Fast Track

Two studies show that SSRIs are not major teratogens, but more investigation is needed

A. No. However, these two studies found some evidence that use of selective serotonin-reuptake inhibitors (SSRIs) at the time of conception or during pregnancy is associated with anencephaly, craniosynostosis, and omphalocele—although the absolute risk was very low and the association needs to be confirmed by further study. These studies also found a significant association between specific SSRIs and birth defects, such as paroxetine (Paxil) and right ventricular outflow tract obstruction, but, again, the absolute risk was very low and the birth defects in question are rare.

Expert Commentary

Because depression is fairly common among women of reproductive age and is often treated with SSRIs, the issue of teratogenicity is important. Earlier investigations suggested that use of these drugs—particularly paroxetine—during early pregnancy increases the risk of heart defects. These two ongoing case-control studies help clarify the relationship between prenatal use of SSRIs and birth defects, although the issue still has not been addressed definitively.

Both studies involved large populations

The first study was conducted by investigators from the Centers for Disease Control and Prevention and the University of British Columbia. It involved 9,622 infants with major birth defects and 4,092 control infants, all of whom were born between 1997 and 2002. Case infants were identified using birth-defect surveillance systems in eight US states, and control infants were randomly selected from the same regions. A woman was considered exposed to an SSRI if she used any of the medications from 1 month before to 3 months after conception.

Investigators found no significant association between maternal SSRI use in early pregnancy and most categories of birth defects, including congenital heart defects. However, they found a significant association between maternal SSRI use and anencephaly (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0), and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). Use of paroxetine correlated with higher pooled ORs for these three birth defects, as well as a significantly increased risk of right ventricular outflow tract obstruction.

The study by Louik and associates was funded by the National Institutes of Health and GlaxoSmithKline, the manufacturer of Paxil. It involved 9,849 infants with major birth defects and 5,860 control infants, all of whom were born in the United States or Canada between 1993 and 2005. All infants in the case and control groups were identified through their participation in the Slone Epidemiology Center Birth Defects Study, a continuing analysis of medication use in pregnancy. Because Louik and colleagues focused on first-trimester use of SSRIs, exposure was defined as use of any SSRI from 28 days before the last menstrual period through the fourth lunar month (112 days after the last menstrual period.

Use of SSRIs overall was not associated with heart defects, craniosynostosis, or omphalocele, but a significant association was found between paroxetine use and right ventricular outflow tract obstruction (based on 6 exposed subjects) and between septal defects and sertraline use (based on 13 exposed subjects).

TABLE

SSRIs in pregnancy: How they stack up

ANTIDEPRESSANT	ADVANTAGES	DISADVANTAGES*	PREGNANCY CATEGORY
Citalopram (Celexa)	Few interactions with other medications	No behavioral studies in human pregnancy	C
Escitalopram (Lexapro)	Few interactions with other medications	No systematic studies in human pregnancy	C
Fluoxetine (Prozac)	Has been studied in human pregnancy, with data from meta-analysis and neurodevelopmental follow-up	More reports of neonatal side effects than some other antidepressants	C
Paroxetine (Paxil)	None	No behavioral studies in human pregnancy	D; ACOG recommends that this drug be avoided in pregnancy, if possible
		More reports of neonatal side effects than most other antidepressants
		Association with right ventricular outflow tract obstruction, anencephaly, craniosynostosis, and omphalocele, but absolute risk is small
Sertraline (Zoloft)	Relatively well studied in human pregnancy	Possible association with omphalocele and septal defects, but absolute risk is small	C
Sertraline (Zoloft)	Fewer neonatal side effects reported
* ACOG reports that neonates exposed to SSRIs late in the third trimester have developed complications such as jitteriness, mild respiratory distress, transient tachypnea, and poor tone.
Pregnancy category C–Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
Pregnancy category D–Has been found to have a harmful effect on fetuses.
Adapted from “Information for Physicians on Prescription Products to Treat Perinatal Depression,” University of Illinois at Chicago Perinatal Mental Health Project, August 2007 (www.psych.uic.edu/research/perinatalmentalhealth/).

Weigh slight risk of defects against risks associated with discontinuation

These studies confirm that SSRIs are not major teratogens. Nevertheless, any woman planning to conceive and who is worried about using an SSRI during pregnancy should weigh these findings against the risks associated with discontinuing an SSRI during pregnancy.

Heightened surveillance may be justified

Consider second-trimester targeted ultrasonography to rule out fetal anomalies in women who take an SSRI in early pregnancy. And consider psychiatric monitoring for women who discontinue an SSRI before conception or in early pregnancy.

Q. Do SSRIs cause major birth defects?