Wogelius, Pia*†; Nørgaard, Mette*; Gislum, Mette*; Pedersen, Lars*; Munk, Estrid*; Mortensen, Preben Bo‡; Lipworth, Loren§; Sørensen, Henrik Toft*
Selective serotonin reuptake inhibitors (SSRIs) have become widely used antidepressants.1 Because depression is common in pregnant women,2 the safety of SSRIs during pregnancy is an important public health concern. Human data about the teratogenicity of SSRIs are limited, however, and conclusions are uncertain due to small sample sizes.3–8
We examined the association between maternal use of SSRIs during early pregnancy and the risk of congenital malformations in the offspring.
Study Population and Design
We conducted a cohort study in 4 Danish counties that account for 31% of the Danish population (1.6 million people) with data from 3 overlapping time periods: North Jutland County (data from 1991–2003), Aarhus County (data from 1996–2003), and Ringkjoebing and Viborg Counties (data from 1998–2003). The study includes data on all female county residents who had a live birth or a stillbirth after the 20th week of gestation identified through the Danish Medical Birth Registry, which contains computerized records of all births in Denmark since 1 January 1973.9
Data on Antidepressants and Other Drugs
Since 1968, all Danish residents are assigned a unique civil registration number, which we used to link prescription records with data from the Danish Medical Birth Registry and the hospital discharge registries. The Danish National Health Service reimburses part of the patient expenditure for a wide range of prescribed medicines, including SSRIs. The 4 study counties are served by pharmacies equipped with electronic accounting systems that include the civil registration number of the patient, type of drug prescribed according to the Anatomic Therapeutic Chemical Classification System, amount prescribed, and date of dispensing the drug. All data are transferred to a research database at Aarhus University Hospital. Using the civil registration number, we obtained data on all prescriptions for an SSRI among women in our study from the beginning of the study period until the end of each pregnancy. In Denmark, antidepressant medication is available at pharmacies only if the patient has a prescription from a medical doctor. The prescriptions included were citalopram (N06A B04), sertraline (N06A B06), fluvoxamine (N06A B08), fluoxetine (N06A B03), and paroxetine (N06A B05).
We likewise collected data about prescriptions for antiepileptics (N03A), antidiabetics (A10), and nonsteroidal antiinflammatory drugs (NSAIDs) (M01A) because epilepsy, diabetes, and use of NSAIDs have each been associated with an increased risk of congenital malformations.10–12 Finally, we collected data about prescriptions for non-SSRI antidepressants (N06AA, N06AF, N06AG, N06AX) to examine the proportion of children with congenital malformations after maternal use of other antidepressants.
Data on Congenital Malformations
Through linkage using the civil registration number, data on congenital malformations were abstracted from the hospital discharge registries of the 4 counties. These registries were established in 1977 and include dates of admission and discharge, surgical procedures performed, and up to 20 discharge diagnoses coded by medical doctors according to the Danish version of the International Classification of Diseases (ICD), 8th revision (ICD-8) until the end of 1993 and 10th revision (ICD-10) thereafter. The codes for malformations were 740–759 in ICD-8 and Q00–Q99 in ICD-10. To standardize the observation period, we included only malformations registered during the first year of life. We excluded congenital dislocations of the hip and undescended testes due to the expected poor validity of these discharge diagnoses.13 Furthermore, we excluded children with chromosomal defects from the analysis because of the genetic origin of these malformations.
We obtained data on maternal age, birth order, birth weight, gestational age, and maternal smoking status from the Danish Medical Birth Registry.9 Smoking status is recorded by physicians during the first pregnancy consultation.
We examined the association between SSRI exposure and congenital malformations among women who redeemed a SSRI prescription in early pregnancy (from 30 days before conception until the end of the first trimester) and in the second or third month of pregnancy, which corresponds to the periods during which the fetus is most vulnerable to teratogenic exposures. The comparison group consisted of women with no SSRI prescriptions in the period from 30 days before conception to the end of the pregnancy.
To examine the influence of the underlying disease or disease-related factors, we also examined the association between SSRI exposure and congenital malformations in women who redeemed an SSRI prescription from 6 months until 30 days before conception, in women who redeemed an SSRI prescription in second or third trimester, and in women who redeemed a prescription for a non-SSRI during early pregnancy. The comparison group for these analyses consisted of women with no SSRI prescriptions during the entire study period (1999–2003). First, we constructed frequency tables and computed crude relative risks (RRs) with 95% confidence intervals (CIs). Next, we used logistic regression to estimate the adjusted relative risks (aRRs) for congenital malformations after SSRI exposure while adjusting for the following variables: maternal smoking during pregnancy (smoker, nonsmoker); birth order (1, >1); maternal age (<25, 25–30, and >30 years); prescriptions for antiepileptics, antidiabetics, and NSAIDs during pregnancy; birth year (1991–1994, 1995, 1998); and county (Aarhus, Ringkjoebing, Viborg, North Jutland). All analyses were stratified according to length of gestation (<37 weeks, ≥37 weeks).
We identified the 3 most prevalent congenital malformations in the offspring of women with an SSRI prescription in early pregnancy. The proportions of these malformations were compared with the corresponding proportions among women with no SSRI use to examine any specificity of SSRI with respect to risk of malformations.
Among 151,831 women who had a live birth or stillbirth during the study period, 1051 (0.7%) women redeemed a prescription for an SSRI in early pregnancy (ie, from 30 days before conception until the end of the first trimester); of those, 453 (0.3%) women redeemed the prescription during the second or third month of pregnancy (Table 1). Women with SSRI prescriptions differed from women without prescriptions with regard to maternal age, birth year, county, smoking, prescriptions for antiepileptics and NSAIDs, and preterm delivery.
The 1051 women with SSRI prescriptions any time during early pregnancy gave birth to 51 (4.9%) children with congenital malformations. The aRR for congenital malformations associated with SSRI use in early pregnancy were 1.34 (95% CI = 1.00–1.79) (Table 2). The increased risks were most pronounced among preterm births. Our sample size was too small to allow a stratified analysis according to type of SSRI.
The 453 women with prescriptions during the second or third month of pregnancy gave birth to 31 (6.8%) children with congenital malformations. The corresponding aRR was 1.84 (1.25–2.71) (Table 2). The increased risks were observed in both preterm and term births.
For the subanalyses, we identified 377 women with SSRI prescriptions from 6 months to 30 days before conception. These women gave birth to 17 (4.5%) children with congenital malformations. A total of 62 women with SSRI prescriptions during the second or third trimester gave birth to 2 (3.2%) children with congenital malformations. Finally, 246 women redeemed prescriptions for non-SSRI antidepressants in early pregnancy and gave birth to 2 (0.8%) children with congenital malformations. None of the latter 3 groups had SSRI or non-SSRI prescriptions before or after these periods.
Among the offspring of women with SSRI use during early pregnancy, the majority of the malformations were cardiovascular (29%), muscle and bone (31%), and digestive organ (14%). Among offspring of the SSRI users, the proportion with cardiovascular malformations was 1.4%, with muscle and bone malformations was 1.5%, and with malformations of the digestive organs was 0.7%. The corresponding proportions among the offspring of women with no SSRI prescriptions were 1.0%, 1.1%, and 0.3%.
Our study found an association between maternal use of SSRIs in early pregnancy and an increased risk of congenital malformations in the offspring. The validity of this finding depends on several factors. Data on malformations were obtained from population-based hospital discharge registries, which have been shown to have high validity for these diagnoses, with a misclassification rate of 12% for congenital malformations.13,14 Any coding errors of malformation diagnoses are probably unrelated to exposure to SSRIs and would therefore lead to an underestimation of the relative risk. Physician awareness of the woman's use of SSRIs during pregnancy or of neonatal symptoms associated with SSRI exposure may, however, lead to more thorough examinations of the newborns; this could introduce surveillance bias and lead to an overestimation of risk.15 Although we included malformations diagnosed during the first year of life, we cannot rule out that surveillance bias may explain at least some of the increased risks in our study.
Our definition of the early pregnancy period is wide, and we do not know the exact timing of exposure. We therefore conducted a separate analysis among women with prescriptions during the second and third month of pregnancy, when organogenesis mainly takes place. The observed association between SSRI use and risk of congenital malformations was stronger during this period, which is consistent with a causal effect.
We do not know whether the patients actually took the drugs prescribed. However, because patients were required to pay part of the costs, and because more than half of the women who gave birth to children with congenital malformations redeemed 2 or more prescriptions for SSRIs during the pregnancy, it seems plausible that many (if not most) were taking the drug as prescribed. Moreover, we were not able to identify either malformations detected at prenatal examinations that led to subsequent elective abortions or spontaneous abortions after SSRI exposure.16 If SSRI use increased either type of abortion, the relative risk of malformations in our study may be underestimated.
Finally, we have no information on the woman's underlying psychiatric disease. We cannot rule out an increased risk of congenital malformations caused by the disease itself or by related factors rather than by SSRI use. The proportion of congenital malformation in the offspring was elevated among previous SSRI users in comparison with women who did not use SSRIs, which could indicate an increased risk of congenital malformations related to the underlying disease. However, we found no association with congenital malformations among women using other antidepressants or among women exposed to SSRIs during late pregnancy.
Our study was population-based and included the largest group of pregnant women with prescriptions for SSRIs studied to date. Our risk estimates are not consistent with some previous studies.3–5,7 Most of those studies were based on data from Teratogen Information Service centers in the United States and Canada,3–5 which offer advice to women who are concerned about the potential teratogenic effects of drugs and other exposures and thus represent a selected population. A recent meta-analysis of 7 cohort studies reported a summary risk ratio of 1.01 (95% CI = 0.57–1.80) for congenital malformations after first-trimester exposure to newer antidepressants.8 This result is difficult to interpret, however, because the analysis combined results for SSRIs with those for other antidepressive drugs.
Teratogens presumably do not uniformly increase the rates of all congenital malformations, but rather tend to increase the rates of selected congenital malformations.17 Data from the Swedish Medical Birth Registry6 have shown that among 969 children prenatally exposed to SSRIs and other antidepressants, the relative risk for congenital malformations overall was 1.12 compared with a relative risk between 1.25 and 1.43 for congenital cardiovascular defects. A recent study conducted by United Healthcare found 11 children with congenital cardiovascular malformations (the majority were ventricular septal defects) among 591 children prenatally exposed to paroxetine; compared with children exposed to other antidepressants, the risk associated with paroxetine use was about doubled.18 Our study had limited power to distinguish effects on selected malformations. SSRI exposure was associated with an increase overall as well as within several major categories including cardiovascular malformations. The specific SSRIs do not share chemical structures, and it has been speculated that any teratogenicity may be explained by serotonin-mediated effects on the embryonic development.19 The nonspecific increase in risks in our study could support a theory of generalized serotonin-mediated effect on malformations.
Our data indicate a moderately increased risk of congenital malformations associated with prenatal exposure to SSRIs. Further studies are needed to confirm this risk and to clarify whether the risk is attributable to the drugs themselves, to underlying psychiatric disease, or to other confounding factors.
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© 2006 Lippincott Williams & Wilkins, Inc.