Depression and SSRI Exposure

June 15, 2009

June 2009, ObGyn News, Lee S. Cohen, M.D.

Studies conducted over the last decade  have consistently supported the conclusion that pregnancy is not protective with respect to risk for new onset or recurrence of major depression. The last decade also has produced numerous studies evaluating the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) with respect to the risk for major malformations, with most data supporting safety or suggesting a small absolute risk of malformations. Therefore, despite some earlier concerns about a possible increased risk for cardiovascular malformations associated with first trimester exposure to paroxetine (Paxil), data suggest that the absolute risk of major congenital malformations associated with first-trimester exposure to SSRIs is small.

There remain, however, residual concerns regarding the risk for preterm labor and neonatal withdrawal syndromes associated with SSRI use during pregnancy, particularly during the latter stages of gestation. The absolute risks for these types of obstetrical and neonatal difficulties remain unclear. With respect to the flip side of the risk-benefit decision, the potential impact of depression alone on the risk for major malformations and other obstetrical and neonatal outcomes, unfortunately, data also are inconclusive. Some studies have used large administrative databases to examine the effects of antidepressants and depression on various obstetric and neonatal outcomes, but these studies have obvious methodologic limitations with respect to being able to confirm either exposure.

Separating out the effects of exposure to depression versus SSRI use during pregnancy is critical because these two factors must be weighed against each other and balanced in one direction or the other when patients and clinicians make decisions about the relative risks and benefits of taking a medication during pregnancy or assuming the risk of an untreated psychiatric disorder.

One recent study represents an important effort to delineate the differential effects of depression and SSRI exposure during pregnancy on obstetric and neonatal outcomes (Am. J. Psychiatry 2009;166:557-66). The prospective, multicenter study evaluated the relative impact of depression and SSRIs on minor physical anomalies, maternal weight gain, infant birthweight, pregnancy duration, and neonatal characteristics in 238 pregnant women who were divided into three groups: those with no SSRI, no depression; those with continuous or partial exposure to an SSRI during pregnancy; and those with major depressive disorder (continuous or partial). As noted previously, while this question has been addressed in previous studies using  large administrative databases, this is the first prospective study to do so.

Although limited by small sample sizes in the different groups, the study found no association between partial or continuous exposure to SSRIs and an increased risk in minor anomalies, or between depression and an increased risk of minor anomalies. No major malformations were observed in any group. These results are at variance with the landmark 1996 study reporting an increased risk for minor anomalies associated with first-trimester SSRI exposure (N. Engl. J. Med. 1996;335:10105). In this new study, there was also no association between depression or SSRI exposure and reduced maternal weight gain. Mean infant birth weights were similar in the groups (doi:10.1176/appi.ajp.2008.08081170).

What was particularly noteworthy in this study was that, among women with continuous depression without exposure to an SSRI and those with continuous SSRI exposure, more than 20% of the infants were delivered preterm, compared with 4%-9% of the infants in the other groups. Hence, these results don’t provide compelling data driving the risk-benefit decision with respect to the differential effects of either exposure to SSRI or depression, at least with respect to certain outcomes.

Finally, there were no differences associated with exposure to either continuous SSRI treatment or continuous depression with no SSRI and neonatal adaptation, including respiratory signs (with the exception of 5-minute Apgar scores) or admissions to the neonatal intensive care unit, after adjusting for maternal age, race, and gestational age.

In my view, the data from this study—although advancing the field and representing one more step forward in scientifically delineating the relative risks of antidepressants during therapy—don’t let the clinician off the hook, because the clinician can neither discount the impact of exposure to the medicine or to the disorder. Therefore, patients and their doctors again are left making these individual decisions based on the patient’s wishes, available reproductive safety data, and the severity of the underlying psychiatric disorder.


Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, Boston, which provides information about pregnancy and mental health at He also is a consultant to manufacturers of SSRIs.