Different SSRIs associated with specific birth defects; fluoxetine safest

Clinical Question

Does use of a selective serotonin reuptake inhibitor during the first trimester cause birth defects?

Bottom Line

The risk of specific birth defects appears to vary with the particular selective serotonin reuptake inhibitor (SSRI) used by a pregnant woman. Although there were some associations, the absolute risk is quite small of any single birth defect. The safest SSRI in early pregnancy appears to be fluoxetine. (LOE = 3b)


Louik 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.  [PMID:17596601]

Study Design



Industry + govt




Previous research has identified a possible link between SSRIs and birth outcomes such as low birth weight, preterm birth, pulmonary hypertension, and neonatal seizures (Am J Obstet Gynecol 2006;194:961-966 and N Engl J Med 2006;354:579-587). Fetal malformations have not increased with the use of venlafaxine, bupropion, or citalopram (Am J Psychiatry 2001;158:1728-1730, Am J Obstet Gynecol 2005;192:932-936, and Am J Obstet Gynecol 2005;193:2004-2009). In this study, 9849 infants with congenital malformations and 5860 without malformations were identified. Infants with isolated minor defects or with a known Mendelian inherited disorder or a birth defect caused by a known teratogen were excluded. Women were interviewed to determine use of SSRIs during the first 4 months of pregnancy. This study was specifically designed to look for evidence of an association between SSRIs in general (and specific SSRIs) with several previously reported birth defects. The class of drugs as a whole was not associated with an increased risk of craniosynostosis, omphalocele, or cardiac defects other than right ventricular outflow tract obstruction (adjusted odds ratio [AOR] = 2.0; 95% CI, 1.1 - 3.6). However, this risk was primarily associated with paroxetine and, to a lesser extent, sertraline. Similarly, sertraline was associated with an increase in the risk of omphalocele (AOR = 5.7; 1.6 - 20.7) and septal defects (AOR = 2.0; 1.2 - 4.0). The authors also did some exploratory analyses for other birth defects, and found associations between sertraline and diaphragmatic hernia and limb-reduction defects and between paroxetine and clubfoot and neural tube defects. All of the odds ratios for birth defects in this exploratory analysis were greater than 1 for citalopram but confidence intervals were broad and nonsignificant because of small absolute numbers of users. Fluoxetine was not associated with an increase in the risk of any birth defects, with relatively narrow confidence intervals.