ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are used as first-line treatment of depression/anxiety disorders because of their efficacy and safety. Because SSRIs cross the placenta, cognitive and behavioral development in the child is a concern. Autism spectrum disorders (ASDs) have been linked to maternal use of SSRIs during pregnancy. In this study, data from Danish health registries were used to assess a nationwide cohort for SSRI use during pregnancy and the risk for ASDs in the offspring.
The cohort comprised all singleton live births in Denmark from 1996 to 2005 and included information on SSRI prescriptions filled by women in the cohort. Follow-up and diagnoses of autism were aggregated according to maternal use or nonuse of SSRIs during pregnancy. Poisson regression was used to compare the rates of ASD among offspring of women exposed or not exposed to SSRIs. The use of SSRIs was defined as use during the period 4 weeks before the beginning of the pregnancy until delivery. To evaluate the potential for confounding by indication, use of SSRIs was also examined from 2 years until 6 months before the beginning of the pregnancy. This allowed classification of women as those who used SSRIs during that period but not during pregnancy, those who used SSRIs before and during the pregnancy, and those who did not use SSRIs before pregnancy but did use them during pregnancy.
From 658,755 live births, the final cohort included 626,875 children (51.3% were boys); 6068 mothers (1.0%) used SSRIs during pregnancy. During 5,057,282 person-years of follow-up, 3892 cases of ASD were identified, including 1603 cases of autistic disorder and 2289 cases of other ASDs, for an incidence rate of 77.0 per 100,000 person-years. The median age at ASD diagnosis was 5.6 years (interquartile range, 4.1–7.5). Strong associations were found between ASDs and maternal psychiatric diagnoses and use of drugs other than SSRIs during pregnancy. The associations suggested possible confounding by indication, especially because mothers with psychiatric diagnoses were also more likely to use SSRIs during pregnancy. During 42,400 person-years of follow-up, 52 cases of ASD were noted among offspring of women exposed to SSRIs during pregnancy (incidence rate, 122.6/100,000 person-years). Compared with no SSRI use before or during pregnancy, this rate corresponded to a crude rate ratio (RR) of 1.62 (95% confidence interval [CI], 1.23–2.13). In a fully adjusted analysis, the use of SSRIs before and during pregnancy or only during pregnancy was not associated with a significantly increased risk for ASDs in the offspring (RR, 1.20; 95% CI, 0.90–1.61). The fully adjusted RRs associated with SSRI use in the first trimester, during pregnancy but not before, and before pregnancy but not during were 1.35 (95% CI, 0.97–1.87), 1.40 (95% CI, 0.92–2.13), and 1.46 (95% CI, 1.17–1.81), respectively. In 574,020 pregnancies that had complete information, the fully adjusted RR was 1.15 (95% CI, 0.85–1.56).
In this study, the use of SSRIs during pregnancy was not associated with a significantly increased risk for ASD in the offspring. The increased risk associated with SSRI use before but not during pregnancy suggests that any risk associated with the use of SSRIs during pregnancy may be related to the indications for their use rather than an effect of the drugs. The potential effect of confounding by indication must be considered in future study designs.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark