October 15, 2005
October 15, 2005 from ObGynNews By Lee S. Cohen, M.D.
Over the past few years, several studies have addressed the reproductive safety of the selective serotonin reuptake inhibitors. Recent studies have focused on the risk for neonatal discontinuation syndrome or symptoms of perinatal jitteriness associated with maternal use of SSRIs during the latter portions of pregnancy. Estimates of risk of first-trimester exposure to SSRIs derive from data accumulated over the last 15 years, which support the absence of major congential malformations associated with first-trimester exposure. Data on the teratogenicity of SSRIs come from relatively small cohort studies and larger, international teratovigilance programs, and they have cumulatively supported the reproductive safety of fluoxetine (Prozac) and certain other SSRIs. These include a Scandinavian-based registry study of 375 women exposed to citalopram (Celexa) in the first trimester, which failed to indict SSRI as a teratogen. A recent meta-analysis conducted by researchers at the Motherisk Program in Toronto supported the absence of teratogenicity associated with first-trimester exposure to a number of SSRIs.
Another recent report from the Swedish Medical Birth Registry failed to identify higher rates of congenital malformations associated with prenatal exposure to a number of SSRIs, including fluoxetine, citalopram, paroxetine (Paxil), and sertraline (Zoloft). But at the Teratology Society’s annual meeting in June, investigators from the University of British Columbia, Vancouver, reported an increased risk of omphalocele and craniosynostosis associated with first-trimester exposure to SSRIs. Using data from the National Birth Defects Prevention study, they compared data on 5,357 infants with selected major birth defects with 3,366 normal controls and interviewed mothers about exposures during pregnancy and other possible risk factors. Children with chromosomal anomalies or known syndromes were excluded.
They found an association between exposure to any SSRI during the first trimester and omphalocele (odds ratio of 3). Paroxetine accounted for 36% of all SSRI exposures and was associated with an odds ratio of 6.3 for omphalocele. Use of any SSRI during the first trimester was also associated with having an infant with craniosynostosis (odds ratio of 1.8). No association was noted between SSRI use and the other classes of major malformations studied.
This preliminary unpublished report is also described in a letter to physicians from GlaxoSmithKline, which markets paroxetine as Paxil. The letter also includes additional data from an uncontrolled study of SSRI use during pregnancy, which noted a twofold increased risk in overall congenital malformations and cardiovascular malformations (most were ventricular septal defects) in offspring exposed to paroxetine, compared with other SSRIs. These data were derived from an HMO claims database.
Many clinicians who prescribe SSRIs may be confused by the volley of new reports that suggest some potential teratogenic risk associated with this class of compounds. Indeed, previous reports fail to describe such an association. Many more recent findings derive from either retrospective data sets taken from HMO claims data or from case-control studies, which also have certain methodologic limitations, compared with prospective cohort studies.
These recent findings of increased risk with prenatal SSRI exposure are inconsistent with earlier findings. Nevertheless, large case-control studies can uncover an association not previously identified because of the inadequate statistical power of previous cohort studies, which were not large enough to detect an infrequent anomaly.
Even if we assume the associations from the new case-control study are true and that they are indeed causal, an odds ratio of 6.4 is associated with an absolute risk for omphalocele of only 0.18%. Absolute risk is of far greater clinical value than relative risk and should be taken into account before patients are arbitrarily counseled to discontinue antidepressants during pregnancy.
The new findings are not necessarily cause for alarm. Patients who are planning to conceive and are at significant risk for depressive relapse associated with antidepressant discontinuation may benefit from switching to an antidepressant for which there are the most data supporting reproductive safety. These include fluoxetine, citalopram, escitalopram (Lexapro), as well as the older tricyclics.
However, for women who present when pregnant and still taking SSRIs, including paroxetine, discontinuation should not be arbitrarily pursued. Abrupt discontinuation of antidepressants can threaten maternal affective well-being. That is an unacceptable outcome, which can be stated absolutely.