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Birth Defects and SSRIs
Louik C, Lin A, Werler M, Hernandez-Diaz S, et al.
Posted: September 2007  
NEJM  2007;356:2675-2683

In a case-control study, no overall association was found between birth defects and use of SSRIs during the first trimester of pregnancy. Several associations of individual drugs with specific anomalies were identified, but the absolute risks of these rare defects are small.

Methods:   Data was gathered from an epidemiologic database that included patients living in or near Boston, Philadelphia, Toronto, San Diego, and parts of New York. The analysis included women who became pregnant between 1993 and 2004 and excluded those who gave birth to an infant with a genetic or chromosomal birth defect or one with a known cause (e.g., fetal alcohol syndrome). First trimester antidepressant use and birth defects were assessed in 9849 infants with congenital malformations and 5860 infants without. Odd ratios were calculated for overall defects and for specific defects that had been suggested in previous studies to be associated with SSRIs: craniosynostosis, a congenital deformity of the infant skull that occurs when the fibrous joints between the bones close prematurely and leads to an abnormally shaped skull; omphalocele, an abdominal wall defect that allows intestinal organs to protrude through the navel; and congenital heart defects.

Results:   No association was found between SSRI exposure and craniosynostosis, omphalocele, or overall congenital heart defects. However, sertraline was significantly associated with omphalocele, which occurred in 127 infants, 3 of whom had been exposed to sertraline and with septal defects in 13 exposed patients. Paroxetine was significantly associated with right ventricular outflow tract obstruction defects in 6 exposed patients. Exploratory analyses also found several previously unreported associations: sertraline and anal atresia and limb-reduction defects; paroxetine and neural tube defects, club foot, and undescended testes; and non-SSRI antidepressants and anal atresia. All of these exploratory findings were based on small numbers of cases. Fluoxetine was not found to be associated with any congenital anomaly.

Discussion:   The analysis did not confirm previous reports of associations of overall SSRI use with craniosynostosis, omphalocele, or heart defects. It should be noted that because of the large number of comparisons made in the present study, some or all could have achieved statistical significance by chance. In addition, because few infants were exposed to fluvoxamine and citalopram these agents were not included in the analysis. Despite the large sample size, individual outcomes and exposures were rare. The reported associations should not be viewed as strong evidence of SSRI teratogenicity.