As reported in a previous review,1 approximately 10% of pregnant women experience depression, and up to 20% exhibit depressive symptoms.2 More women have been using the new antidepressants, including the selective serotonin reuptake inhibitors (fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, and escitalopram); research shows up to 3%–6% of pregnant women are using these drugs.3 Although selective serotonin reuptake inhibitors and their effects on pregnancy outcome have been more widely investigated than many other drugs, conflicting data for possible increased risk of major congenital anomalies have been published.4–26 Fluoxetine, citalopram, paroxetine, and sertraline exposure in early pregnancy have been associated with an increased risk of cardiovascular anomalies; fluoxetine with overall cardiovascular anomalies5; citalopram with septal heart defects6; paroxetine with right ventricular outflow tract defects,7,8 atrial septal defects,9 and overall major cardiovascular anomalies10–12; and sertraline with cardiac septal defects.6,8 An increased risk for several other organ group anomalies or overall major congenital anomalies after exposure to fluoxetine (overall major congenital anomalies), citalopram and paroxetine (pooled birth defects including anencephaly, craniosynostosis, and omphalocele), paroxetine (overall major congenital anomalies and neural tube defects), and sertraline (omphalocele, anal atresia, limb reduction defects) has also been observed in meta-analyses or individual studies.7,8,10,11,13 However, the results have been inconsistent and direct teratogenicity for any of the selective serotonin reuptake inhibitors has not been established. On the basis of all current available information, fluoxetine and paroxetine are the individual selective serotonin reuptake inhibitors seriously suspected to cause a marginally increased risk for congenital cardiovascular anomalies.1 We began a register-based study to investigate associations between the use of selective serotonin reuptake inhibitors and major congenital anomalies, including organ group-specific anomalies and subgroups of cardiovascular anomalies using Finnish nationwide register data covering 11 years.
MATERIALS AND METHODS
The data for our study were derived from an ongoing national joint project, Drugs and Pregnancy, in Finland, established by three governmental organizations: the Finnish Medicines Agency; the Social Insurance Institution in Finland; and the National Institute for Health and Welfare for continuous surveillance of safe drug use during pregnancy. The project collects information from three national health registers: The Medical Birth Register and the Register of Congenital Malformations, both maintained by the National Institute for Health and Welfare, and the Drug Reimbursement Register, maintained by the Social Insurance Institution in Finland. The unique personal identification number assigned at birth to all Finnish citizens and permanent residents in Finland makes the linkage of all these registers feasible.
The Medical Birth Register collects data on maternal background and medical history, diagnoses during pregnancy and delivery, and neonatal outcome data up to age 7 days. Data in the register are collected from all maternity hospitals and include all births, including the occasional home births. All neonates are examined at hospital by a pediatrician. All live births and stillbirths with gestational age of 22 weeks or more or birth weight of 500 g or more are included in the register. The register data are confirmed and complemented from the maternity hospital records in cases of conflicting or missing information. Data quality studies have shown that the majority of the register content corresponds well or satisfactorily with hospital record data.27
The Register of Congenital Malformations includes information on live births and stillbirths and fetuses from pregnancy terminations attributable to severe fetal anomaly, all with at least one detected major congenital anomaly, including major structural anomalies, chromosomal defects, and congenital hypothyroidism, classified and coded according to the ninth version of the World Health Organization International Classification of Diseases. Minor anomalies are excluded principally according to the exclusion list of the European Surveillance of Congenital Anomalies, EUROCAT.28 In case of severe fetal major congenital anomalies or disease, permission for termination of pregnancy may be granted on mother's request by a National Board at the National Supervisory Authority for Welfare and Health (Valvira) until 24 completed gestational weeks, but not later. The register obtains information on all these cases from Valvira and confirms data on the termination attributable to severe fetal anomalies from hospitals in charge. More than 10% of all cases of major congenital anomalies in the register are recorded from terminations attributable to severe fetal anomalies.29 The register receives and collects actively data nationwide from several sources, including hospitals, health care professionals, and cytogenetic laboratories. It also obtains and confirms data from the Medical Birth Register, the Register of Induced Abortions, the Hospital Discharge Register, and the Register of Visual Impairments, all nationwide registers maintained by National Institute for Health and Welfare, and from the Cause of Death Register, maintained by Statistics Finland. Information on fetal anomalies diagnosed prenatally and confirmed after termination of pregnancy are included in the register. The validity of the register is considered good and has been ascertained in several studies.29–31
The Drug Reimbursement Register contains data on 98% of reimbursed prescription drug purchases, including data on several chronic illnesses requiring continuous drug treatment.32 Prescription-only medicines deemed necessary for the treatment of an illness are reimbursed under the Social Insurance Scheme, which covers all permanent residents in Finland. The reimbursement system has three levels, including a basic refund category (covering all citizens) and two special reimbursement categories (granted to persons with a diagnosed chronic disease such as severe psychotic and other severe mental disorders, diabetes, and epilepsy, among others).32 Drug purchases are reimbursed concomitantly on purchase at the pharmacy and drugs are supplied to the patient for 3 months at a time. The data in the register include the International Anatomic-Therapeutic-Chemical classification code and information on possible special reimbursement status including indication for treatment. Over-the-counter drugs or medications given to institutionalized persons are not included in the register.
The study material was derived from the Drugs and Pregnancy project database and included the births and terminations attributable to severe fetal anomalies in the years 1996–2006. In that project, beginning of pregnancy has been defined by subtracting the number of days corresponding to gestation length from date of birth or termination attributable to severe fetal anomaly. The best estimated length of gestation at delivery is based on ultrasound examination or the last menstrual period and is recorded in the Medical Birth Register. Data on drug purchases and special reimbursements because of chronic disease were obtained from years 1995 to 2006 originally from the Drug Reimbursement Register and were collected during preconception, each pregnancy trimester, and 3 months after pregnancy. Pregnancy trimesters were defined as 0–12 weeks (first trimester), 13–26 weeks (second trimester), and 27 weeks onward (third trimester). A total of 635,583 mother and child pairs, including all pregnancies ending in live birth, stillbirth, or termination attributable to severe fetal anomaly, were included in the database during the study period.
At least one purchase of one or more selective serotonin reuptake inhibitor drugs (Anatomic-Therapeutic-Chemical classification code on fourth-level, N06AB: selective serotonin reuptake inhibitor antidepressants) and individual selective serotonin reuptake inhibitor drugs during the period of 1 month before pregnancy and first trimester was considered as an indicator for first trimester exposure. The period of 1 month before pregnancy was included to enable inclusion of prescriptions received immediately before pregnancy and potentially used during early pregnancy.
We grouped major congenital anomalies on an organ group level, primarily according to the EUROCAT subgroups.28 Cardiovascular anomalies were further grouped as follows: atrial septal defects; ventricular septal defects (excluding ventricular septal defects in tetralogy of Fallot); right ventricular outflow tract defects (including pulmonary valve stenosis, pulmonary valve atresia, and infundibular pulmonary stenosis, and excluding tetralogy of Fallot); transposition off great arteries; conotruncal heart defects (including tetralogy of Fallot, pulmonary artery atresia with ventricular septal defects, double outlet right ventricle, persistent or common truncus arteriosus, aortic septal defect including aortopulmonary window, and Fallot pentalogy); and left ventricular outflow tract defects (including aortic valve atresia and stenosis). In the Register of Congenital Malformations, patent foramen ovale and patent ductus arteriosus are not considered as major anomalies, whereas ventricular septal defects are considered as major congenital anomalies because no extensive follow-up information is available for possible spontaneous closure of these defects. Neonates exposed to selective serotonin reuptake inhibitors while in utero during the third trimester are at an increased risk for experiencing neonatal adaptation problems, which may further lead to more active diagnostic procedures. When indicated, we performed a subanalysis for ventricular septal defects by excluding neonates needing treatment in the neonatal care unit. Chromosomal defects are registered in the Register of Congenital Malformations as major congenital anomalies, except for sex chromosomal numerical defects, and were included in the basic analyses in the whole study population. We hypothesized that exposure to selective serotonin reuptake inhibitors or any individual selective serotonin reuptake inhibitor does not increase the risk of congenital anomalies.
The use of sensitive health register data in the joint project and for scientific research was approved by the data protection authority. The register linkages have been conducted with the contract between the register-keeping organizations and with permission from the register administrators. The study protocol was approved by the Institutional Ethical Review Board at National Institute for Health and Welfare and Social Insurance Institution in Finland, as well as the Steering Committee of the Drugs and Pregnancy project. The study participants were not contacted and, according to the Finnish legislation, informed consent therefore was not required.
Statistical analyses were performed using SAS 9.1 for Windows. Prevalence of overall major congenital anomalies and specific organ group major congenital anomalies in offspring exposed to selective serotonin reuptake inhibitors or individual selective serotonin reuptake inhibitor drugs in the first trimester was compared with corresponding prevalence in offspring not exposed to selective serotonin reuptake inhibitors or the individual selective serotonin reuptake inhibitor drug (unexposed referent offspring) using χ2 test or Fisher exact test (both two-tailed). Crude and adjusted logistic regression analyses were performed with overall major congenital anomalies and specific organ group major congenital anomalies as dependent outcome variables. Independent variables considered in the adjusted logistic model were maternal age at the end of pregnancy (younger than 20 years or 35 years or older compared with 20–34 years; 0% missing information in the database), parity (no previous deliveries compared with one or more previous deliveries; 0.2% missing information), year of pregnancy ending (0% missing information), marital status (4.9% missing information), smoking during pregnancy (3.1% missing information), purchase of other reimbursed psychiatric drugs (including antiepileptics) during the first trimester, and maternal prepregnancy diabetes (0.3% missing information both). Missing information for categorized variables was categorized as the harmless alternative (ie, not exposed to tobacco). All variables were entered simultaneously in the model. We did not include body mass index because this information was available starting only from the year 2004 and for only 23.7% of all patients. Crude odds ratios (ORs) and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Statistical significance was set at P<.05.
The characteristics of pregnant women purchasing selective serotonin reuptake inhibitor drugs during the first trimester or 1 month before pregnancy (n=6,881) are presented in Table 1. Women with selective serotonin reuptake inhibitor purchases were less likely to be married, twice as likely to smoke or to be entitled to special reimbursement because of chronic disease, and 20-times more likely to have purchased other psychiatric medications than women who had not made any selective serotonin reuptake inhibitor purchases during the corresponding pregnancy period. Of the total number of offspring (n=635,583), 6,976 (1.1%) were exposed to selective serotonin reuptake inhibitors during the first trimester, including 6,902 (98.9%) live births, 30 (0.4%) stillbirths, and 44 (0.6%) fetuses from termination attributable to severe fetal anomalies compared with 623,402 (99.2%) live births, 2,295 (0.4%) still births, and 2,910 (0.5%) fetuses from termination attributable to severe fetal anomalies in unexposed referent offspring.
Overall, major congenital anomalies were more common among the offspring exposed to any selective serotonin reuptake inhibitor, but this difference did not remain statistically significant after adjusting to confounders (Table 2). Variables independently associated with major congenital anomalies in the logistic model were maternal age (OR 1.30, 95% CI 1.26–1.34), year of pregnancy ending (2006 compared with 1996, OR 1.31, 95% CI 1.23–1.39), maternal diabetes (OR 2.74, 95% CI 2.42–3.10), and purchases of other psychiatric drugs (OR 1.53, 95% CI 1.39–1.68). Considering only “other psychiatric drugs” in the logistic model, the association between selective serotonin reuptake inhibitors and major congenital anomalies became statistically insignificant (adjusted OR 1.11, 95% CI 0.98–1.25). When categorizing polytherapy to consist of first trimester use of both selective serotonin reuptake inhibitors and other psychiatric drugs as the exposure, and comparing to unexposed (also including selective serotonin reuptake inhibitor or other psychiatric drugs used either alone), the exposure was statistically significantly associated with overall major congenital anomalies (adjusted OR 1.31, 95% CI 1.04–1.64). Obesity (body mass index 30 or higher) was not independently associated with a statistically significant risk for major congenital anomalies (OR 1.07, 95% CI 0.99–1.17) when restricting the analyses to patients for whom information on body mass index was available. After excluding all major chromosomal anomalies from the study material, the major congenital anomalies rate was 392 of 10,000 in the selective serotonin reuptake inhibitor-exposed cohort and 315 of 10,000 in the unexposed referent offspring and was essentially identical (adjusted OR 1.08, 95% CI 0.96–1.23) to that observed in the whole study. Of individual selective serotonin reuptake inhibitors, fluoxetine and paroxetine use was associated with an increased risk for overall major congenital anomalies, but the risk did not remain statistically significant after adjusting to confounders (Table 2).
Major cardiovascular anomalies were more common in the selective serotonin reuptake inhibitor-exposed offspring when compared with the unexposed referent offspring; however, after adjusting to confounders, the risk did not remain statistically significant (adjusted OR 1.09, 95% CI 0.90–1.32; Table 3). Further, considering only other psychiatric drugs in the logistic model, the association turned insignificant (adjusted OR 1.17, 95% CI 0.96–1.41). For individual selective serotonin reuptake inhibitors, fluoxetine exposure was associated with an increased risk for overall cardiovascular anomalies (adjusted OR 1.40, 95% CI 1.01–1.95) and isolated ventricular septal defects, even when excluding offspring needing treatment in the neonatal care unit from the analysis (P<.01; adjusted OR 2.47, 95% CI 1.50–4.07; Table 3). Exposure to paroxetine was associated with an increased risk for right ventricular outflow tract defects but was based on only three cases (P=.03; adjusted OR 4.68, 95% CI 1.48–14.74; Table 3). No statistically significant associations were observed between the isolated cases of transposition of great arteries, conotruncal heart defects, or left ventricular outflow tract defects and any of the individual selective serotonin reuptake inhibitor drugs (Table 3).
Neural tube defects were more common in the selective serotonin reuptake inhibitor-exposed cohort (prevalence 22 of 10,000 compared with 9 of 10,000 in unexposed fetuses), and eight fetuses among the offspring exposed to citalopram had a neural tube defect diagnosis (prevalence 29 of 10,000; P<.01; adjusted OR 2.46, 95% CI 1.20–5.07; Table 4). Six of the fetuses had spina bifida (including five cases of lumbal, lumbosacral, or sacral meningomyelocele and one case of sacral lipomeningocele), and the remaining two had frontal encephalocele and total craniorachischisis. No difference was observed on individual drug level between the exposed and unexposed offspring in the prevalence of other organ group anomalies (Table 4).
Among the offspring exposed to any selective serotonin reuptake inhibitor, eight8 had fetal alcohol spectrum disorders diagnosed, with a prevalence of 11.5 of 10,000 compared with 75 among the unexposed referent offspring (prevalence 1.2 of 10,000; OR 9.6, 95% CI 4.6–20.0).
We found an increased risk of isolated ventricular septal defects after exposure to fluoxetine, even when excluding neonates needing neonatal care unit treatment from the analysis (adjusted OR 2.47, 95% CI 1.50–4.07). We also observed an increased risk for right ventricular outflow tract defects after exposure to paroxetine (adjusted OR 4.68, 95% CI 1.48–14.74). Citalopram use was associated with neural tube defects (adjusted OR 2.46, 95% CI 1.20–5.07), and we observed a 10-fold increase of fetal alcohol spectrum disorders in offspring of mothers using selective serotonin reuptake inhibitor drugs compared with unexposed offspring.
Our study has several strengths. The register-based approach enabled us to conduct a population-based study with numbers large enough to allow analyses of organ-system specific major congenital anomalies on individual selective serotonin reuptake inhibitor level, focusing on first trimester exposure. The quality of the registers included in the study is high, with the coverage of the Medical Birth Register and Drug Reimbursement Register being close to 100%.27,32 Linkage errors are highly unlikely because of the unique identification number that is assigned to all Finnish citizens and permanent residents in Finland. No validity studies have been performed for the Register of Congenital Malformations regarding cardiovascular malformations, but because of the nationwide collection of data from multiple health care sources and national registers, the quality of the register is considered good.29 In Finland, operative treatment of all severe cardiovascular anomalies is centralized in the Helsinki University Central Hospital Children's Hospital, which actively notifies all these cases to the register. Including all terminations of pregnancy attributable to severe fetal anomaly is an additional strength. Of all cases of major congenital anomalies in the register, 10%–12% are recorded from termination attributable to severe fetal anomalies, with the percentage having remained stable during the past decade.29 The prevalence of termination attributable to severe fetal anomalies in the study material was 47 of 10,000 births and comparable to numbers reported from other European countries.33
Although experimental animal studies have not demonstrated a well-defined increased teratogenic risk for any of the individual selective serotonin reuptake inhibitors, in vitro studies have demonstrated perturbations in neural crest cell migration and heart cell differentiation and proliferation from paroxetine and fluoxetine, possibly referring to cardiac developmental toxicity.34–36 Two previously published studies have suggested an association between fluoxetine and major cardiovascular anomalies,5,14 one of them with partially overlapping material with the present study and covering the years 1996–2001 but presenting no detailed analyses of organ group-specific malformations.14 Neonatal adaptation problems are frequently encountered in neonates exposed to selective serotonin reuptake inhibitors in utero and may predispose to information bias related to diagnostic activity.12,37 We found a risk for isolated ventricular septal defects after fluoxetine exposure when neonates needing treatment in the neonatal care unit were excluded from the analysis, suggesting a true association between fluoxetine and ventricular septal defects. The observed higher rate of right ventricular outflow tract defects in paroxetine-exposed offspring was based on only three cases with a wide CI (adjusted OR 4.68, 95% CI 1.48–14.74). However, the parallel association observed in two previous studies7,8 gives additional strength to our findings.
We found a statistically significant association between citalopram and neural tube defects, with a prevalence more than three-times higher in the exposed than in the unexposed cohort (29 of 10,000 compared with 9 of 10,000; P<.01). Two previous studies with a case-control design have observed unconfirmed associations between selective serotonin reuptake inhibitors and neural tube defects or anencephaly.7,8 Our findings need to be confirmed in future studies. Because of the large number of comparisons performed in our analyses, it is possible that some of the observed associations reflect variation by chance. Some of the associations were also based on small numbers and could reflect random associations. The main findings, however, produced highly significant P values, giving reinforcement to our findings.
We observed a nearly 10-fold higher prevalence of fetal alcohol spectrum disorders in offspring of women using selective serotonin reuptake inhibitors. In Finland, the diagnosis of fetal alcohol spectrum disorders is made according to the U.S. Institute of Medicine criteria,38 which implies that substantial maternal alcohol consumption during pregnancy has been ascertained by the clinician before the fetal alcohol spectrum disorder diagnosis can be made and reported to the Register of Congenital Malformations. The diagnosis of fetal alcohol spectrum disorder is therefore reliable and not dependent on the occasional information on alcohol exposure from the Medical Birth Register or the Register of Congenital Malformations. In addition to the obvious heavy use of alcohol, women using selective serotonin reuptake inhibitors during pregnancy smoke more often and use more prescription drugs, including psychiatric drugs, than selective serotonin reuptake inhibitor nonusers. We found an association between exposure to selective serotonin reuptake inhibitors together with other psychiatric drugs and overall major congenital anomalies, even after adjusting to confounders (adjusted OR 1.31, 95% CI 1.04–1.64).
An important issue capable of reducing the comparability of results obtained in individual studies is which congenital anomalies should be classified as major or minor. The rates of closure for small muscular ventricular septal defects are nearly 90% by the first year of life without surgical or medical intervention. Despite this, ventricular septal defects are mostly classified as major defects because of frequently short follow-up periods in cohort studies, which leave the long-term outcome unknown, or because there is no long-term follow-up in birth register data.1
One limitation is that drug compliance and timing of exposure cannot be confirmed in a register-based setting. However, previous studies have shown that compliance with drugs used for treating chronic illnesses is high during pregnancy.39 If some women did not use their selective serotonin reuptake inhibitor drugs, even if obtaining the prescription from the pharmacy, then this would bias the estimated OR toward unity. Selective serotonin reuptake inhibitor drug treatment is usually discontinued step by step during several weeks with tapering off the dose because abrupt cessation of therapy may give cause withdrawal effects. Therefore, even those women who decided to discontinue the medication when discovering that they were pregnant are likely to have had their fetuses exposed during embryogenesis.
We conclude that exposure to fluoxetine and paroxetine in early pregnancy is associated with a small but established risk of specific cardiovascular anomalies; fluoxetine is associated with isolated ventricular septal defects (0.5% absolute risk increase) and paroxetine is associated with right ventricular outflow tract defects (0.2% absolute risk increase). These findings should guide clinicians to not consider fluoxetine or paroxetine as the first options when prescribing these drugs to women planning pregnancy. Special attention should be given to alcohol use, smoking, and use of other psychiatric drugs in pregnant women using selective serotonin reuptake inhibitors.
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