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Sertraline use during pregnancy and the risk of major malformations

Published:January 28, 2015DOI:https://doi.org/10.1016/j.ajog.2015.01.034

      Objective

      Given the current debate and growing public concerns on selective serotonin reuptake inhibitors (SSRIs) and birth defects generated by Food and Drug Administration warnings, we aim to quantify the association between first-trimester exposure to sertraline, a first-line treatment, and the risk of congenital malformations in a cohort of depressed women.

      Study Design

      This was a population-based cohort study in Quebec, Canada, 1998 through 2010. From a cohort of 18,493 depressed/anxious pregnancies, sertraline-exposed, nonsertraline SSRI-exposed, non-SSRI exposed, and unexposed (reference category) women were studied. Major malformations overall and organ-specific malformations in the first year of life were identified. Generalized estimating equation models were used to obtain risk estimates and 95% confidence intervals (CIs). Analyses were adjusted for potential confounders.

      Results

      Among the 18,493 eligible pregnancies, 366 were exposed to sertraline, 1963 to other SSRIs, and 1296 to non-SSRI antidepressants during the first trimester of pregnancy. Sertraline use was not statistically significantly associated with the risk of overall major malformations when compared to nonuse of antidepressants. However, sertraline exposure was associated with an increased risk of atrial/ventricular defects specifically (risk ratio [RR], 1.34; 95% CI, 1.02–1.76; 9 exposed cases), and craniosynostosis (RR, 2.03; 95% CI, 1.09–3.75; 3 exposed cases). Exposure to SSRIs other than sertraline during the first trimester of pregnancy was associated with craniosynostosis (RR, 2.43; 95% CI, 1.44–4.11; 19 exposed cases), and musculoskeletal defects (RR, 1.28; 95% CI, 1.03–1.58; 104 exposed cases).

      Conclusion

      Sertraline use during the first trimester of pregnancy was associated with an increased risk of atrial/ventricular defects and craniosynostosis above and beyond the effect of maternal depression. Nonsertraline SSRIs were associated with an increased risk of craniosynostosis and musculoskeletal defects.

      Key words

      Depression is common during pregnancy, and selective serotonin reuptake inhibitors (SSRIs) are the most frequently used antidepressants to treat pregnant women.
      • Cooper W.O.
      • Willy M.E.
      • Pont S.J.
      • et al.
      Increasing use of antidepressants in pregnancy.
      • Jimenez-Solem E.
      • Andersen J.T.
      • Petersen M.
      • et al.
      Prevalence of antidepressant use during pregnancy in Denmark, a nation-wide cohort study.
      • Ramos E.
      • Oraichi D.
      • Rey E.
      • et al.
      Prevalence and predictors of antidepressant use in a cohort of pregnant women.
      Studies concerning the adverse effects of SSRI exposure during gestation on the developing fetus have indicated an increased risk of various congenital malformations,
      • Alwan S.
      • Reefhuis J.
      • Rasmussen S.A.
      • et al.
      Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects.
      • Berard A.
      • Ramos E.
      • Rey E.
      • et al.
      First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage.
      • Kornum J.B.
      • Nielsen R.B.
      • Pedersen L.
      • et al.
      Use of selective serotonin-reuptake inhibitors during early pregnancy and risk of congenital malformations: updated analysis.
      • Louik C.
      • Lin A.E.
      • Werler M.M.
      • et al.
      First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.
      • Pedersen L.H.
      • Henriksen T.B.
      • Vestergaard M.
      • et al.
      Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population-based cohort study.
      • Wogelius P.
      • Norgaard M.
      • Gislum M.
      • et al.
      Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations.
      but inconsistencies between study results remain.
      • Huybrechts K.F.
      • Palmsten K.
      • Avorn J.
      • et al.
      Antidepressant use in pregnancy and the risk of cardiac defects.
      • Malm H.
      • Artama M.
      • Gissler M.
      • et al.
      Selective serotonin reuptake inhibitors and risk for major congenital anomalies.
      • Margulis A.V.
      • Abou-Ali A.
      • Strazzeri M.M.
      • et al.
      Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity-score matched cohort in CPRD.
      • Nordeng H.
      • van Gelder M.M.
      • Spigset O.
      • et al.
      Pregnancy outcome after exposure to antidepressants and the role of maternal depression: results from the Norwegian Mother and Child Cohort Study.
      • Reis M.
      • Kallen B.
      Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data.
      These could potentially be explained by indication bias where the effect of the drug and the indication are correlated and not fully accounted.
      Sertraline is one of the most frequently used SSRIs during pregnancy globally
      • Ramos E.
      • Oraichi D.
      • Rey E.
      • et al.
      Prevalence and predictors of antidepressant use in a cohort of pregnant women.
      • Nordeng H.
      • van Gelder M.M.
      • Spigset O.
      • et al.
      Pregnancy outcome after exposure to antidepressants and the role of maternal depression: results from the Norwegian Mother and Child Cohort Study.
      • Reis M.
      • Kallen B.
      Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data.
      • Colvin L.
      • Slack-Smith L.
      • Stanley F.J.
      • et al.
      Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy.
      • Oberlander T.F.
      • Warburton W.
      • Misri S.
      • et al.
      Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data.
      and is one of the first-line treatments for depression at present. Sertraline has been suggested to increase the prevalence of heart defects
      • Kornum J.B.
      • Nielsen R.B.
      • Pedersen L.
      • et al.
      Use of selective serotonin-reuptake inhibitors during early pregnancy and risk of congenital malformations: updated analysis.
      • Louik C.
      • Lin A.E.
      • Werler M.M.
      • et al.
      First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.
      • Pedersen L.H.
      • Henriksen T.B.
      • Vestergaard M.
      • et al.
      Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population-based cohort study.
      • Jimenez-Solem E.
      • Andersen J.T.
      • Petersen M.
      • et al.
      Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study.
      and craniosynostosis.
      • Louik C.
      • Lin A.E.
      • Werler M.M.
      • et al.
      First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.
      It remains, however, that the majority of studies have low statistical power due to small sample size, or are potentially biased by unaccounted maternal depression effect. Given the current debate, and the public health impact and clinical implication of prescribing and using SSRI in general, and sertraline specifically, during pregnancy on the fetus, we aim to study the association between first-trimester exposure to sertraline and the risk of major congenital malformations in a cohort of depressed pregnant women.

      Materials and Methods

      Setting

      We conducted a register-based cohort study using data from the Quebec Pregnancy Cohort (QPC). The QPC is an ongoing population-based cohort with prospective data collection on all pregnancies that occurred from January 1998 through December 2010 in the province of Quebec. Data on the mothers and children after the end of pregnancy are also collected. Individual-level information is obtained from province-wide databases and linked using unique personal identifiers. The QPC was first constructed by identifying all pregnancies in the Régie de l’assurance maladie du Québec (RAMQ) and the Quebec hospitalization archives (MedEcho) databases; subsequently, first day of the last menstrual period (1DLMP) was defined using data on gestational age, which was validated against patients’ charts.
      • Vilain A.
      • Otis S.
      • Forget A.
      • et al.
      Agreement between administrative databases and medical charts for pregnancy-related variables among asthmatic women.
      Prospective follow-up was available from 1 year before the 1DLMP, during pregnancy, and until December 2010. Analyses of major malformations overall and specific malformations were performed. The data sources for this study included the medical service database (RAMQ: diagnoses, medical procedures, socioeconomic status of women and prescribers), Quebec’s public prescription drug insurance database (drug name, start date, dosage, duration), the hospitalization archive database (MedEcho: diagnoses and procedures), and the Quebec statistics database (Institut de la statistique du Quebec: patient sociodemographic, birthweight). The data sources used and the QPC are described in Bérard and Sheehy.
      • Berard A.
      • Sheehy O.
      The Quebec pregnancy cohort–prevalence of medication use during gestation and pregnancy outcomes.

      Patients

      We included pregnancies with continuous prescription drug insurance coverage of at least 12 months before the 1DLMP and during pregnancy; pregnancies with a diagnosis of depression and/or anxiety (Appendix, Supplementary Table 1) or exposed to antidepressants in the 12 months before pregnancy (Supplementary Table 2); and pregnancies ending with a liveborn singleton. Given that we wanted to have a sample of depressed/anxious women diagnosed before pregnancy, we only considered those who had a diagnosis or were treated with antidepressants in the year before their pregnancy, increasing the specificity of the diagnosis. Within this predefined cohort of depressed/anxious pregnancies, we further considered pregnancies that were exposed to only one type of antidepressant or nonexposed to antidepressants during the first trimester of pregnancy. This excluded pregnancies with multiple different antidepressant exposures during organogenesis, which are likely at increased risk of adverse pregnancy outcomes. We excluded pregnancies exposed to known teratogens during the first trimester of pregnancy according to Chaabane and Bérard,
      • Chaabane S.
      • Bérard A.
      Epidemiology of major congenital malformations with specific focus on teratogens.
      Briggs et al,
      • Briggs G.G.
      • Freeman R.K.
      • Yaffe S.J.
      Drugs in pregnancy and lactation.
      and Kulaga et al,
      • Kulaga S.
      • Zargarzadeh A.H.
      • Bérard A.
      Prescriptions filled during pregnancy for drugs with the potential of fetal harm.
      and pregnancies with newborn diagnosed with chromosomal abnormalities. We further excluded pregnancies resulting in minor malformations alone in newborns. All pregnancies meeting eligibility criteria were analyzed. The study was approved by the Quebec Data Access Agency and the Sainte-Justine Hospital Institutional Review Board.

      Sertraline and other antidepressants

      We identified prescription fillings for sertraline dispensed to women in the cohort from the Quebec public prescription drug insurance database, with the timing of exposure determined by the dispensed date and duration of prescription. The relevant exposure time window was the first trimester confirmed by ultrasound.
      Three comparator groups were defined to take into account the underlying maternal depression. First, 2 active comparator groups included pregnancies with exposure to: (1) nonsertraline SSRI and (2) non-SSRI antidepressant during the relevant time window. Codes of all antidepressants considered are presented in Supplementary Table 2. Second, a nonexposure category was defined as pregnancies with no exposure to antidepressants (sertraline or others) during the time window of interest; the reference category was therefore depressed/anxious pregnant women who were not using any antidepressants, enabling us to better control for the underlying indication.
      Duration of exposure during the first trimester of gestation in the 3 exposure study groups was calculated by adding all antidepressant filling durations over the 14 weeks of the first trimester. Average daily dose (mg/d) of sertraline use during the first trimester was calculated by dividing the cumulative daily dose of sertraline exposure (mg) by the total duration of sertraline use during the first trimester of pregnancy (day). Data on prescription fillings have been validated and compared to real-time maternal reports.
      • Jobin-Gervais K.
      • Sheehy O.
      • Berard A.
      Can we rely on pharmacy claims databases to ascertain maternal use of medications during pregnancy?.

      Outcomes

      Major congenital malformations diagnosed in the first year of life were identified in the RAMQ and MedEcho databases and defined according to International Classification of Diseases, Ninth Revision codes and International Statistical Classification of Diseases, 10th Revision codes (Supplementary Table 3). Minor malformations were excluded because they are likely diagnosed selectively (leading to outcome misclassification); chromosomal abnormalities were also excluded given that they are likely not related to the drug of interest. International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases, 10th Revision codes of major congenital malformations in the QPC have been validated against patient charts.
      • Blais L.
      • Berard A.
      • Kettani F.Z.
      • et al.
      Validity of congenital malformation diagnostic codes recorded in Quebec's administrative databases.
      All organ systems were considered but more specifically: overall cardiac defects; atrial septal defect (ASD)/ventricular septal defect (VSD); and craniosynostosis defined according to the European Registration of Congenital Anomalies and Twins registry.
      • Lechat M.F.
      • Dolk H.
      Registries of congenital anomalies: EUROCAT.

      Statistical analyses

      Within the study cohort, we conducted separate analyses for overall major congenital malformations, and for each organ system malformation.
      Potential confounders were considered for all analyses: (1) sociodemographic variables including maternal age on the 1DLMP, maternal marital status (living alone or cohabiting), receipt of social assistance during pregnancy or 1 year before, education level in years (≤12 or >12), and area of residence on the 1DLMP (urban/rural); and (2) maternal chronic comorbidities during the 12 months prior and during pregnancy including hypertension (chronic and pregnancy induced), diabetes (mellitus and gestational), and asthma. The previous conditions were identified from either diagnoses or disease-specific medications. History of depression, anxiety, and other mental conditions were taken into account per design given that this was an inclusion criterion. To further adjust for potential indication bias we also considered health care utilization during the 12 months prior to the 1DLMP including visits to a psychiatrist; hospitalizations or emergency department visits; the number of medications used other than antidepressants; and number of different prescribers. We also considered pregnancy-related variables including previous pregnancy, abortion, or miscarriage in the year prior to the 1DLMP, and follow-up by a gynecologist. All these variables were either risk factors or determinants for adverse pregnancy outcomes.
      Crude and adjusted risk ratios with 95% confidence intervals (CIs) were calculated for each outcome separately using generalized estimating equations models. For all analyses, the reference category was depressed/anxious pregnant women who were not taking any antidepressant during pregnancy. Statistical analyses were done using software (SAS, version 9.2; SAS Institute Inc, Cary, NC).

      Results

      Within the study population (Figure), 18,493 pregnancies met inclusion criteria, and were thus included in this study; 366 pregnancies (2.0%) were exposed to sertraline, 1963 (10.6%) to nonsertraline SSRIs, and 1296 (7.0%) to non-SSRI antidepressants. Other SSRIs used during the first trimester were paroxetine (1130 [6.1%]), citalopram (587 [3.2%]), fluoxetine (191 [1.0%]), and fluvoxamine (55 [0.3%]); non-SSRI antidepressants used during the first trimester were mainly venlafaxine (739 [4.0%]) and amitriptyline (318 [1.7%]). Sertraline users were exposed to 74.2 mg/d on average (SD 42.6) for a mean duration of 50.9 days (SD 33.1) during the first trimester of pregnancy. The mean exposure duration was 53.3 days (SD 30.7) among nonsertraline SSRI users, and 49.9 days (SD 33.1) for non-SSRI antidepressant users.
      Figure thumbnail gr1
      FigureFlowchart representing cohort study
      1DLMP, first day of last menstrual period; ISQ, Institut de la statistique du Quebec.
      Bérard. Sertraline use during pregnancy and risk of major malformations. Am J Obstet Gynecol 2015.
      We identified 2094 cases of major congenital malformations. Table 1 presents the sociodemographics, medical and pregnancy history, and health care utilization in the year prior to pregnancy for exposed and nonexposed subjects. Table 2 presents the crude and adjusted estimates for the association between the risk of overall and organ-specific major congenital malformations and the use of sertraline, nonsertraline SSRIs, and non-SSRI antidepressant during the first trimester. Adjusting for potential confounders, sertraline use during the first trimester of pregnancy was not statistically significantly associated with the risk of overall major congenital malformations when compared to nonuse of antidepressants in a cohort of depressed women (odds ratio [OR], 1.11; 95% CI, 0.81–1.52; 45 exposed cases). However, sertraline exposure during the first trimester was associated with an increased risk of ASD/VSD specifically (OR, 1.34; 95% CI, 1.02–1.76; 9 exposed cases) and craniosynostosis (OR, 2.03; 95% CI, 1.09–3.75; 3 exposed cases). Exposure to SSRIs other than sertraline during the first trimester of pregnancy was also statistically significantly associated with a 2.4 times increased risk (OR, 2.43; 95% CI, 1.44–4.11) of craniosynostosis, and 1.3 times increased risk (OR, 1.28; 95% CI, 1.03–1.58) of musculoskeletal defects.
      Table 1Characteristics of study cohort
      CharacteristicDepressed nonexposed, n (%) 14,868 (80.4)Sertraline exposed, n (%) 366 (2.0)Nonsertraline SSRIs exposed, n (%) 1963 (10.6)Non-SSRIs exposed, n (%) 1296 (7.0)
      Pregnancy-related
       Gestational age (wk), mean ± SD38.7 ± 1.938.5 ± 1.938.4 ± 1.938.4 ± 2.2
       Birthweight (g), mean ± SD3317.7 ± 601.13259.7 ± 553.73266.4 ± 644.33233.5 ± 607.2
       Newborn sex, male7607 (51.2)194 (53.0)999 (50.9)672 (51.9)
      Socioeconomic status
       Maternal age (y), mean ± SD27.6 ± 5.728.6 ± 6.028.4 ± 5.628.4 ± 5.7
       Urban dweller, n (%)12,420 (83.5)296 (80.9)1602 (81.6)1069 (82.5)
       Welfare recipient, n (%)5863 (39.4)157 (42.9)905 (46.1)555 (42.8)
       Living alone, n (%)3061 (20.6)83 (22.7)487 (24.8)338 (26.1)
      Maternal comorbidities in year before or during first trimester:
       Diabetes, n (%)297 (2.0)11 (3.0)43 (2.2)34 (2.6)
       Hypertension, n (%)685 (4.6)20 (5.5)103 (5.3)103 (8.0)
       Asthma, n (%)2659 (17.9)85 (23.2)445 (22.7)309 (23.8)
      Health services utilization in year before pregnancy
      Visit to physician, mean ± SD9.2 ± 7.110.3 ± 8.99.4 ± 7.99.7 ± 8.1
       Visit to general practitioner, mean ± SD6.6 ± 5.27.3 ± 6.47.0 ± 5.87.2 ± 5.9
       Visit to specialist other than psychiatrist or obstetrician1.7 ± 3.02.3 ± 4.71.8 ± 4.01.8 ± 3.4
       At least 1:
      Psychiatrist visit137 (0.9)3 (0.8)11 (0.6)17 (1.3)
      Obstetrician visit4798 (32.3)101 (27.6)465 (23.7)317 (24.5)
      Emergency department /hospitalization3419 (23.0)85 (23.2)403 (20.5)286 (22.1)
       No. of medications used other than antidepressants
      02375 (16.0)24 (6.6)131 (6.7)72 (5.6)
      1–24124 (27.7)79 (21.6)483 (24.6)292 (22.5)
      3–54748 (31.9)120 (32.8)703 (35.8)444 (34.3)
      ≥63621 (24.4)143 (39.1)646 (32.9)488 (37.7)
       No. of different prescribers
      02375 (16.0)24 (6.6)131 (6.7)72 (5.6)
      1–25651 (38.0)130 (35.5)695 (35.4)456 (35.2)
      ≥36842 (46.0)212 (57.9)1137 (57.9)768 (59.3)
      SSRI, selective serotonin reuptake inhibitor.
      Bérard. Sertraline use during pregnancy and risk of major malformations. Am J Obstet Gynecol 2015.
      Table 2Prevalence of major congenital malformations by organ system among depressed/anxious pregnant women
      Congenital malformationsUnexposed n = 14,868Exposed, n = 3625First-trimester antidepressant exposureCrude prevalenceAdjusted prevalence
      Adjusted for maternal age, welfare status, diabetes, hypertension, asthma, and other medication use.
      Sertraline n = 366Nonsertraline SSRIs n = 1963Non-SSRIs n = 1296Risk ratio (95% CI)Risk ratio (95% CI)
      Major congenital malformations overall1651 (11.10)45 (12.30)236 (12.02)162 (12.50)Sertraline1.13 (0.83–1.55)1.11 (0.81–1.52)
      Nonsertraline SSRIs1.09 (0.94–1.26)1.08 (0.93–1.25)
      Non-SSRI antidepressants1.14 (0.96–1.36)1.12 (0.94–1.33)
      Nervous system117 (0.79)5 (1.37)20 (1.02)10 (0.77)Sertraline1.78 (0.73–4.34)1.67 (0.68–4.13)
      Nonsertraline SSRIs1.30 (0.81–2.10)1.24 (0.77–2.00)
      Non-SSRI antidepressants0.98 (0.51–1.87)0.91 (0.48–1.74)
      Eye, ear, face, and neck86 (0.58)1 (0.27)10 (0.51)11 (0.85)Sertraline0.47 (0.06–3.39)0.46 (0.06–3.32)
      Nonsertraline SSRIs0.88 (0.46–1.70)0.86 (0.45–1.66)
      Non-SSRI antidepressants1.47 (0.79–2.76)1.45 (0.77–2.72)
      Circulatory system408 (2.74)13 (3.55)64 (3.26)32 (2.47)Sertraline1.31 (0.75–2.30)1.28 (0.73–2.23)
      Nonsertraline SSRIs1.19 (0.91–1.56)1.16 (0.88–1.52)
      Non-SSRI antidepressants0.89 (0.62–1.29)0.87 (0.60–1.25)
      Respiratory system81 (0.54)0 (0.00)8 (0.41)13 (1.00)NA
      Digestive system176 (1.18)5 (1.37)23 (1.17)21 (1.62)Sertraline1.15 (0.47–2.83)1.13 (0.46–2.77)
      Nonsertraline SSRIs0.99 (0.64–1.54)0.98 (0.63–1.52)
      Non-SSRI antidepressants1.38 (0.87–2.17)1.33 (0.84–2.11)
      Genital organs160 (1.08)4 (1.09)18 (0.92)13 (1.00)Sertraline0.98 (0.35–2.72)0.97 (0.34–2.75)
      Nonsertraline SSRIs0.84 (0.51–1.38)0.86 (0.53–1.41)
      Non-SSRI antidepressants0.92 (0.51–1.67)0.92 (0.51–1.65)
      Urinary system141 (0.95)3 (0.82)7 (0.36)14 (1.08)Sertraline0.86 (0.27–2.72)0.86 (0.27–2.72)
      Nonsertraline SSRIs0.37 (0.17–0.80)0.37 (0.18–0.79)
      Non-SSRI antidepressants1.14 (0.66–1.98)1.12 (0.65–1.95)
      Musculoskeletal system619 (4.16)16 (4.37)104 (5.30)61 (4.71)Sertraline1.06 (0.64–1.75)1.04 (0.63–1.72)
      Nonsertraline SSRIs1.29 (1.04–1.59)1.28 (1.03–1.58)
      Non-SSRI antidepressants1.14 (0.87–1.49)1.12 (0.85–1.46)
      Cardiac malformations344 (2.31)10 (2.73)51 (2.60)28 (2.16)Sertraline1.19 (0.63–2.25)1.16 (0.62–2.19)
      Nonsertraline SSRIs1.13 (0.84–1.52)1.10 (0.82–1.48)
      Non-SSRI antidepressants0.93 (0.63–1.37)0.91 (0.62–1.34)
      Ventricular/atrial septal defect272 (1.83)9 (2.46)41 (2.09)22 (1.70)Sertraline1.35 (1.01–1.79)1.34 (1.02–1.76)
      Nonsertraline SSRIs1.14 (0.82–1.60)1.13 (0.81–1.58)
      Non-SSRI antidepressants0.93 (0.60–1.43)0.91 (0.59–1.42)
      Omphalocele15 (0.10)0 (0.00)2 (0.10)0 (0.00)NA
      Craniosynostosis63 (0.42)3 (0.82)19 (0.97)7 (0.54)Sertraline1.94 (0.99–3.81)2.03 (1.09–3.75)
      Nonsertraline SSRIs2.30 (1.38–3.85)2.43 (1.44–4.11)
      Non-SSRI antidepressants1.27 (0.58–2.79)1.31 (0.59–2.90)
      Cleft palate26 (0.17)0 (0.00)1 (0.05)1 (0.08)NA
      Nonsertraline SSRIs included paroxetine, citalopram, fluoxetine, and fluvoxamine. Non-SSRI antidepressants included amitriptyline, desipramine, doxepin, imipramine, nortriptyline, trimipramine, clomipramine, tryptophan, trazodone, buspirone, moclobemide, venlafaxine, bupropion, and mirtazapine.
      CI, confidence interval; NA, not applicable due to empty cells; SSRI, selective serotonin reuptake inhibitor.
      Bérard. Sertraline use during pregnancy and risk of major malformations. Am J Obstet Gynecol 2015.
      a Adjusted for maternal age, welfare status, diabetes, hypertension, asthma, and other medication use.

      Comment

      To our knowledge our study is one of a few to investigate the risk of major malformations associated with sertraline and other SSRI exposure during the first trimester of pregnancy in a cohort of depressed pregnant women. We found that women using sertraline during the first trimester were 34% more at risk of having a child with ASD/VSD, and at 2-fold risk of having a newborn with craniosynostosis. Use of nonsertraline SSRIs was also associated with the risk of craniosynostosis and musculoskeletal defects. Given that indication bias is of concern in pharmacoepidemiological studies,
      • Berard A.
      Paroxetine exposure during pregnancy and the risk of cardiac malformations: what is the evidence?.
      using a group of depressed pregnant women not using antidepressants as reference category enables the adjustment for the indication (depression/anxiety) and lifestyles that are associated with the underlying indication (smoking, alcohol use).
      Our results are in accordance with previous studies.
      • Kornum J.B.
      • Nielsen R.B.
      • Pedersen L.
      • et al.
      Use of selective serotonin-reuptake inhibitors during early pregnancy and risk of congenital malformations: updated analysis.
      • Louik C.
      • Lin A.E.
      • Werler M.M.
      • et al.
      First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.
      • Pedersen L.H.
      • Henriksen T.B.
      • Vestergaard M.
      • et al.
      Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population-based cohort study.
      • Colvin L.
      • Slack-Smith L.
      • Stanley F.J.
      • et al.
      Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy.
      • Jimenez-Solem E.
      • Andersen J.T.
      • Petersen M.
      • et al.
      Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study.
      Indeed, Pedersen et al
      • Pedersen L.H.
      • Henriksen T.B.
      • Vestergaard M.
      • et al.
      Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population-based cohort study.
      found an increased prevalence of ASD among children whose mothers were prescribed sertraline in early pregnancy (OR, 3.25; P < .05). This study was similar to ours in terms of data source, time window of antidepressant exposure (first trimester), and congenital malformation detection (first year after birth); however, the general population was used as reference group. Consequently, underlying maternal disease and associated lifestyles could explain the difference in the magnitude of the estimates. A recent Danish study
      • Jimenez-Solem E.
      • Andersen J.T.
      • Petersen M.
      • et al.
      Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study.
      found similar increased risks of cardiac malformation in women exposed to SSRIs during pregnancy. Although a group of women who had discontinued their SSRI before pregnancy was studied in Jimenez-Solem et al,
      • Jimenez-Solem E.
      • Andersen J.T.
      • Petersen M.
      • et al.
      Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study.
      they were allowed to switch to other antidepressants during gestation, thus not enabling for the adjustment of untreated depression. Finally, our results are inconsistent with Margulis et al
      • Margulis A.V.
      • Abou-Ali A.
      • Strazzeri M.M.
      • et al.
      Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity-score matched cohort in CPRD.
      and Huybrechts et al.
      • Huybrechts K.F.
      • Palmsten K.
      • Avorn J.
      • et al.
      Antidepressant use in pregnancy and the risk of cardiac defects.
      This can partly be explained by the fact that in both of these studies, gestational age was estimated and potentially resulted in exposure misclassification, which was more noticeable among preterm pregnancies. Given that prematurity has been associated with SSRI use,
      • Huybrechts K.F.
      • Sanghani R.S.
      • Avorn J.
      • et al.
      Preterm birth and antidepressant medication use during pregnancy: a systematic review and meta-analysis.
      this led to underestimation of exposure among SSRI-exposed pregnant women, resulting in null estimates. Nevertheless, the prevalence of depressed untreated women in our study was comparable to Huybrechts et al.
      • Huybrechts K.F.
      • Sanghani R.S.
      • Avorn J.
      • et al.
      Preterm birth and antidepressant medication use during pregnancy: a systematic review and meta-analysis.
      Our results are consistent with animal and experimental studies, which demonstrated a mechanism whereby alterations in serotonin by SSRIs can impact morphogenesis and organogenesis.
      • Sari Y.
      • Zhou F.C.
      Serotonin and its transporter on proliferation of fetal heart cells.
      • Shuey D.L.
      • Sadler T.W.
      • Tamir H.
      • et al.
      Serotonin and morphogenesis: transient expression of serotonin uptake and binding protein during craniofacial morphogenesis in the mouse.
      • Yavarone M.S.
      • Shuey D.L.
      • Tamir H.
      • et al.
      Serotonin and cardiac morphogenesis in the mouse embryo.
      • Sadler T.W.
      Selective serotonin reuptake inhibitors (SSRIs) and heart defects: potential mechanisms for the observed associations.
      Study strengths include the use of large registers, administrative and clinical databases that provide population-based coverage of Quebec pregnant women, with linkage of data on the individual level; this permitted analysis of a large number of exposed pregnancies with detailed information regarding exposure, outcomes, and potential confounders, limiting selection bias. Exposure data and major congenital outcomes have both been validated against maternal report (medication data) and medical charts (major congenital malformations including ASD/VSD).
      • Jobin-Gervais K.
      • Sheehy O.
      • Berard A.
      Can we rely on pharmacy claims databases to ascertain maternal use of medications during pregnancy?.
      • Blais L.
      • Berard A.
      • Kettani F.Z.
      • et al.
      Validity of congenital malformation diagnostic codes recorded in Quebec's administrative databases.
      Furthermore, although it is true that this does not necessarily mean that women actually took their medications, De Jong van den Berg et al
      • De Jong van den Berg L.T.
      • Feenstra N.
      • Sorensen H.T.
      • et al.
      Improvement of drug exposure data in a registration of congenital anomalies. Pilot-study: pharmacist and mother as sources for drug exposure data during pregnancy. EuroMAP Group. European Medicine and Pregnancy Group.
      reported that 94% of all drugs dispensed to pregnant women are actually taken. In addition, given that antidepressants are given on a continuous basis and over extended periods of time, that women in our study took their antidepressants for 50 days on average during the first trimester of pregnancy increased the likelihood that they were exposed during the appropriate time window of interest (organogenesis). Gestational age has been validated,
      • Vilain A.
      • Otis S.
      • Forget A.
      • et al.
      Agreement between administrative databases and medical charts for pregnancy-related variables among asthmatic women.
      decreasing exposure misclassification bias for the studied time window of interest. Although data on the specific indications for antidepressant use were not available, only pregnant women with a diagnosis of depression or anxiety, or use of antidepressants in the year before pregnancy were studied to control for indication bias per design and to increase the specificity of the diagnosis before pregnancy; depressed untreated pregnant women were therefore used as the reference category. Data in our study were collected prospectively, limiting recall bias.
      The main limitations include missing information on potentially important confounders such as smoking, folic acid intake, and alcohol intake. Although we could not adjust for these variables specifically, we adjusted for these per design by studying only depressed/anxious pregnant women. Indeed, all these variables are associated with depressive status
      • Berard A.
      • Ramos E.
      • Rey E.
      • et al.
      First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage.
      regardless of antidepressant use. Given that it may take many months before obtaining an appointment to a psychiatrist in Quebec, data on psychiatrist visits are used as a proxy for severity of disease rather than presence of depression; diagnoses of depression with or without antidepressant use is a better suited definition for the presence of depression, which was used in this study. Even if our estimates are based on high numbers of exposed cases, we cannot eliminate increased risk in analyses on specific malformations due to lower statistical power for some organ-specific groups. In addition, given the number of comparisons made in this study, we cannot rule out the fact that some of our findings could have occurred by chance alone. Only singletons were considered due to the fact that singleton and multiple pregnancies have different risk factors for adverse pregnancy outcomes. Although it would have been interesting to study multiple births separately, <1% of our sample was excluded because of this criterion. Only liveborns were considered as is the case in all studies like ours. However, it is known that antidepressants are increasing the risk of spontaneous abortions.
      • Nakhai-Pour H.R.
      • Broy P.
      • Bérard A.
      Use of antidepressants during pregnancy and the risk of spontaneous abortion.
      • Einarson A.
      • Choi J.
      • Einarson T.R.
      • Koren G.
      Rates of spontaneous and therapeutic abortions following use of antidepressants in pregnancy: results from a large prospective database.
      Because spontaneous abortion is a determinant of severe malformations,
      • Berard A.
      Paroxetine exposure during pregnancy and the risk of cardiac malformations: what is the evidence?.
      our results are likely underestimates of the true risk. Finally, as we considered pregnant women insured by the public prescription drug insurance program, generalizability of results to those insured by private drug insurance could be affected. However, validation studies have shown that pregnant women receiving medication insurance from Quebec’s public system have similar characteristics and comorbidities as those who have private medication insurance. Although socioeconomic status might differ between the 2 groups, it does not affect internal validity given that all subjects studied have similar socioeconomic status.
      • Berard A.
      • Lacasse A.
      Validity of perinatal pharmacoepidemiologic studies using data from the RAMQ administrative database.

      Conclusion

      In this population-wide cohort study, we found that infants were at increased risk of ASD/VSD and craniosynostosis from maternal exposure to sertraline during the first trimester of pregnancy; they were also at greater risk of craniosynostosis and musculoskeletal defects when exposed to nonsertraline SSRIs, suggesting an SSRI class effect. This confirms results from other studies performed in populations of depressed and nondepressed women. Given that an increasing number of women are depressed during pregnancy, these results have direct implications on their clinical management. Benefits should be weighted against the risk of antidepressants during gestation.

      Appendix. This appendix has been provided by the authors to give readers additional information about their work.

      Supplementary Table 1ICD-9 and ICD-10 codes for diagnoses of depression and anxiety, and other cognitive disorders
      ICD-10ICD-9
      Episodic mood disorders (296)
      F3092960
      F3002960
      F3012960
      F3082960
      F3022960
      F3382961
      F3342961
      F3332961
      F3322961
      F3312961
      F3302961
      F3282961
      F3222961
      F3392961
      F3232961
      F3102962
      F3112962
      F3122962
      F3152963
      F3142963
      F3132963
      F3802964
      F3162964
      F3172965
      F3192965
      F3182966
      F3812966
      F3192967
      F3172967
      F3482968
      F3882968
      F3492969
      F392969
      Neurotic disorders (300)
      F4103000
      F4133000
      F4183000
      F4113000
      F4193000
      F4473001
      F4483001
      F4453001
      F4463001
      F4493001
      F4443001
      F6803001
      F4403001
      F4433001
      F4423001
      F4413001
      F4023002
      F4013002
      F4003002
      F4083002
      F4093002
      F4293003
      F4293003
      F4283003
      F4223003
      F4223003
      F4203003
      F4213003
      F4283003
      F4203003
      F4213003
      F3203004
      F3413004
      F3413004
      F4123004
      F4123004
      F3203004
      F4803005
      F4803005
      F4813006
      F4813006
      F4523007
      F4523007
      F4503008
      F4883008
      F4513008
      F993009
      F4893009
      F4893009
      F993009
      Adjustment reaction (309)
      F4323090
      F4323090
      F9303092
      F4383098
      F4313098
      Depressive disorder, not elsewhere classified
      F5303119
      F3293119
      ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Statistical Classification of Diseases, 10th Revision.
      Bérard. Sertraline use during pregnancy and risk of major malformations. Am J Obstet Gynecol 2015.
      Supplementary Table 2Antidepressant medications
      Antidepressant medication classesAntidepressant generic names
      SSRISertraline
      Citalopram
      Escitalopram
      Fluoxetine
      Fluvoxamine
      Paroxetine
      SNRIVenlafaxine
      TCAAmitriptyline
      Clomipramine
      Desipramine
      Doxepin
      Imipramine
      Nortriptyline
      Trimipramine
      BupropionBupropion excluding Zyban
      OtherBuspirone
      Mirtazapine
      Trazodone
      Moclobemide
      L-tryptophan
      SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
      Bérard. Sertraline use during pregnancy and risk of major malformations. Am J Obstet Gynecol 2015.
      Supplementary Table 3ICD-9 and ICD-10 diagnostic codes used to identify major congenital malformation by organ system
      Congenital malformationICD-9 diagnostic codesICD-10 diagnostic codes
      Major congenital malformations overall740–759 Excluding minor congenital malformations (743.6, 744.1, 744.2–744.4, 744.8, 744.9, 747.0, 747.5, 750.0, 752.4, 752.5, 754.6, 755.0, 755.1, 757.2–757.6, 757.8, 757.9)Q00–Q89 Excluding minor congenital malformations (Q10, Q162, Q17–Q182, Q184–Q189, Q250, Q270, Q381, Q515, Q516, Q520–Q527, Q53, Q664–Q666, Q69, Q70, Q81–Q84, Q950–Q952, Q954, Q955, Q959)
      Nervous system740–742Q00–Q07
      Eye, ear, face, and neck743–744Q10–Q18
      Circulatory system745–747Q20–Q28
      Respiratory system748Q30–Q34
      Digestive system749–751Q35–Q45
      Genital organs752Q50–Q56
      Urinary system753Q60–Q64
      Musculoskeletal system754–756Q65–Q79
      Other congenital malformations757 and 759Q80–Q89
      Cardiac malformations745–746Q20–Q22
      Ventricular/atrial septal defect745.4 and 745.5Q21.0–Q21.2
      Omphalocele756.7Q79.2
      Craniosynostosis756.0Q75
      Cleft palate749Q35–Q37
      ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Statistical Classification of Diseases, 10th Revision.
      Bérard. Sertraline use during pregnancy and risk of major malformations. Am J Obstet Gynecol 2015.

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