The FDA advisory on paroxetine.(DRUGS, PREGNANCY, AND LACTATION)

Multiple studies over the past decade have been supportive of the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs) when used during the first trimester; these studies include one recent metaanalysis and other extensive reviews. Particularly reassuring have been the prospective data on fluoxetine (Prozac) and citalopram (Celexa). As a result, clinicians have been relatively reassured about the absence of teratogenic risk associated with the SSRIs.

New concerns were recently raised about the reproductive safety of paroxetine by a presentation at the Teratology Society annual meeting that reported an increased risk of omphalocele associated with first-trimester exposure. This report was based on preliminary, unpublished data from the National Birth Defects Center, which I reviewed in a recent column (OB.GYN. NEWS, Oct. 15, 2005, p. 9). A weaker association was also found between omphalocele and other SSRIs.

A Food and Drug Administration public health advisory about paroxetine followed in December, describing preliminary results of two other unpublished studies indicating that paroxetine exposure in the first trimester may increase the risk of congenital malformations, particularly cardiac malformations. At the FDA's request, paroxetine manufacturer GlaxoSmithKline has changed the pregnancy category label for paroxetine from C to D.

It is surprising that the FDA's recommendation and advisory are based on preliminary analyses from several recent, unpublished, non-peer-reviewed epidemiologic studies, as these are data that should be considered, at least at this point, inconclusive.

Using data from the Swedish National Registry, one study found a 2% rate of cardiac defects among infants exposed during the first trimester to paroxetine vs. 1% among all registry infants. But a previous study using registry data that was based on a slightly smaller number of children exposed to paroxetine did not report this association (J. Clin. Psychopharmacol. 2005;25:59-73).

Another study, using data from a U.S. insurance claims database, found the rate of cardiovascular malformations was 1.5% among infants exposed to paroxetine during the first trimester vs. 1% among infants exposed to other antidepressants. The majority were atrial or ventricular septal defects, which are common congenital malformations.

The modest increases in relative risk of a common anomaly, when derived from a claims database with inherent methodologic limitations, make interpretation of these data problematic. ...