t rimeste r (n = 229) Paroxet ine unpublish ed co ho rt (n = 1174), paroxetin e histori cal co ho rt (n = 206 1)

Co nt ro ls Ma tch ed pregn ant contro ls w ith no reim bursed dru g purch a ses (n = 178 2)

Main Find ings Incid en ce o f major mal form a tions: 4. 2% SS RI purch a se in a ny peri o d , 3 .5% no purch a se (P = 0.6) Risk o f maj or ma lform ations w it h I sttrimester purch a se- all SSRls: AOR = 1.0 (95% CI, 0.6-1.7); citalopra m (n = 554): AOR = 0.4 (95% CI, 0 .1-1.4); flu o xet ine (n = 525 ): AOR = 1.7 (95% CI, 0 .9 - 3 .3); paroxetin e (n = 152): AOR = 0.4 (95 % CI, 0.1-3 .3) ; se rt ra line (n = 118): AOR = 0 .7 (95% CI, 0 .1- 5 .3); f luvoxa m ine (n = 65) : AOR = 1.0 (9 5% CI, 0 .1-7.8 ) Incid en ce o f card iac malform ation s, paroxetin e (u n pub lished + historica l co ho rts) vs no ex posure: 1.2% (O R = 1.7; 95% CI, 1.1- 2 .1) Risk o f card iac malform ation s, paro xetine (u n pu b lished co ho rt) vs no expo s u re : O R = 1.1 (9 5% CI, 0 .3 6 - 2 .78 ) Risk o f co nge nita l malformation s- SSRI prescription s from 1 mo befo re co nce ptio n to e nd of 1st trim ester : ARR = 1.3 4 (95% CI, 1.00-1.79); SSRI prescrip tions in 2nd o r 3 rd mo: ARR = 1.84 (95% CI, 1.25 2.71)

Eina rso n et a l4 1 Retro sp ective co hort stu dy, Au strali a a nd Ca nada (T IS d a t a)

No ex pos ure to know n te ratoge ns (n = 33 79)

Wo geliu s et a l42 Co ho rt study, De nm ar k (N M R d a t a)

SS RI pr escripti on s fro m 1 mo befo re co nce ptio n to e nd of 1st trim ester (n = 1051 ), SSRI prescrip tions in 2nd o r 3 rd mo (n = 4 53)

Non -SSRI prescripti on s (n = 15 0,7 80)

T IS ~ te rato logy informat ion service; RR ~ risk ratio; TCAs ~ tri cyclic a nt ide pressa nts; NMR ~ nation al medical registr y (including nation al birth registri es, registr ies of co ngenita l malformation s, hospit al discha rge registri es, prescription registries); CPR ~ co mpa ny pregnan cy registry; SNRls ~ seroto nin- no repinephrine reuptake inhibitors; NRls ~ nor epinephrin e reupta ke inhibitor s; AO R ~ adjusted odds ratio; O R ~ odds rat io; SRls ~ seroto nin reuptake inhibitors; BD ~ Zs be nzodiazepines; ARD ~ adj usted risk difference; ARR ~ adj usted risk rati o.

this matter using different methodologies in other populations. Using data from the Swedish national medical registry, Killen and Otterblad Olausson-? found that women who received paroxetine in early pregnancy had an ~2-fold increase in risk for delivering an infant with cardiac defects compared with births in the entire population (risk ratio [RR] = 2.63; 95% CI, 1.40-4.50). Berard et a13l performed a 6-year, population-based, case-control analysis of data 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 relationship between paroxetine use and cardiac defects. Among 1403 pregnant women, they identified 101 infants with major congenital malformations, including 24 cardiac defects. Exposure to paroxetine at a dose >25 mg/d during the first trimester was associated with increased risks of major congenital malformations (AOR = 2.23; 95% CI,
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Clinical Therapeutics

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 of data from the Slone Epidemiology Center Birth Defects Study involving 9849 infants with birth defects and 5860 without such defects. SSRIs were associated with right ventricular outflow tract obstruction defects in 15 exposed infants (AOR = 2.0; 95% CI, 1.1-3.6). Among individual SSRIs, significant associations were found between sertraline and ornphalocele in 3 exposed infants (AOR = 5.7; 95% CI, 1.6-20.7), sertraline and cardiac 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 exposed infants (AOR = 3.3; 95% CI,1.3-8.8). Another case-control analysis compared 9622 cases of major malformation in the National Birth Defects Prevention Study with 4092 controls residing in the same geographic areas.v-' A significant association was found 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), and ornphalocele (AOR = 2.8; 95% CI, 1.3-5.7); no association was found between SSRI exposure and congenital heart defects or other birth defects. Significant associations were found between individual SSRIs (paroxetine, sertraline, and fluoxetine) and specific major malformations (P < 0.05), but the small number of exposed cases limited the strength of the findings. Furthermore, SSRI exposure was determined using a standardized telephone interview of the mothers, which may have introduced recall bias. Using data from 5 health maintenance organization databases in the United States, Davis et a134 conducted a retrospective cohort study comparing 1441 infants exposed to antidepressants during gestation and 49,654 unexposed controls. Exposure to SSRIs during pregnancy was 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 associated with the risk of congenital heart defects compared with no paroxetine exposure (RR = 1.98; 95% CI, 0.64-6.15). However, there was a significant risk for congenital abnormalities of the eye in infants exposed to paroxetine compared with unexposed infants (RR = 2.36; 95% CI, 1.20-4.66).
1436

Einarson et a1 41 compared outcomes in 1174 infants from 8 teratology information services and a historical cohort of 2061 infants exposed to paroxetine during the first trimester of pregnancy from 5 previously published database studies with outcomes in 3379 infants from the same information services with no exposure to known teratogens. In the teratology information services cohort, rates of cardiovascular defects were 0.7% in the exposed group and 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, the mean 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 paroxetine did not appear to be associated with an increased risk of cardiac defects, as they considered the estimated incidence well within the incidence in the general population (~1 %). They did not comment on the significant results obtained when the 2 exposed groups were combined; however, the heterogeneity of the data would appear to render this finding of limited relevance. The role of chance in at least some of the study findings cannot be ruled out, and additional research is warranted to assess the actual degree of risk for cardiovascular malformations associated with the use of paroxetine during pregnancy. In a retrospective cohort study that employed data from the Canadian national medical registry, Oberlander et a135 assessed the potential association between congenital abnormalities and prenatal exposure to SRIs (paroxetine, sertraline, fluoxetine, venlataxine, fluvoxamine, and citalopram], alone or in combination with benzodiazepines (BDZs). After adjustment for several maternal clinical features that were used as a proxy for the severity of depression, combined SRIIBDZ exposure was associated with an increased risk of congenital heart defects compared with no 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 significant risk for congenital heart defects (ARD = 2.28; 95% CI, 0.19-4.36), and the combination of fluoxetinel BDZ was associated with an increased risk for major congenital abnormalities (ARD = 5.18; 95% CI,0.3010.07).
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Diav-Citrin et a136 conducted a prospective cohort study 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 exposure to known teratogens. There were significant risks for cardiovascular 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 regression analysis with adjustment for a maternal smoking habit of >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 study of data from 150 women exposed to venlataxine during the first trimester of pregnancy, 150 exposed to SSRIs, and 150 who received nonteratogenic drugs. They found no significant increase in the incidence of major malformations between venlafaxine, SSRIs, and nonterato genic 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 not associated with teratogenic risk. 48 However, no clinical data concerning the risks of duloxetine exposure during pregnancy were identified. Little information was identified regarding the safety of gestational use of NaSSAs and NRIs. After examining the outcomes of 104 pregnancies from 5 teratology information services, Djulus et a138 reported that the incidence of major malformations did not differ significantly between infants born to women who received mirtazapine, other antidepressants (SSRIs, SNRIs, or tricyclic antidepressants [TCAs]), or nonteratogenic drugs during pregnancy (1.9%, 1.0%, and 1.9%, respectively). In the only study identified that reported on the use of reboxetine (although in combination with other antidepressants), Lennestal and Killen 24 found no evidence of 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 for major 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
2009

and other serotonergic/noradrenergic antidepressants during 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 trimester of pregnancy,4 9-51,53 although 3 of these had methodologic limitations that may have resulted in underestimation of the risks. 49-51 The meta-analysis by Addis and Koren 49 evaluated the overall occurrence of major malformations in 4 studies of pregnancy outcomes in women exposed to fluoxetine during pregnancy, only 2 of which included a control population. The small population (367 pregnancies) and low specificity may have limited the ability of this analysis to detect increases in the risk of specific malformations, 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 different mechanisms of action, it was not possible to evaluate potential class effects. Moreover, specific malformations were not investigated, and 5 of the 7 included studies involved women who were not representative of the general population or comparable to patients from the other studies, as they were participants in the Motherisk Program in Toronto, Canada, and had been specifically educated to follow teratology information service instructions. The meta-analysis by Rahimi et a15 1 is valuable for its inclusion of the specific end point of congenital heart defects. However, it assessed exposure to a group of drugs (citaloprarn, fluoxetine, fluvoxamine, paroxetine, and sertraline) rather than to specific antidepressants. Moreover, exposure to this group of drugs was limited to the first trimester in 6 of 9 studies, while the remainder considered exposure at different times during gestation. This is an important limitation, as women who are first exposed to potential teratogens in the second or third trimester have a lower risk of delivering infants with major malformations compared with those with first-trimester exposure. 54 The remaining 2 meta-analyses were performed by the same research group and had conflicting findings. Bar-Oz et a15 2 found a significant increase in the risk of cardiac malformations in infants exposed to paroxetine in the first trimester (OR = 1.72; 95% CI, 1.222.42). This was a well-designed meta-analysis, evaluating specific end points in a large number of patients
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Clinical Therapeutics

Tab le II I. Meta-analyses of st udies includ ing data on major malformations a ssociat ed wit h maternal use of selective seroton in reuptake inhibitors (SSRls) a nd other serotonergic/norad renergi c a nt id e p ressan ts during pregnancy. Ma in Selecti o n Cr iteria and Comparato rs Pro spective co nt ro lled a nd un con tr o lled stud ies with d ata o n expo sure t o fl uoxetin e in 1st t rimes te r vs no expos ure to known te ra toge ns Pro s pect ive co ho rt stu d ies wit h d ata o n expo s ure to SSRls , SNRls, NR ls, Na SSAs, bupropion , tr az od on e, or nefaz od o ne in 1st trimester vs co nt ro ls wit h no exposu re t o known t er atoge ns Cohort stu d ies wit h d ata o n expo su re to SRls (cit alopra m, f luoxe ti ne, fl uvoxa mine, paroxetin e, or sert ra line) in 1st t rimeste r o r t hro ug ho ut preg nan cy vs no expo su re Case-co nt ro l a nd co ho rt stu die s wit h d ata o n expo s ure to paroxet ine in 1st trim ester vs no exposure Exp o s ure to pa roxeti ne in 1st trim est er vs no expo s ure (caseco nt ro l a na lysis) o r vs exposure to ot he r a nti de p res sa nts in 1st tr im est er (co hort a na lysis)

Auth ors/ Descr ipti on Addis a nd Koren "? 4 Stu d ies (N = 36 7) , 2 co nt ro lled a nd 2 un contro lled

Ma in Find ings Sum ma ry O R for po o led re lat ive risk of major ma lformati ons: 1.33 (95% CI, 0.49 -3 .58)

Eina rso n and Einarson - ? 7 Stu d ies (N = 1774 )

Sum ma ry RR fo r majo r structu ra l o r fu ncti on a l ma lfo rmat io ns: 1.01 (95% CI, 0.57- 1.80)

Ra him i et al S1 9 Stud ies (N = 2699)

Su mm ary O R, major ma lfo rma tion s: 1.39 (95% CI, 0.91- 2.15 ) Summary O R, ca rd iac malfo rm at io ns: 1.1 9 (95% CI, 0.5 3 -2 .68 )

Bar-Oz et a ls2 Meta-an a lysis of major ma lformatio ns (7 stud ies, n = 17,226) Meta-an alysis of ca rdiac ma lformations (6 studies, n = 16,789) O' Brien et a ls3 Cas e- control ana lysis (3 stu d ies, n = 30 ,247) Co ho rt a na lysis (6 stud ies, n = 66 ,4 09)

Sum mar y O R, major ma lfo rm a t ion s: 1.31 (95 %C I, 1.03 -1 .67) Su m ma ry OR , ca rd iac malfo rm atio ns: 1.72 (95% CI, 1.22 - 2.4 2) Risk of co nge nita l malfo rm a tion s, case-co ntro l a na lysis: O R = 1.1 8 (95 % CI, 0.8 8 -1 .59) Risk o f ca rd iac ma lfo rma t io ns, co ho rt a na lysis: WA D = 0.3% (95% CI, - 0.1 to 0.7 ); P = 0.19

O R = o dds ra t io ; SN Rls = se ro to nin- no re pi ne p hr ine re upt a ke inhi b itors; NRls = no re p ine ph r ine re up t a ke inhibi t or s; NaSS As = noradrenergic a nd s pecific sero t o ne rgic a nt ide pressa nts; RR = r isk ra t io ; SR ls = sero t o ni n reuptak e inhib ito rs; WA D = we ighted ave rage differen ce.

(n = 2621) exposed to a single drug (paroxetine) and including 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 exam1438

ine access to diagnostic testing as a potential confounder for congenital malformation. They found that users of paroxetine, other SSRIs, and non-SSRI antidepressants had significantly higher mean numbers of diagnostic tests (ultrasound, echocardiography, and amniocentesis) during pregnancy compared with those who used no antidepressants (2.4,2.5, 2.3, and 1.9,
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M. Tuccori et al.

respectively; P < 0.001). Based on this finding, all women who use antidepressants during pregnancy might be expected to have a higher risk of exposure to potential teratogenic procedures. However, the authors suggested that the higher risk associated with paroxetine may relate to its more frequent prescription for patients with anxiety, whose anxiety might prompt them to seek more diagnostic testing and result in more exposure to potential 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 risk of cardiac malformations was lost (OR = 1.18; 95% CI,0.88-1.59). In summary, data published mainly before 2000 and obtained from small teratology information service databases supported the lack of an association between use of SSRIs during pregnancy and an increased risk for development of major malformations. However, more recent data from large population-based studies using more appropriate pharrnacoepidemiologic approaches have challenged this assumption. Recent guidelines and updated teratogenic classifications recommend cautious use of SSRIs during pregnancy and avoidance of paroxetine. 55-57 Paroxetine was the first SSRI to be associated with an enhanced risk of birth defects, particularly cardiac defects. Similar concerns do not appear to apply to other SSRIs, despite recent findings suggesting a certain degree of risk with other SSRIs, particularly fluoxetine. The possible "channeling" of paroxetine prescriptions toward women with anxiety disorders, who are characterized by more frequent exposure to potentially teratogenic diagnostic procedures, may have biased the findings of studies that reported a significant association between paroxetine use during pregnancy and the occurrence of congenital malformations. This hypothesis warrants further investigation. MINOR MALFORMATIONS AND MILD STRUCTURAL ANOMALIES Minor malformations are considered of limited clinical relevance, do not generally require medical or surgical treatment, and do not greatly affect the infant's appearance. Examples include ear abnormalities, mongoloid eyes, overriding toes, absence of a hair whorl, extra nipples, frontal bossing, iris freckles, tapered fingers, and cleft uvula. 58 In a study in 228 women exposed to fluoxetine in the first trimester of pregnancy compared with 254 wom2009

en who were not exposed to known teratogens, Chambers et aIlo reported that significantly more infants exposed to fluoxetine were born with ::::3 minor defects compared with controls (15.5% vs 6.5%, respectively; P = 0.03). A study by Casper et a15 9 found no 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) throughout gestation compared with infants born to 13 mothers with depression and no exposure to SSRIs (76% and 54%, respectively). Both studies were included in a meta-analysis that found no increase in the risk of minor malformations in users of SSRIs compared with nonusers (OR = 0.97; 95% CI,0.14-6.93).51 There are few available data on the risk for minor malformations and mild structural abnormalities associated with SSRI exposure during pregnancy. Accurate prospective evaluations of these risks in pregnant women exposed to SSRIs and other serotonergicl noradrenergic antidepressants are required. MISCARRIAGE In studies that have evaluated the risk of miscarriage in women using SSRIs or SNRIs during pregnancy, crude estimates of the incidence of pregnancy loss did not differ significantly from controls or did not exceed expected 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 IV summarizes the main findings of studies that reported miscarriage rates. A pooled analysis by Kulin et al 12 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 involving a total of 2699 pregnancies reported a significant association between SSRI use and spontaneous abortion (OR = 1.7%; 95% CI, 1.28-2.24; P < 0.001).51 Based on the findings of Bassiouni and Rafei,60 who reported that blood concentrations of 5-HT were higher in women with spontaneous abortion in early pregnancy compared with those with a normal course of early pregnancy, the authors of the meta-analysis suggested a possible serotonergic mechanism for pregnancy loss. A meta-analysis by Hemels et a1 61 compared rates of spontaneous abortion in women taking antidepres1439

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Tab le IV. Studi es eva luat ing rates of miscarriage a ssociate d with th e us e of selecti ve se ro to nin reuptak e inhibito rs (SSRls) o r other serotonergic/norad ren er gic a nt ide pressants du ring pr egn an cy. Authors/Description (Data Source) Kulin et a J1 2 Prosp ectiv e co ho rt stu d y, Canada a nd Unit ed St ates (T IS da ta) McElhatton et a J1 8 Prosp ectiv e case seri es , Europe and Isr ael (TIS data) Active Drugs Fluvo xamin e, paroxetine, a nd se rt ra line (n = 267 ) TCA expos ure (n = 33 0), non TCA expos ure (n = 416 )

Co nt ro ls No expos ure to known te ratoge ns (n = 267 )

Main Findin gs Incide nce of miscarriage: 11.2% fluvoxamine, paroxetine, or sertraline; 7.9% no expos ure (P = 0.24) Incid en ce of miscarriage: 11.0% TCA monoth erapy, 13.2% TCA + o t he r drugs, 13.0% non -TCA mon otherapy, 10.6% no n-TCA + o t he r drugs, 13.5% f luo xetine, 9.0% fluvoxamin e (no st a t ist ica l a na lysis provid ed ) Inciden ce of miscarriag e: 10.0% fluoxetine, 8.5% no exposure (P= 0.59) Incid en ce of miscarriag e: 13.5% f luoxetine, 12.2% TCAs, 6.8% no expo sure (P = 0.31) RR, flu oxet ine vs no expo sure: 1.9 (95% CI, 0.92-3 .92) Incide nce of miscarriage: 13.8% (no difference rep orted vs historic new bo rn surveys , a lt ho ug h no st a t ist ica l analysis provid ed ) Incid en ce of miscarriag e: 11% cit a lo pra m, 10% d isease-ma t ch ed group, 10% no expo sure (no st a t ist ica l analysis provid ed) Incidence of miscarriag e: 11.8% f luoxe t ine (P < 0.05 vs no expo sure), 9.1 % paroxetine (P = NS vs no exposure), 6.6% no exposure Incid en ce of miscarriage : 12.0% ven lafax ine, 10.7% SSRls , 7.3% no exposure (P = 0.38) Incid e nce of miscarriag e: 19% mirtazapine (P = 0.86 vs other a nt ide pres sa nt s; P = 0.12 vs no exposure), 17% other a nt ide pressa nts, 11% no exposure
=

Non e

Chamb ers et a l20 Prosp ecti ve stu dy, Unit ed St a t es (TIS da t a) Pa stuszak et a l21 Prosp ective co ho rt stud y, Canada (T IS data)

Fluoxetin e (n = 228) Fluoxetin e (n = 128 )

No expos ure to known teratog ens (n = 254) TCAs (n = 74), no expo sure to known t eratogen s (n = 128)

Gold stein et a l22 Retrospective coh ort stu dy, United St ates (CPR data) Sivojelezova et a l23 Prospect ive coh ort stud y, Canada Diav-Cit rin et a l36 Prosp ectiv e co ho rt st ud y, Germ any, Israel, and Italy (TIS data)

Fluoxet ine (n = 796 )

Rates o f miscarriag e from the Nation al Ho spital Disch arge Survey Disease-ma tc hed g ro up (n = 132), no expo sure to kno wn t eratogen s (n = 132) No expos ure to known teratogen s (n = 1467) No expos ure to known teratogens (n = 150) No expos ure to known teratogens (n = 104)

Citalopram (n = 132)

Fluoxetin e (n = 314) , paroxetine (n = 419)

Einarson et a l37 Venlafaxine Prosp ectiv e co ho rt st ud y, (n = 150), SSRls Canada and United St ates (n = 150) (T IS data) Djulus et a P8 Mirtaz apin e Prosp ective co ho rt st ud y, (n = 104 ), Austra lia, Canada , Isra e l, o t her It a ly, a nd United States antid epressants (T IS data) (n = 104 )

TIS = 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 without depression (n = 2033) from 6 cohort studies. The baseline rate of spontaneous abortion was 8.7% (95% CI, 7.5-9.9), compared with 12.4% in the women 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 among studies and the quality score for all studies was adequate (>50%), it should be noted that the results of this meta-analysis may have been biased by indication. The conclusions of some of the preceding analyses were based on crude comparisons that do not support an increased rate of miscarriage in association with maternal use of SSRIs.18-20,22,23,28,36,37 Several factors may have influenced these observations (eg, time of contact with a teratogen information service, rate of induced abortion, maternal age, severity of depression). When calculating the incidence of spontaneous abortion, the majority of the reviewed studies used the total number of pregnancies as a denominator, which is an inappropriate procedure, given that an early induced abortion would rule out a later spontaneous abortion and an early spontaneous abortion would rule out a later induced abortion. Thus, the rate of miscarriage should 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 or other serotonergidnoradrenergic antidepressants. Finally, the inclusion of untreated control populations in the identified studies suggests a potential for bias by indication. Studies that employ this type of control population should include an adjustment for disease severity when investigating the potential for miscarriage associated with the use of SSRIs or other serotonergid noradrenergic antidepressants. NEONATAL BEHAVIORAL SYNDROME A 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 to women who used SSRIs during pregnancy.v- Mild central nervous system (CNS), motor, respiratory, and gastrointestinal signs and metabolic dysfunction are usually present but disappear during the second week after birth. This clinical picture has been interpreted as representing a neonatal withdrawal syndrome or a direct toxic effect of antidepressants on the newborn.
2009

Because the withdrawal mechanism has not been established, the designation neonatal behavioral syndrome is preferred. Medical management of this syndrome consists mainly of supportive treatment in a special-care nursery. This syndrome may be severe, with symptoms ranging from seizures to dehydration, excessive weight loss, and hyperpyrexia, and even a need for intubation.vWith regard to SSRIs and SNRIs, 18 case reports were 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 analysis of spontaneous reports of neonatal behavioral abnormalities associated with SSRIs in the World Health Organization adverse drug reaction database up to the second quarter of 2003 identified 93 cases from 11 countries that involved maternal SSRI use associated with either neonatal convulsions or behavioral alterations.s'' Paroxetine was implicated in nearly two thirds 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/noradrenergic antidepressants from the last trimester through delivery (Table V).20,24,25,34,40,81-94 Overall, these studies indicated the potential for symptoms consistent with a neonatal behavioral syndrome or a high risk of admission to a special-care nursery in relation to maternal exposure to antidepressants, mainly SSRIs, during the 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, and mothers with untreated depression have occasionally been enrolled in studies to adjust for possible confounding by indication.V However, women with untreated disease are generally likely to have less severe psychiatric problems than women with treated psychiatric disease. Therefore, Oberlander et a1 89 used propensity score matching to compare outcomes in newborns whose mothers received SSRIs for depression during pregnancy and those whose mothers did not receive SSRIs for depression, thus controlling for potential confounders such as disease severity, maternal psychotropic medication use, and concurrent illness. The incidence of symptoms of behavioral syndrome in
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Tab le V. Studies eva luat ing t he occurrence of neonatal behavioral syndro me associated with matern a l use of selective serotonin reu ptake inhibitors (SSRls) or other serotonergic/noradre nergic anti depressants during pregnancy. Aut hors/ Description Cham bers et a l20 Prospective/ ret rospect ive materna l re port s and infant med ical record review, United States Comparato rs Early expo sure 25 wk) to f luoxeti ne (MDO, 28 mg) (n = 101), lat e exposu re (~2 5 wk) to f luoxet ine (MOD, 25 mg) (n = 73) Ma in Find ings Risk of poor neo natal ada ptation , late vs ea rly exposure: RR = 3 .5 (95% CI, 1.7- 7.2) Risk of special-ca re nur ser y ad miss ion (excludi ng prem ature infa nts), late vs ea rly expos ure: RR = 2.7 (95% CI, 1.4-5.0)

l.enn est al a nd Kiille n 24 Retros pect ive co ho rt study using recordlinkage met hodo logy, Sweden

Expo su re (ea rly pregnan cy-deliver y) to SNRls/ NRls/ NaSSAs (n = 737) (mianserin [611, mirtaza pine [1 45], venlafaxine [505], reboxeti ne [14], mian serin + venlafaxi ne [2], mirt aza pine + venlafaxine [9], reboxetine + ven lafaxi ne [1]) or SSRls (n = 6481); all deliveries in pop ulation (n = 873,876)

Early exposure (before wk 12 in 90% of wo men) to SNRls/ NRls/ NaSSAs not associated wit h a significant increase in risk fo r an y o utco me vs a ll d eliveries Early exposure to SSRls- risk of res pirato ry prob lems: RR = 1.17 (95% CI, 1.03- 1.23); risk of low Apgar score 7 at 5 min): RR = 1.35 (95% CI, 1.08-1 .68); risk of hypoglyce mia : RR = 1.17 (95% CI, 1.02-1 .33) Late expos ure to SNRls/NRl s/N aSSAs-risk of hypoglycemia : RR = 2.11 (95% CI, 1.10- 3.89) Late exposure to SSRls-risk of res pirato ry problems: RR = 1.72 (95% CI, 1.41- 2.11 ); risk of low Apgar sco re 7 at 5 min): RR = 2.22 (95% CI, 1.58- 3 .1 2); risk of hypoglyce mia: RR = 1.32 (95% CI, 1.05-1.68); risk of neonatal co nvulsions: RR = 2.94 (95% CI, 1.34 - 5.58)

Ma schi et a l25 Pros pective co hort stu dy, Italy

Exposure (befo re concept ion to deliver y) to unspecified a ntid ep ressants (n = 200 ), pa roxetine (n = 58), f luoxeti ne (n = 32), or other a ntidepressa nts (n = 90); no exposure (n = 1200)

Incide nce of poo r neo natal ad a ptat io n: 7.0% exposed , 4 .2% no exposure (P = NS)

Davis et aJ3 4 Ret ros pect ive insur an ce databas e ana lysis, United States

Exposu re (3rd t rimeste r) to a ntidepressa nts (SS Rls, TCAs, o t hers) (n = 220 1), no expos ure (n = 75,833)

Risk of z l perinatal event : RR = 1.1 6 (95% CI, 1.0 6-1. 26); risk offeta l d ist ress: RR = 6.00 (95% CI, 1.88-19.1 8); risk of respirator y distress syndro me: RR = 1.97 (95% CI, 1.65 -2 .35); risk of e ndocrine/ meta bo lic disturban ce: RR = 1.61 (95% CI, 1.15- 2.27 ); risk of temperature regulatio n d isord ers: RR = 1.56 (95% CI, 1.06-2 .31); risk of co nvulsions: RR = 2.60 (95% CI, 1.1 6- 5.8 4) (contin ued)

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Table V (continued). Aut hors/ Description Maim et a l40 Retr os pect ive co hort stu dy using reco rdlin kage meth od ology, Finlan d
~1

Compara to rs SSRI pur chase duri ng pregna ncy (n = 178 2), ~ 1 SSRI pu rchase in 1st t rimester (n = 1398), ~ 1 SSRI pu rchase in 2nd t rimester (n = 54 8), ~ 1 SSRI purch a se in 3 rd trim ester (n = 597), ~ 1 SSRI purc ha se in each tri mester (n = 229); ma tch ed pregna nt co nt ro ls wit h no reimbursed drug purc ha se (n = 178 2) Earlyexpos ure (1 wk-6 mo) to pa roxetine (MOD, 20 mg) (n = 27), late exposure (3 rd trimester) to paroxet ine (MOD, 20 mg) (n = 65), no exposure (n = 27 )

Ma in Findin gs 3rd- vs 1st-Trimes te r purch a se-ris k of low Apgar sco re 7 at 1 min): AOR = 1.6 (95% CI, 1.0-2.4); risk of spe cia l-ca re nurser y o r int en sive ca re uni t ad miss io n: AOR = 1.6 (95% CI, 1.1-2 .2)

Cost ei et a l8 1 Pro sp ective mat ern al re po rt (inte rview), Ca nada

Late expo sure vs ea rly a nd no expo su re-risk of neon atal co mplicat ions (respirato ry distress, hypoglycemia , bradycardi a , sucking probl em s, prolon ged hospita liza tion ): RR = 4 .0 (95% CI, 1.2- 13.1 ); risk of respiratory difficult ies: RR = 4.4 (95% CI, 1.0 -1 9.5 ) Sum of Serotonin Syndrome Scale scores on d ays 1-4: 121 citalo pra m o r fluo xetin e, 3 0 no exposure (P = 0.0 08) Risk of z l se ro to nergic sign o n days 1- 4 , cita lo pra m or flu oxetin e vs no expo sure: O R = 6.9 (95% CI, 1.6- 29.2) Expos ure in 3rd trimester vs first 2 trimeste rsrisk for po or neonatal ada ptat io n: RR = 3.3 (95% CI, 0.5-22.5); risk for special-ca re nursery ad missio n: RR = 2.1 (95% CI, 0.3 -14 .6) 3rd -Trimes te r exposure to flu oxetin einciden ce of poor neon at al a da ptat ion: 13.4% (no statistica l an alysis provid ed ); risk of resp ira to ry sig ns: RR = 0.6 (95% CI, 0.1-2 .2); risk of slee p probl em s: RR = 1.7 (95% CI, 0.4 - 6.6 )

Lain e e t a l82 Pros pect ive pediatrician evaluat ion of newbo rns, Finland

Exposure (mean, 38 w k befor e d eliver y) to cita lo pra m 20 mg (n = 10) or flu oxetin e 20 mg (n = 10), no expos ure (n = 20)

Coh en et a l8 3 Retr osp ective c ha rt review, Unit ed States

Expos ure to fluoxetine (MOD, 27 mg) in fir st 2 trim est er s (n = 11), exposure to flu oxet ine (MO D, 27 mg) fro m 3rd t rimester to d eliver y (n = 53) Expo sure (3rd trim est er to de livery) to fluoxetine (MOD, 20 mg) (n = 112), histori cal co nt ro ls from Na tion al Hospita l Disch arge Su mma ry (n = 3,888 ,0 00 )

Gold stein '" Co m pa ny registry of o utco mes of pregn a ncies wit h flu oxetin e exposu re (pros pe cti ve a nd retro specti ve), Unit ed States O ber lande r et a l85 Pros pecti ve co hort stu dy wit h infa nt med ical reco rd review, Can ad a

Exposure (1st t rimester to delivery) t o a n SSRI (n = 28) (pa roxeti ne [M OD, 22 .2 mg] [17], fl uo xetin e [MOD, 21.3 mg] [7], a nd se rt ra line [MOD, 8 1 mg] [4]) o r a n SSRI + clo naze pa m (n = 18) (pa roxetine [MOD , 21.6 mg] [16] a nd f luoxe ti ne [MOD , 15 mg] [2]); no exposure (n = 23)

Incide nce of specia l-ca re nursery ad missio n: 2% SSRls, 0% no exposure (no stat ist ica l an alysis provid ed ) Risk of poor neo natal ada ptatio n (jitteriness, res piratory d ifficulti es, hypoglycemia): RR = 3.5 (95% CI, 0.9 -14 .1 )

(co nt inued)

2009

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Table V (continued). Aut hor s/ Description Kallen8 6 Prospective cohort study wit h review of ant enatal and pediat ric registry , Swed e n Zes kind an d St ep hen s'i/ Prosp ective co ho rt stu dy wit h materna l medical record review, United St ates Compara to rs Exposur e to SSRls (n = 558) (most freq uent: cita lopram [285 ], paroxeti ne [106], fluoxetin e [61], sert ra line [77]); a ll wom en giving birth (n = 573,728) Expos ure to SSRls at a ny ti me d uring pregnan cy (n = 17) (cita lop ra m [MOD, 24 mgJ [5], fluoxetine [MOD, 30 mgJ [1], pa roxetine [MOD, 17.4 mg] [3], sertra li ne [MOD , 56 mgJ [5], SSRI mon o t hera py fo llowed by SSRI + bupropi o n [2], a nd SSRI + bu propi on [1]); no expos ure (n = 17) Exposur e (late pregnan cy) to cita lo pra m (MOD, 20 mg) (n = 4), fluoxetine (MOD, 20 mg) (n = 15), pa roxetin e (MOD, 20 mg) (n = 8), a nd se rtra line (MOD, 75 mg) (n = 11) Main stu dy: d epression wit h exposure (1st t rimester to d elivery) to SSRls (n = 1451); depression with no exposure (n = 14,234); no depression, no exposure (n = 92, 192) Pro pe nsity sco re- matched stu d y: depression wit h exposure (1st trimeste r to de livery) to SSRls (n = 817); depression wit h no exposure (n = 8 05) Expos ure (3rd t rimeste r to delivery) to SSRI + venlafaxine (n = 76), cita lo pra m (n = 6), fluo xetin e (n = 10), f luvoxa mine (n = 2), pa roxetin e (n = 46), sertra line (n = 3), a nd venlafaxine (n = 9); no expos ure (unmatc hed) (n = 90) Expos ure (ea rly pregnan cy to de livery) to a nt ide p ressa nt s (n = 84) (SRls [42], TCAs [37], ot hers [5]); no expo sure (n = 168) Main Findin gs Risk of res pirato ry d ist ress : 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 co nvulsio ns: RR = 4 .1 (95% CI, 1.5-10.9) Differe nce in measures of ne urobehaviora l de velop me nt , exposed vs no expos uretremulousness: +29% (P = 0.08); motor ac tivity: +49% (P = 0.1 6) ; no . of differe nt be havio ra l sta tes : - 32% (P = 0.02); no . of c ha nges in beh avioral states: - 57% (P = 0.01); no . of bo uts of ac tive sleep : -49% (P < 0.0 01); no . of startles: +49 % (P = 0.26) Incidence of ad missio n to special-care nurser y in exposed infa nt s: 10.5% (statistica l a na lysis not provid ed )

Hendrick et a l88 Unco nt rolled , pros pective review of psychiatric, obstet ric, an d pediat ric records, United St ates O be rlande r et a l89 Retr os pective record linkage stu dy w ith prop en sit y sco re matchin g , Ca nada

Main stu dy- d iffere nce in incid e nce of hospi tal stay >3 d , exposed vs non exposed infan ts: 5.0 % (P < 0.00 1); differen ce in incidence of resp iratory distress, exposed vs non expo sed infa nt s: 6.3% (P < 0.0 01) Prop ensity score-matc hed study- d iffere nce in incid en ce of respiratory distress, exposed vs non exposed infa nts: 4.4% (P = 0.006) Incid e nce of a ll neo nata l beh avioral signs: 77.6% expo sed vs 41.1 % no expo sure (P < 0.001); a bno rma l movem ent s: 40 .8% vs 11.0% (P < 0.001 ); to nus a bno rma lities : 28 .9% vs 7.8% (P < 0.00 1); irritability: 19.7 % vs 1.1 % (P < 0.001); resp iratory syste m a bno rma lities: 4 0.8% vs 15.5% (P < O.001) Mean (SO) Apga r score (1 min), a nt ide pressa nt exposure vs no expo sure: 7.55 (1.5) vs 7.89 (1.5), respectively (P = 0.009 ); specia l-ca re nursery adm ission , a nt ide pressa nt exposure vs no expo sure: 17.9% vs 10.1 % (P = 0.084) ; special-ca re nursery ad missio n, SRls vs TCAs : 17.9% vs 10.1 %, resp ectively (P = 0.062) (co ntinued)

Ferr eira et a l9 0 Ret ros pective co ho rt stu dy, Ca na da

Pea rso n et al 9 1 Retr os pective co ho rt stu dy, Unit ed States

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Ta b le V (co ntin ue d) . Auth ors/D es cripti o n Suri et a l92 Prosp ective nat ura listic stu dy, Un ited St ates Co m pa rato rs Group 1: maj or d epressive disord er treat ed w ith a nt ide p ressa nts, mainl y SSRl s (n = 4 9; 40 in 1st trim ester ) Gro up 2: majo r d epressive disord er not treated w ith a nt ide p ressa nts o r w it h limited a ntide pressa nt expos ure (n = 22) Gro up 3: su bject s with out d epression (n = 19) Exp o sure (late pr eg nan cy) to a nt ide pressa nts, mainl y SSRls (n no ex posu re (n = 73)
=

Main Finding s Sp ecia l-care nu rser y a dm ission : 26 .7% gro up 1,17.1% g ro u p 2, 7.1% g ro u p 3 (P = 0.36)

Bou ch er et a l9 3 Retro sp ect ive co ho rt stu dy, Cana da

73);

Inc rea se in risk, exposed vs no ex pos ure a lte rat io n in a lert ness : O R = 37 (95% CI, 8 - 174); a lte red m uscu lar to ne: O R = 20 (95% CI, 5 -71 ); feedin g a nd gastro intestina l pr ob lem s: O R = 3 .8 (95% CI, 1.7- 8. 1); tac hyp nea : O R = 2.5 (95% CI, 1.1 -5. 3) No . of infa nts w it h neuro lo gic pro b lem s: 8/ 73 exposed vs 0/73 non exposed (P < 0 .00 6) Neo na t a l be havioral synd ro me (a ny co m po ne nt) , exposed vs non exp o sed : 28% vs 17%, resp ective ly; neurol og ic eve nts: 20% vs 12%; respiratory eve nts: 7% vs 7%; gast ro intestina l events: 6% vs 8% (a ll, P = NS)

Jordan et a l9 4 Ret ro sp ect ive co ho rt stu dy, Unit ed States

Expo su re (last mo nth t o deliver y) to SRls (n = 4 9) (citalo pra m [33], se rtra line [11], venlafax ine [3], escitalo pra m [2]); no ex posu re (n = 59)

MDD - median daily dose; RR - relat ive risk; SNRls - seroto nin- no repinephrine reupt ake inhibito rs; NRls - norepin ephrine reuptake inhibitors; NaSSAs = noradrenergic and specific sero to nergic antide pressa nts; TeAs = tricyclic ant ide pressa nts; AOR = adjusted odds ratio; SRls = seroto nin reuptake inhibitors; O R = odds rat io .

infants born to depressed mothers who had not been exposed to SSRIs was similar to that in infants born to depressed mothers who were exposed to SSRIs, with the exception of respiratory distress (difference in incidence, 4.4%; P = 0.006). Thus, it appeared that previous studies had not controlled for the severity of depression and that the use of SSRIs during pregnancy may not be associated with an increased risk for neonatal behavioral syndrome. In a subsequent study, Oberlander et a195 used the propensity score approach to assess whether lategestational exposure to SRIs (n = 1925) was associated with an increased risk of adverse neonatal outcomes compared with early exposure (n = 1575). Late versus early exposure was associated with significant risks of lower birth weight, respiratory distress, and gestational age <37 weeks (P < 0.01). However, after adjustment for disease severity using propensity score
2009

matching, only the risk of lower birth weight remained statistically significant (P = 0.04). Statistical significance was definitively lost after performance of a Bonferroni correction for multiple comparisons. The only study identified that was specifically designed to evaluate neonatal adverse outcomes related to exposure to SNRIs, NRIs, and NaSSAs (venlataxine, rnianserin, re boxetine, and rnirtaza pine) reported an increased risk of hypoglycemia with late-gestational exposure to these drugs (RR = 2.11; 95% CI, 1.10-3.89).24 Both maternal mood and treatment with SSRIs during pregnancy have been associated with biochemical abnormalities that may be related to the development of postnatal alterations in behavior or respiratory distress. The neurochemical role of 5-HT is central to understanding the mechanism for a possible effect of SSRI exposure on neonatal behavior. Despite differences between SSRIs in their ability to inhibit reuptake
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of 5-HT at presynaptic sites,96 all increase central synaptic 5-HT concentrations'" and can cross the placenta,"? potentially inhibiting 5-HT reuptake in the developing fetus. During gestation, 5-HT regulates cardiovascular and respiratory function'f and circadian rhythm,"? and acts as a trophic signal regulating the development of serotonergic and other monoaminergic pathways in the brain. 100 Moreover, in animal models, 5-HT was found to playa direct role in the development of pulmonary artery smooth muscle in the 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 extrauterine environment, leading to neonatal respiratory distress and behavioral alterations. Oberlander et a1 85 analyzed 2 groups of infants7 with symptoms of transient poor neonatal adaptation and 9 without such symptoms-whose mothers had similar mean (SD) levels of exposure to paroxetine during 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 antidepressants during the third trimester of pregnancy and symptoms of neonatal behavioral syndrome. However, most of the 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 EVENTS
Persistent Pulmonary Hypertension

Persistent pulmonary hypertension of the newborn (PPHN) is a rare and potentially fatal condition that occurs in an estimated 1 or 2 infants per 1000 live births. 102.103 The hypothesis that maternal use of SSRIs, particularly fluoxetine, in late pregnancy may be a risk factor for PPHN arose from a cohort study in which 2 of 73 infants (2.7%) exposed to fluoxetine in the third trimester developed the condition, compared with an expected frequency in the general population rang1446

ing from 0.07% to 0.1 %.20 The potential mechanism for this adverse effect remains undetermined, although it may involve a direct action of SSRIs in the lungs. In particular, it has been suggested that high circulating levels of 5-HT in the fetus and accumulation of 5-HT in the fetal lungs may lead to vasoconstriction of pulmonary vessels or to proliferation of pulmonary smooth muscle, with consequent increases in pulmonary vascular resistance.l'" Consistent with this hypothesis, a rat study found that after in utero exposure to low concentrations of fluoxetine (10 mg/kg/d), the rate of proliferation of pulmonary arterial smooth muscle was significantly increased in fetal cells (P < 0.01), but not adult cells. 105 Another potential mechanism might involve the inhibitory effect of SSRIs on the synthesis of nitric oxide, a potent vasodilator that plays a role in the regulation of vascular tone and reactivity, both in utero and during early postnatal life. 106 A case-control study (377 cases, 836 controls) of risk factors for PPHN, with a focus on exposure to NSAIDs and SSRIs after the twentieth week of gestation, found an association between maternal exposure to particular SSRIs (fluoxetine, paroxetine, and sertraline) during late pregnancy and the occurrence of PPHN (AOR = 6.1; 95% CI, 2.2-16.8; P = 0.001).107 In contrast, no association was found between the risk of PPHN and use of SSRIs (citalopram, fluoxetine, paroxetine, and sertraline) before the twentieth week of gestation (AOR = 0.3; 95% CI, 0.1-1.2) or the use of 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 an association between maternal use of SSRIs in early pregnancy (n = 7587) and PPHN in full-term infants (RR = 2.4; 95% CI, 1.2-4.3).108 A subgroup analysis that included only data from mothers taking SSRIs during late gestation (n = 2350) indicated an increase in 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 during the third trimester of pregnancy and 1104 control infants with no exposure to antidepressants during gestation. Only 5 cases of PPHN were identified in the entire cohort, with no difference in prevalence between cases (2.14 per 1000 births; 95% CI, 0.26-7.74) and controls (2.72 per 1000 births; 95% CI, 0.56-7.93). A retroVolume 31 Theme Issue

M. Tuccori et al. spective cohort analysis of pregnancy records from the Mayo Clinic (N = 25,214) found no cases of PPHN in the group that used SSRIs or venlataxine at any point during pregnancy (n = 808), whereas there were 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 (retrospective design, potential for inaccurate recall or recall bias) of the case-control study by Chambers et al,107 the high OR for development of PPHN in that study was confirmed, at least in part, by the findings of Killen and Olausson.l-" Furthermore, given its small sample size and difficulty of determining past recorded cases of PPHN, the study by Andrade et a1 109 neither rules out nor minimizes the risk. The findings of Wichman et al 27 may also have been affected by methodologic limitations, predominantly the retrospective design, which made it difficult to retrieve information on exposure to potential teratogens in both study groups. Nonetheless, even if an association between SSRI intake during pregnancy and development of PPHN were eventually confirmed, the absolute risk would not be substantially different from that observed in the general population. Additional evidence is needed to determine the true risk of PPHN associated with SSRI use during pregnancy. Effects on Neurobehavioral Development Five studies were identified that evaluated longterm developmental effects after exposure to SSRIs and other serotonergic/noradrenergic antidepressants during pregnancy.17,59,1 10- 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 a control group of infants born to 84 women who had been exposed to nonteratogens (ie, acetaminophen, oral penicillins, and dental radiography). At the age of 16 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 (risk difference = 2.1; 95% CI, -5.0 to 9.2). N ulman et all 10 used several scales to assess neurologic development in infants (age range, 15-71 months) born to mothers exposed to fluoxetine (n = 40) or TCAs (n = 46) during pregnancy compared with infants born to 36 nondepressed women with no expo2009

sure to these drugs. There were no significant differences between either group of exposed children and controls in mean IQ scores (obtained using the Bailey Mental Development Index or the McCarthy Scales of Children's Abilities) or mean scores for temperament, behavior, reactivity, or mood (obtained using the Reynell Developmental Language Scales and the Child Behavior Checklist). Oberlander et all 11 prospectively evaluated externalizing behaviors in -l-year-old children with prolonged prenatal exposure (mean [SD], 181.5 [75.0] days) to SSRIs (n = 22) compared with nonexposed controls (n = 14). The main study measures included maternal mood, duration of SSRI exposure, drug levels in umbilical cord blood, history of poor neonatal adaptation, and direct observation of attention, activity, and impulsiveness. No significant differences were found between groups. Significant predictors of externalizing behavior at 4 years of age were maternal mood at the time of observation (measured using the Hamilton Rating Scale for Depression, the Hamilton Anxiety Scale, and a symptom questionnaire) and parental stress at the time of observation (measured using the Parenting Stress Index) (both, P < 0.05), regardless of maternal mood before delivery or SSRI treatment during pregnancy. In contrast, Casper et a15 9 found that maternal exposure to SSRIs (fluoxetine, sertraline, paroxetine, and fluvoxamine) (n = 31) was associated with lower scores on the psychomotor and behavioral development subscales of the Bayley Scales of Infant Development at 6 to 40 months compared with infants born to untreated 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: 89.5 vs 76.0 [P = 0.04]). Drug-specific evaluations were not performed, probably because of the small sample size. Mortensen et al 112 performed a follow-up analysis using data from a regional prescription registry in Denmark and identified 340 children born to women with prescriptions for CNS drugs, including 50 born to women with prescriptions for unspecified antidepressants. This cohort was compared with a randomly selected control population of 755 children born to women who were pregnant during the same period but had no prescriptions for CNS drugs. The BOEL test was performed when children were 7 to 10 months old. Abnormal scores on this test were recorded in
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16% (n = 8) of children exposed to antidepressants and 4 % (n = 31) of the control population; the AOR for abnormal BOEL scores in children exposed to antidepressants was 5.9 (95% CI, 1.1-31.0). Although this study had limitations (eg, testing of a select group of children, possible role of the mother's underlying disease, lack of information on postnatal medical and social factors), it raised concerns that should be addressed in well-designed studies.
Bleeding Complications Because bleeding may be associated with the use of SRIs,l13 a variety of blood-related clinical conditions have been investigated in infants born to mothers receiving serotonergic antidepressants during pregnancy. Intracranial hemorrhage is regarded as an uncommon condition, at least in newborns who are not extremely prernature.U" Predisposing factors for intracranial hemorrhage in newborns include preterm delivery, respiratory distress syndrome, hypoxic injuries, reperfusion damage, increased or decreased cerebral blood flow, and large fetal head size in relation to the maternal pelvic outlet. 114 There have been 4 case reports describing neonatal subarachnoid and/or intraventricular hemorrhage after exposure to SSRIs in late pregnancy.llS-11S Three of the mothers received paroxetine and 1 received fluoxetine. However, intracranial hemorrhage represents a possible complication of delivery.U" and therefore the causal relationship between these adverse events and drug exposure remains uncertain. Maayan-Metzger et al 120 evaluated platelet function in 27 infants born to mothers who had been treated with SSRIs (paroxetine, fluoxetine, or citalopram) from the last month of gestation to delivery compared with 27 nonexposed controls. No correlation was found between SSRI exposure in newborns or mothers and 2 indexes of platelet function, the mean (SD) surface coverage (10.44% [3.7%] exposed, 9.34% [3.3%] unexposed) and mean size of platelet aggregates (27.9 [9] and 23.9 [6] urn", respectively). The authors concluded that maternal treatment with SSRIs did not impair whole-blood platelet function in these healthy full-term newborns. More recently, in a population-based, nested casecontrol study from Ontario, Salkeld et al 121 examined whether use of SSRIs in late pregnancy was associated with an increased risk of hemorrhagic complications compared with use of non-SSRI anti1448

depressants (2460 cases of postpartum bleeding complications and 23,943 matched controls). The AOR for the association between postpartum hemorrhage and exposure to SSRIs within 90 days before delivery was 1.30 (95% CI, 0.98-1.72), compared with an AOR of 1.12 for exposure to non-SSRI medications (95% CI, 0.62-2.01), indicating lack of statistical significance to support the study hypothesis. QTc-lnterval Prolongation Of the SSRIs, fluoxetine has been suspected of inducing torsades de pointes in humans,l22 whereas citaloprarn appears to have the potential to alter cardiac repolarization.L'v Following publication of a report of QT c-interval prolongation in a newborn after in utero exposure to fluoxetine.P" a retrospective cohort study assessed the proarrhythmic potential of SRIs (paroxetine, citaloprarn, fluoxetine, fluvoxamine, and venlafaxine) in 52 exposed newborns compared with 52 unexposed controls matched by gestational age. 12S The newborns exposed to antidepressants had a longer mean (SD) QTc interval compared with unexposed controls (409 [42] vs 392 [29] msec, respectively; P = 0.02), but there were no cases of arrhythmia. Although this study did not include drug-specific evaluations or measurement of serum electrolytes, its findings sparked debate about possible alterations in cardiac electrophysiology associated with gestational use of the studied antidepressants. Therefore, further well-designed studies are warranted to investigate these preliminary observations, establish their clinical relevance, and assess whether specific drugs may carry a major risk compared with other drugs of the same class.
DISCUSSION Complications have been reported in newborns after maternal use of SSRIs and other serotonergidnoradrenergic antidepressants during pregnancy. Risks of major malformations, particularly cardiac malformations, have emerged in regard to paroxetine. However, the causal relationship between exposure to antidepressants and these adverse events is subject to debate, and the conflicting findings of the available studies make it difficult to quantify the risk. The teratogenic potential of paroxetine is unlikely to represent a class effect of SSRIs, although the results of recent studies suggest that 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 paroxetine for the treatment of depression during pregnancy. 55-57 Several studies found a moderately increased risk for miscarriage with the use of SSRIs and other serotonergic/ nor adrenergic antidepressants. However, studies of fetal survival on a week-by-week basis are warranted to further assess the extent of this risk. In utero exposure to SSRIs from the last trimester to delivery has been associated with a self-limiting neonatal behavioral syndrome. The apparent increase in this syndrome may reflect a greater frequency of gestational SSRI use, although this remains to be determined. All infants with neonatal behavioral syndrome should be monitored carefully in the first days of life for the clinical evolution of specific symptoms. Better understanding of the pharmacodynamics and pharmacokinetics of SSRIs and potential withdrawal consequences is necessary, and there is a need for further research focusing on the safety of SSRI use during the last trimester of pregnancy. The potential for SSRI exposure to induce alterations in neurobehavioral development remains undefined, and further investigations are required. Evidence supporting the risk of bleeding complications (eg, intracranial hemorrhage) in association with use of SSRIs and other serotonergic/noradrenergic antidepressants during pregnancy is inconsistent. The possibility of QTc-interval prolongation in newborns exposed to SRIs in late pregnancy requires further study. Most available data on the use of antidepressants during pregnancy involve SSRIs, with limited information on other antidepressants. Therefore, there is a need for more data on the safety of gestational use of newer antidepressants such as escitalopram, rnirtazapine, and venlataxine. In addition, there is a need for substantial improvement in the methodology used to analyze antidepressant safety in pregnant women, as well as to assess a drug's teratogenic potential. For example, the potential contribution of the severity of depression to neonatal outcomes cannot be overlooked. Use of propensity score matching, as in the study by Oberlander et al,89 represents a potentially useful approach to this matter. This review has some limitations. Articles were not selected for review using quality-based assessment, which may have led to possible overestimation of the evidence. Furthermore, the possibility of publication bias cannot be ruled out. Although these limitations warrant cautious interpretation of the data, a thor2009

ough presentation of the available evidence may be useful when considering options for the treatment of depression during pregnancy.
CONCLUSION The available evidence suggests that SSRIs and other serotonergic/noradrenergic antidepressants should be used with caution during pregnancy, with careful follow-up of infants exposed to these agents in utero. ACKNOWLEDGMENT The authors have indicated that they have no conflicts of interest regarding the content of this article. REFERENCES
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Address correspondence to: Prof. Mario Del Tacca, Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Via Rorna 55, 56126, Pisa, Italy. E-mail: m.deltacca@ ao-pisa. toscana.it
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