Antidepressants in pregnancy: a systematic review

Part of three systematic reviews on the effects of psychotropic medication exposure in pregnancy, this paper critically reviews the literature on adverse effects of antidepressant use during pregnancy, and derives recommendations for clinical practice. Electronic databases were searched for original research studies examining the effects of gestational exposure to antidepressants on pregnancy, neonatal and longer-term developmental outcomes. Most results were derived from cohort (prospective and retrospective) and casecontrol studies. There were no randomized controlled trials. Congenital malformations: 35 studies identified, 12 demonstrated a significant association between antidepressant use in early pregnancy and congenital malformations. Pregnancy outcomes: 35 articles identified, outcomes measured rates of spontaneous abortion (4 out of 7 studies reporting elevated risk), preterm birth (15 out of 19 reporting elevated risk) and abnormal birth weight (8 out of 23 reporting elevated risk). Neonatal outcomes: 17 controlled studies including one meta-analysis were identified concerning neonatal adaptation. 15 studies showed an association between gestational exposure to antidepressants and neonatal adaptation difficulties. Three studies examined an association between selective serotonin reuptake inhibitor (SSRI) exposure and persistent pulmonary hypertension in the neonate with conflicting results. Longer-term developmental outcomes: 6 of 7 studies comparing developmental outcomes of children exposed to antidepressants in utero with non- exposed children reported no significant differences. Most of these medications remain relatively safe in pregnancy, but some significant areas of concern exist, particularly some evidence of higher risk of preterm birth, neonatal adaptation difficulties and congenital cardiac malformations (with paroxetine). The impact of these findings on the risk-benefit analysis when treating pregnant women with antidepressants is discussed.     

Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective,controlled study

OBJECTIVE: Previous work suggested that first-trimester exposure to tricyclic antidepressants or fluoxetine does not affect adversely child IQ and language development. However, many women need antidepressants throughout pregnancy to avoid morbidity and suicide attempts. Little is known about the fetal safety of tricyclic antidepressants and fluoxetine when taken throughout pregnancy. The goal of this study was to assess the effects of tricyclic antidepressants and fluoxetine used throughout gestation on child IQ, language, and behavior. METHOD: In a prospective study, mother-child pairs exposed throughout gestation to tricyclic antidepressants (N=46) or fluoxetine (N=40) and an unexposed, not depressed comparison group (N=36) were blindly assessed. The three groups were compared in terms of the children's IQ, language, behavior, and temperament between ages 15 and 71 months. The authors adjusted for independent variables such as duration and severity of maternal depression, duration of pharmacological treatment, number of depression episodes after delivery, maternal IQ, socioeconomic status, cigarette smoking, and alcohol use. RESULTS: Neither tricyclic antidepressants nor fluoxetine adversely affected the child's global IQ, language development, or behavior. IQ was significantly and negatively associated with duration of depression, whereas language was negatively associated with number of depression episodes after delivery. CONCLUSIONS: Exposure to tricyclic antidepressants or fluoxetine throughout gestation does not appear to adversely affect cognition, language development, or the temperament of preschool and early-school children. In contrast, mothers' depression is associated with less cognitive and language achievement by their children. When needed, adequate antidepressant therapy should be instituted and maintained during pregnancy and postpartum.     

The use of psychiatric drugs in pregnancy and lactation

To help determine which drugs can be used with relative safety during pregnancy, we reviewed the literature on the possible teratogenic, perinatal, behavioral or developmental effects of the various groups of commonly used psychiatric drugs, and their effects on lactation. Tricyclic antidepressants, fluoxetine, phenothiazines, and most benzodiazepines are not considered to be teratogenic and may be used during pregnancy. All anti-epileptic drugs seem to have an embryotoxic and teratogenic potential and we recommend, if possible, avoiding these drugs. Lithium administration during the first trimester of pregnancy increases the risk of cardiac malformations, but the risk is not as high as originally reported. Therefore lithium may be continued whenever it seems to be the "drug of choice" if fetal echocardiography and ultrasonography are performed. There is a lack of information on the teratogenic effect of the newer drugs, and in spite of the fact that similar "older" drugs do not seem to adversely affect the fetus, they should be used with care. Although the data on the development of children following in-utero exposure to psychiatric drugs is limited, there seems to be no evidence of any long-term adverse effects on the development of children exposed to most psychotropic medications. However, children exposed in utero to anti-epileptic drugs may exhibit long-term developmental problems. Most of the drugs are detected in breast milk only at low concentrations. In nursing women taking these drugs, breastfeeding is possible. The infant should be carefully monitored for any clinical side effects and whenever observed, nursing should be discontinued. In light of our knowledge today, there seems to be only rarely an indication for pregnancy interruption following maternal exposure to psychiatric drugs during pregnancy.     

Birth defects and epilepsy medication

Epilepsy is one of the most common neurological problems in pregnancy. Approximately one in 200 pregnancies is to a woman with epilepsy taking antiepileptic drugs. For the majority of women, pregnancy proceeds without any apparent difficulties but there is growing evidence of an increased risk of major malformations and later cognitive problems in children exposed to antiepileptic drugs in utero. This review summarizes the available evidence for these risks and examines the implications of these in the counseling and treatment of women with epilepsy.     

Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study

OBJECTIVE: Because there are no studies available on the safety of venlafaxine during pregnancy, the authors' goal in this study was to determine whether venlafaxine increases the risk for major malformations. METHOD: Data on 150 women exposed to venlafaxine during pregnancy in seven pregnancy counseling centers were compared with data from studies of pregnant women who 1) received selective serotonin reuptake inhibitor antidepressants (SSRIs) (N=150) and 2) who received nonteratogenic drugs (N=150). RESULTS: Among the 150 women who were exposed to venlafaxine during pregnancy, 125 had live births, 18 had spontaneous abortions, and seven had therapeutic abortions; two of the babies had major malformations. There were no significant differences between these women and the two comparison groups on any of the measures analyzed. CONCLUSIONS: These results suggest that the use of venlafaxine during pregnancy does not increase the rates of major malformations above the baseline rate of 1%-3%.     

Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero

Purpose: Use of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. We sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register. Methods: The United Kingdom Epilepsy and Pregnancy Register is a prospective, observational registration and follow‐up study set up to determine the relative safety of antiepileptic drugs in pregnancy. We have extracted data for those women who prospectively registered more than one pregnancy and calculated the recurrence risks for fetal malformations. Key Findings: Outcome data were available for 1,534 pregnancies born to 719 mothers. For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01–2.96). The risk for recurrence was 50% for women who had had two previous children with a congenital malformation. There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68–3.20) and topiramate (50%, relative risk 4.50, 95% CI 0.97–20.82), but not for other drugs such as carbamazepine and lamotrigine. Recurrence risks were also higher for pregnancies exposed to polytherapy regimens and for those where the dose of antiepileptic drug treatment had been increased after the first pregnancy. Significance: Women who have had a child with a malformation are at increased risk of having other children with malformations. This is in keeping with previous reports that have suggested that genetic influences may be one of the factors determining the teratogenic risk of antiepileptic drugs.     

Early cognitive development in children born to women with epilepsy: A prospective report

Purpose: In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230). Methods: The children were assessed when younger than the age of 2 years using the Griffiths Mental Development Scales, either in their local participating hospital or in their home. The assessments were completed by an assessor who was blinded to whether the child’s mother had epilepsy and to antiepileptic drug type. Results: Children exposed to sodium valproate had a statistically significant increased risk of delayed early development in comparison to the control children. Linear regression analysis showed a statistically significant effect of sodium valproate exposure on the child’s overall developmental level that was not accounted for by confounding variables. Delayed early development is also noted for children within an ad hoc group of less commonly utilized antiepileptic drugs, although conclusions cannot be drawn due to the size of this group (n = 13). Children exposed to either carbamazepine or lamotrigine in utero did not differ significantly in their overall developmental ability. Differences noted in specific developmental areas for these two groups were not statistically significant after the control for confounders such as socioeconomic status and maternal IQ. Discussion: Women with epilepsy should be informed of the risks posed to their potential offspring prior to pregnancy to allow for informed decisions regarding treatment. Children exposed in utero to antiepileptic drugs should be monitored throughout childhood to allow for early intervention when necessary.     

Valproate and the risk for congenital malformations: Is formulation and dosage regime important?

BackgroundUse of valproate in pregnancy, especially in doses over 1000 mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate.MethodsThe UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure.ResultsOutcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000 mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000 mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1–2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67–1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58–1.70).ConclusionPrescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.     

A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy.

OBJECTIVES: Trazodone and nefazodone are phenylpiperazine antidepressants. Currently, there are no adequate, well-controlled studies on the fetal safety of these drugs. Our primary objective was to determine whether the use of trazodone or nefazodone during pregnancy is associated with an increased risk for major malformations. Secondary outcomes of interest included rates of spontaneous and therapeutic abortions, rates of premature labour, and birth weight. METHODS: Pregnant women from 5 centres who had been exposed to these drugs (n = 147) were enrolled in the study during their first trimester. We compared the women with 2 groups of women who took either other antidepressant drugs (n = 147) or nonteratogenic drugs (n = 147). All the women were followed up after delivery to ascertain pregnancy outcome and the health of the baby. RESULTS: We have completed 147 follow-ups. There were 121 (82.4%) live births, 20 (13.6%) spontaneous abortions, and 6 (4%) therapeutic abortions. Of the live births, there were 2 (1.6%) major malformations. In all cases, drug exposure occurred during the first trimester, with 52 (35%) of the women using these drugs throughout pregnancy. The mean gestational age at birth was 38 weeks (SD 4.2), and the mean birth weight was 3306.34 g (SD 655). We found no statistically significant differences among the 3 groups in any of the endpoints of interest that we examined. Of the sample, 58 women were exposed to trazodone, and 89 were exposed to nefazodone. CONCLUSION: Our results suggest that these drugs do not increase the rates of major malformations above the baseline rate of 1% to 3%.     

Antiepileptic drugs and neurodevelopment

Clinical studies have documented the teratogenic potential of antiepileptic drugs (AEDs). More recent cohort studies have been trying to sort out which AEDs impose the highest risk of teratogenicity. Currently, there is evidence demonstrating an increased risk of major congenital malformations (MCMs) for valproate, phenobarbital, and polytherapy during pregnancy. Based on the current data from multiple studies, the risk for valproate is the highest. Additional studies are needed to fully delineate if differences exist for other AEDs, especially the newer AEDs. However, although MCMs are easy to recognize and have been shown to be more common after in utero exposure to AEDs, there are insufficient data regarding their long-term effects on cognition and behavior in exposed children. Although most children born to women with epilepsy are healthy, in recent years there has been increasing awareness of the long-term effects of in utero exposure to AEDs. Recent discovery of neuronal apoptosis following in utero AED exposure in animals during a period that corresponds to the third trimester and early infancy in humans raises further concerns. Prospective clinical studies seem necessary in order to better understand the long-term neurodevelopmental effects of in utero exposure to AEDs.     

The longer term outcome of children born to mothers with epilepsy

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.     

Prenatal and family risks of children born to mothers with epilepsy: effects on cognitive development

The offspring of mothers with epilepsy are considered to be at developmental risk during pregnancy from: (1) generalized maternal seizures (hypoxia); (2) teratogenicity of antiepileptic drugs (AEDs); and (3) adverse socio-familial conditions associated with having a chronically sick mother. Sixty-seven children of mothers with epilepsy and 49 children from non-affected mothers, matched for control variables, were followed from birth to adolescence (53 males, 63 females; mean age 14y 2mo, range 10-20y). Prediction of intellectual performance of these children during adolescence was calculated from the following variables: maternal generalized seizures, prenatal exposure to AEDs, and quality of family stimulation (HOME Inventory) assessed in children at 2 years of age. Children who were prenatally exposed to AEDs achieved lower IQs than control children at adolescence. This effect was moderately significant for children who had been exposed to monotherapy (6 IQ points lower), but was considerable in those exposed to polytherapy (12 IQ points lower). Generalized seizures during pregnancy, observed in half the mothers, did not exacerbate this effect. Relative to prenatal risk status, the quality of the family environment had varied effects on intellectual development. Children with prenatal risks appeared to be more vulnerable to environmental disadvantage than control children, but they also showed longer-lasting effects of environmental support.     

Neurodevelopmental effects of prenatal exposure to psychotropic medications

Until now, studies on the reproductive safety of psychotropics have typically assessed the risk of congenital malformations and perinatal complications associated with in utero exposure to such medications. However, little is known of their inherent potential neurobehavioral teratogenicity. The objective is to analyze available data from studies investigating developmental outcome of children exposed prenatally to psychotropics. A computerized Medline/PubMed/TOXNET/ENBASE search (1960–2010) was conducted using the following keywords: pregnancy, child/infant development/neurodevelopment, antidepressants, benzodiazepines, mood stabilizers, and antipsychotics. A separate search was also run to complete the safety profile of single specific medications. Resultant articles were cross‐referenced for other relevant articles not identified in the initial search. A noncomputerized review of pertinent journals and textbooks was also performed. All studies published in English and reporting primary data on the developmental outcome of infants exposed in utero to psychotropics and born without malformations were collected. As regards antiepileptic drugs, only studies that provided data on specific medications approved for psychiatric practice use (carbamazepine, lamotrigine, and valproate) were considered. Data were extracted from 41 articles (38 identified electronically and 3 nonelectronically), which met the inclusion criteria. Despite reviewed studies showing relevant methodological limitations, concordant, albeit preliminary, information seems to exclude that prenatal exposure to both selective serotonin reuptake inhibitors and tricyclic antidepressants may interfere with the infants' psychological and cognitive development. Conversely, information on valproate strongly discourages its use in pregnant women. Moreover, although data on carbamazepine remain controversial, information on whole classes of drugs and single medications is either absent (second‐generation antipsychotics) or too limited (first‐generation antipsychotics, benzodiazepines, lithium, and lamotrigine) to inform the decision‐making process. For all classes of psychotropics, new and/or further studies are warranted to answer definitively the urgent question about the impact of prenatal exposure to such medications on infant development. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

Intellectual and language functions in children of mothers with epilepsy

PURPOSE: To compare the intellectual and language functions of children of mothers with epilepsy (CME) with that of controls matched for age and socioeconomic status. METHODS: Cases were CME, aged six years or more (n = 71), drawn from a prospective cohort in the Kerala Registry of Epilepsy and Pregnancy. Controls were 201 children of parents without epilepsy, matched for age and socioeconomic status. The outcome measures included Indian adaptation of Wechsler Intelligence Scale for children and MLT-a locally developed proficiency test for regional language. All relevant data were abstracted from the registry records. RESULTS: The Full Scale IQ and MLT scores were significantly lower for the cases (87.7 +/- 22.6 and 73.4 +/- 17.3) compared to controls (93.0 +/- 14.4 and 83.2 +/- 11.8). Compared to controls, CME scored poor on all subtests of MLT but their impairment was confined to only some of the subtests of IQ. Maternal education and maternal IQ significantly correlated with low IQ and MLT scores for CME whereas type of epilepsy, seizures during pregnancy or low birth weight did not have any significant association with these outcome measures. Polytherapy and higher dosage of antiepileptic drugs (AEDs) were associated with significant impairment in outcome measures. Infants with low developmental quotient at one year of age continued to have low scores on outcome measures at six years. CONCLUSIONS: Low maternal IQ, maternal education, and antenatal AED exposure were associated with significant impairment of intellectual and language functions for CME at six years.     

Effects of In Utero Antiepileptic Drug Exposure

Recent studies demonstrate an increased teratogenic risk for valproate and a probable increased risk for phenobarbital. Carbamazepine and lamotrigine appear relatively safe; however, results are inconclusive concerning a specific risk for cleft lip/palate for both drugs as well as a dose-dependent effect for malformations associated with lamotrigine. Data regarding teratogenic risks for other antiepileptic drugs are inadequate. Additional studies are needed to delineate further the risks for all antiepileptic drugs and determine the underlying mechanisms.Although the majority of children born to women with epilepsy are normal, they are at increased risk for malformations as well as for poor neuropsychological outcomes (1,2). Antiepileptic drugs (AEDs) have the potential to affect fetal development throughout pregnancy. In the United States alone, at least 45,000 children are exposed to AEDs during pregnancies of mothers with epilepsy (2). Given that less than half of AEDs are prescribed for epilepsy and that the majority are prescribed for psychiatric and pain indications, the total number of children exposed to this category of drugs is substantially higher. The risk of in utero exposure has to be measured against the risk of the underlying disease. For most women with epilepsy, the risks imposed by seizures affecting both the mother and child usually outweigh the risks of drug exposure. Women should not discontinue AEDs without discussion with their physicians, as trauma is the leading cause of nonobstetrical death in pregnant women with epilepsy (3). In a UK survey, the death rate during pregnancy for women with epilepsy was increased tenfold compared to the general population, primarily as a result of seizures (4). Thus, understanding the magnitude and differential effects of AEDs on teratogenesis is important.     

School performance at age 16 in children exposed to antiepileptic drugs in utero--a population-based study

Purpose: In order to evaluate long‐term effects on neurodevelopment in children born to women with epilepsy during pregnancy we studied the children’s school grades at age 16. Methods: We used the Patient Register, the Medical Birth Register, and a local study at South Hospital, Stockholm, to identify women with epilepsy in Sweden who had given birth between 1973 and 1986. The Swedish School Mark Registry was used to obtain information about school grades from the last year of compulsory school, at age 16. Exposed children were compared to all other children born in Sweden between 1973 and 1986. Key Findings: Medical records were analyzed for 1,235 children. Six hundred forty‐one children had been exposed in utero to antiepileptic drugs (AEDs) in monotherapy, 429 in polytherapy, and 165 to no known AED. Children exposed to polytherapy had an increased risk of not receiving a final grade—odds ratio (OR) 2.99 [95% confidence interval (CI) 2.14–4.17]. Children exposed to monotherapy, mainly carbamazepine or phenytoin, did not have a significantly increased risk of not receiving a final grade—OR 1.19 (95% CI 0.79–1.80). Children born to women with epilepsy had a decreased chance of getting a “pass with excellence.” Significance: Exposure to several AEDs in utero may have negative effects on neurodevelopment, and polytherapy should, if possible, be avoided in pregnant women.     

Neuropsychological outcomes in children of mothers with epilepsy.

The study investigated the nature of the effects of maternal epilepsy on cognitive performance of the offspring. One hundred fifty-four children of mothers with epilepsy aged 5 to 11 years (study group), along with 130 control children, comparable with respect to IQ, socio-economic status, age, and gender underwent a neuropsychological assessment using subtests from the NEPSY: A Developmental Neuropsychological Assessment, tapping attentional, auditory-verbal, visuomotor, fine motor, and memory abilities. The study group scored significantly lower than the controls on measures of attention, memory, and fine-motor function. Deficits were more marked in but not limited to the subset of the study group exposed to maternal medication in utero. Group differences on auditory attention were found only in younger children. Valproate-exposed children obtained lower scores on sentence repetition, as well as on the more demanding part of a test of auditory attention, than other children in the study group, suggesting weaknesses in working memory in the former subgroup. Confounding by maternal epilepsy type and polytherapy complicate interpretation of this finding. Differences between subsets of children not exposed to anti-epileptic drugs in utero and controls suggest that both drug exposure and genetic factors may contribute to cognitive deficits associated with maternal epilepsy.     

抗癫药物对妊娠癫癎患者子代的致畸风险

目的:旨在评估抗癫癎药物(AEDs)对妊娠癫癎患者子代出现先天畸形的风险。方法:对妊娠癫癎患者采用登记和随访研究,分析其孕期AEDs用药情况、癫癎发作、妊娠结局及子代出现畸形的风险。结果:入选105例妊娠癫癎患者。服用AEDs患者79/105例(75.2%),未服用AEDs患者26/105例(24.8%)。单药治疗60/79例(75.9%),其中1/60例(1.7%)流产;患者子代中2/60例(3.3%)先天性畸形(1例服用卡马西平,出现先天性心脏动脉导管未闭;1例服用拉莫三嗪,出现无胚心)。联合用药19/79例(24.1%),子代无先天畸形出现。未服用AEDs患者中有2/26例(7.7%)流产,其余患者子代未出现先天畸形。结论:妊娠癫癎孕妇多数于孕期仍服用AEDs,且以单药治疗居多;使用AEDs(分别为卡马西平和拉莫三嗪)患者子代出现2例先天性畸形;丙戊酸钠易致畸但仍在妊娠癫癎中经常使用,本研究中服用丙戊酸钠孕妇未出现子代先天性畸形。     

Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth

OBJECTIVE: The authors evaluated the effects of prenatal antidepressant exposure and maternal depression on infant gestational age at birth and risk of preterm birth. METHOD: Ninety women were followed in a prospective, naturalistic design through pregnancy with monthly assessments of symptoms of depression and anxiety using the Structured Clinical Interview for DSM-IV mood module for depression, the Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Perceived Stress Scale. Participants included 49 women with major depressive disorder who were treated with antidepressants during pregnancy (group 1), 22 women with major depressive disorder who were either not treated with antidepressants or had limited exposure to them during pregnancy (group 2), and 19 healthy comparison subjects (group 3). The primary outcome variables were the infants' gestational age at birth, birth weight, 1- and 5-minute Apgar scores, and admission to the special care nursery. RESULTS: Groups 1, 2, and 3 differed significantly in gestational age at birth (38.5 weeks, 39.4 weeks, 39.7 weeks, respectively), rates of preterm birth (14.3%, 0%, 5.3%, respectively), and rates of admission to the special care nursery (21%, 9%, 0%, respectively). Birth weight and Apgar scores did not differ significantly between groups. Mild to moderate depression during pregnancy did not affect outcome measures. CONCLUSIONS: Prenatal antidepressant use was associated with lower gestational age at birth and an increased risk of preterm birth. Presence of depressive symptoms was not associated with this risk. These results suggest that medication status, rather than depression, is a predictor of gestational age at birth.