SSRIs in First-Trimester Pregnancy: Small Risks to the Fetus

Summary and Comment |
June 27, 2007

SSRIs in First-Trimester Pregnancy: Small Risks to the Fetus

  1. Peter Roy-Byrne, MD

New data from two large, well-performed studies

  1. Peter Roy-Byrne, MD

Data on the safety of SSRIs in pregnancy are sparse but suggest a small risk for birth defects. Two studies using maternal interviews to determine preconception and first-trimester SSRI exposure provide more data.

The National Birth Defects Prevention Study involved 9622 infants with birth defects (cases) and 4092 controls in eight states; pregnancies occurred between 1997 and 2002. Rate of SSRI exposure was 2.3% (cases, 2.4%; controls, 2.1%). After adjustment for demographics and known or suspected risk factors, SSRIs were significantly associated with anencephaly (9 cases among 214 patients with anencephaly; odds ratio, 2.4), craniosynostosis (24/432; OR, 2.5), and omphalocele (11/181; OR, 2.8). Although the primary analyses did not examine specific SSRIs, a post hoc analysis uncontrolled for multiple tests associated paroxetine with anencephaly, omphalocele, gastroschisis, and cardiac right ventricular outflow defect; fluoxetine with craniosynostosis; and sertraline with anencephaly.

In an analysis partially funded by the manufacturer of paroxetine, the Slone Epidemiology Center Birth Defects Study concentrated on birth defects previously associated with SSRIs among 9849 case infants and 5860 controls at five study sites; pregnancies occurred between 1993 and 2005. Researchers found no elevated risk for craniosynostosis, omphalocele, or heart defects. However, specific SSRIs were associated with elevated risks: sertraline with omphalocele (OR, 5.7) and cardiac septal defects (OR, 2.0), and paroxetine with right ventricular outflow defects (OR, 3.3). Exploratory analyses of 11 other defects (a total of 66 comparisons) revealed some possible associations with sertraline and paroxetine. Non-SSRI antidepressants were not associated with any birth defects.


These two large, carefully performed studies are limited because the rates of SSRI exposure and individual birth defects were so low, because self-reported SSRI use was not confirmed by pharmacy records, and because this research method does not address whether the medication or the depression itself is responsible for these birth defects. Differences in geographic regions and subjects likely led to the divergent results between studies. The only common association, of paroxetine with right ventricular outflow defects, has been reported elsewhere. The lack of association between birth defects and non-SSRI antidepressants in the second study does not eliminate the possibility that depression, rather than SSRIs, is the culprit, as tricyclic antidepressants are these days typically used, in low doses, to treat insomnia and pain, rather than depression.

These data highlight the difficulty of determining treatment for the 10% of pregnant women with depression. Maternal depression itself poses a risk to the developing fetus; women who discontinue antidepressants during pregnancy are three times more likely to redevelop depression than those who continue them; yet, first-trimester SSRI use poses a small but significant fetal risk. Use of established, evidence-based psychotherapies for depression (e.g., cognitive-behavioral and interpersonal psychotherapies) could solve this dilemma for at least some depressed patients, although some women are likely to need medication to effectively treat their depression.


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