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There is a small risk of congenital malformations with fetal exposure to selective serotonin reuptake inhibitors, particularly paroxetine (Paxil and others), during the first trimester.
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Are SSRIs Teratogens?
About 2 years ago, emerging data suggested that fetuses exposed to paroxetine (Paxil and others) had an increased risk of developing major congenital malformations—primarily cardiovascular (BTP 2005;28:45). The most common anomaly was ventricular septal defect. It appeared that the risk of developing any malformation was more than twice as great with paroxetine than with other antidepressants. The US Food and Drug Administration (FDA) moved paroxetine from category C to D, indicating a demonstrated risk to the fetus. Nonetheless, both the FDA and the Canadian Medical Association observed that the absolute risk of heart defects due to paroxetine was small: roughly 2% in fetuses exposed to paroxetine versus 1% among unexposed infants.1
A subsequent Swedish study found no increased risk of malformations with SSRIs as a group during pregnancy.2 Paroxetine, however, was associated with about a 60% increase in the risk of cardiac malformations. Another study found about a threefold increase in major cardiac malformations when paroxetine was used during pregnancy, but only at daily doses greater than 25 mg,3 while independent research calculated about a 34% increased risk for all congenital malformations from any SSRI.4
Two new studies of SSRIs in pregnancy have just been published. Louik and coauthors assessed the association between first trimester maternal SSRI use and the risk of birth defects.5 Using records from five metropolitan areas in the United States and Canada, investigators identified 9849 infants with and another 5860 without birth defects and interviewed the mothers. Overall use of SSRIs was not associated with statistically significantly increased risks of craniosynostosis, omphalocele, or heart defects overall. However, significant associations were identified between sertraline (Zoloft and others) and omphalocele and septal defects and between paroxetine and right ventricular outflow tract obstruction defects. The authors conclude that individual SSRIs might increase the risk of some particular birth defects, but that these are rare and the absolute risks are small.
In an independent study, Alwan and others obtained data on 9622 infants with major birth defects and another 4092 control infants.6 They found no significant association between overall maternal use of SSRIs early in pregnancy and congenital heart defects or most other birth anomalies. Maternal SSRI use—especially paroxetine and citalopram (Celexa)—was associated with anencephaly, craniosynostosis, and omphalocele. Again, the authors note that the absolute risks are small and that the association of SSRIs with these particular anomalies requires confirmation by subsequent research.
In an accompanying editorial, Greene compares the two studies and points out the difficulty of interpreting the data.1 As noted earlier, Alwan et al found significantly increased risks of craniosynostosis, omphalocele, and anencephaly (but not spina bifida) with SSRIs as a group and especially strong associations with paroxetine and citalopram. Louik et al, however, found no relationship between first trimester SSRI exposure and craniosynostosis, omphalocele, or neural tube defects. Neither study found a significant relationship between SSRIs and either diaphragmatic hernia or cardiac malformations overall. And in contrast with previous studies, neither of these two studies found a relationship between SSRIs, individually or as a group, and ventricular septal defects. Louik et al found a significant relationship between all SSRIs and right ventricular outflow tract lesions, but Alwan et al did not. Both studies, however, found a moderate but significant relationship between paroxetine and right ventricular outflow tract lesions.
Greene points out that even among infants exposed to paroxetine during pregnancy, the absolute incidence of right ventricular outflow tract lesions is unlikely to exceed 1%, and the incidence of all congenital heart defects is unlikely to exceed 2%.
Treating a woman during pregnancy always presents a dilemma. While it appears there is a small risk with fetal exposure to SSRIs during the first trimester—probably greater with paroxetine than with other agents—allowing a pregnant woman to experience episodes of depression or anxiety also has adverse consequences for both mother and fetus. An ideal treatment team should include a psychiatrist, obstetrician, spouse or partner, and of course, the patient. A full range of treatment options should be considered, with risks and benefits weighed carefully.
1Greene MF: Teratogenicity of SSRIs—Serious concern or much ado about little? N Engl J Med 2007;356:2732-2733.
2Källén BA, Otterblad Olausson P: Maternal use of selective serotonin reuptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007;79:301-308.
3Bérard A, Ramos E, Rey E, Blais L, St-André M, Oraichi D: First trimester exposure to paroxetine and risk of cardiac malformations in infants: The importance of dosage. Birth Defects Res B Dev Reprod Toxicol 2007;80:18-27.
4Wogelius P, Nørgaard M, Gislum M, Pedersen L, Munk E, Mortensen PB, Lipworth L, Sørensen HT: Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 2006;17:701-704.
5Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA: First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007;356:2675-2683.
6Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, for the National Birth Defects Prevention Study: Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684-2692.