Over the past 15 years, multiple studies have addressed the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs). Data on the overall teratogenicity of SSRIs come from relatively small cohort studies and larger international programs, and they have cumulatively supported the reproductive safety of fluoxetine (Prozac) and certain other SSRIs. However, several recent studies have raised concerns regarding the use of SSRIs during pregnancy.

In a study presented at the annual meeting of the Teratology Society in June, investigators from the University of British Columbia, Vancouver analyzed data from the National Birth Defects Prevention study (Alwan et al, 2005). In this case control study 5,357 infants with selected major birth defects were compared with 3,366 normal controls, and their mothers were interviewed regarding exposures during pregnancy and other possible risk factors for major malformations. The investigators found an association between exposure to an SSRI during the first trimester and a three-fold increased risk of omphalocele. The strongest effect was observed with paroxetine, which accounted for 36% of all SSRI exposures and was associated with a 6.4-fold increase in risk for omphalocele. (Omphalocele, an abnormality in which the infant’s intestines or other abdominal organs protrude from the navel, occurs in approximately 1 out of every 4,000 births.) For women who used SSRIs during the first trimester, the risk of giving birth to an infant with craniosynostosis was 1.8 times higher. (Craniosynostosis occurs when the bones in an infant’s skull fuse prematurely, resulting in a malformation of the skull; its prevalence in the general population has been estimated to be 1 per 2,200 births.) No association was noted between SSRI use and any of the other classes of major malformations studied.

In an unpublished report from GlaxoSmithKline, the manufacturer of paroxetine as Paxil, data derived from an HMO claims database were used to estimate risk of major malformations in children exposed to SSRIs and bupropion (Wellbutrin). A preliminary analysis was recently conducted which demonstrated a 2.2-fold increase in risk for congenital malformations as a whole and a 2.08-fold increase in risk for cardiovascular malformations in infants exposed to paroxetine, as compared to children exposed to the other antidepressants in the database. The majority of cardiovascular malformations observed in paroxetine-exposed children were ventral septal defects. When the study was updated to include a larger sample, now including 5956 infants born to 5791 women, the risk of major malformation appeared to be somewhat lower than originally calculated. The updated analysis demonstrated a 1.8-fold increase in overall risk of malformations and showed a trend toward an increased risk for cardiovascular malformation (odds ratio of 1.54) in paroxetine-exposed infants. The prevalence of congenital malformations as a whole and cardiovascular malformation alone were approximately 4% and 1.5%, respectively (see communication, GlaxoSmithKline, December 2005).

In another preliminary report, presented at the 21st International Conference of Pharmacoepidemiology and Therapeutic Risk Management, Wogelius and colleagues (2005) studied pregnancy outcome in women (n=1054) who filled a prescription for SSRls from 30 days before conception to the end of the first trimester, as compared with women with no SSRI prescriptions during this period (n=150,908). The investigators observed a 1.4 fold increase in risk for major malformations as a whole and a 1.6 fold increase for cardiovascular malformations among the infants born to women who filled a prescription for SSRIs, as compared to women who did not. (Paroxetine-specific data were not presented in this report.)

While an earlier report from the Swedish Medical Birth Registry, including 709 children exposed to paroxetine, did not demonstrate an increased risk of major malformations among children exposed in utero to paroxetine or other SSRIs (Hallberg & Sjoblom, 2005), the most recent analysis of this registry has suggested an increased risk of cardiovascular malformation in infants exposed to paroxetine (see communication, GlaxoSmithKline, December 2005). This analysis assessed outcomes in 5,175 infants born to mothers taking SSRIs in early pregnancy and included 822 exposed to paroxetine. The overall prevalence of major malformations in the paroxetine-exposed infant was 4.9%, which did not differ significantly from the rate (4.8%) observed in unexposed infants. There was, however, a 1.78-fold increased risk of cardiovascular malformation in paroxetine-exposed children; the majority of these defects were ventricular or atrial septal defects. Infants exposed to other SSRIs did not have an increased risk of cardiac defects.

These recent findings of increased risk with prenatal paroxetine exposure are inconsistent with earlier findings. Ericson and colleagues published a study which included 122 paroxetine-exposed infants and demonstrated no difference in the rates of major malformations between paroxetine-exposed infants and controls (Ericson et al, 1999).

Similarly, another report including 97 paroxetine-exposed infants did not show an association between paroxetine exposure in utero and an increased risk of malformation (Kulin et al, 1998). These reports are complemented by a recent meta-analysis conducted by researchers at the Motherisk Program in Toronto; an analysis of seven prospective studies including a total of 1774 infants exposed to newer antidepressants in utero suggests that the newer antidepressants are not associated with an increased risk of major malformations above the baseline risk (Einarson et al, 2005).

This volley of conflicting reports has left many clinicians confused and uncertain about how to counsel their patients regarding the use of SSRIs during pregnancy. The differences in the results from the available studies and the diversity in the types of abnormalities reported make it difficult to definitively draw a causal link between paroxetine exposure and any particular congenital abnormality. While the recent studies raise concerns, it is important to note their limitations. Several of these studies use data from prescription databases, where it is not known whether the mothers actually took the medication in question. Furthermore, the data may be confounded by the use of other medications during pregnancy. Also complicating the matter is the fact that these data are preliminary; re-analysis of these data has often yielded findings that are significantly different from the original reports.

While there is clearly a need for more thorough analysis of the existing data, these reports, taken together, may signal an increase in risk of malformations in children exposed to paroxetine. However, it is important to put this risk in perspective. Even if we assume the associations from the new case-control study are true, a 6.4-fold increase in risk for omphalocele translates into an absolute risk of only 0.16% (approximately 2 out of every 1,200 births). Absolute risk is of far greater clinical value than relative risk and should be taken into consideration 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 in the setting of antidepressant discontinuation may benefit from using an antidepressant for which there are more data supporting reproductive safety. These include fluoxetine and citalopram, as well as the older tricyclic antidepressants. However, for women who present when pregnant and are still taking paroxetine, discontinuation should not be arbitrarily pursued. Abrupt discontinuation of antidepressants can threaten maternal affective well-being and may increase the likelihood of postpartum depression. If, after having a discussion with her physician, a woman does decide that she wants to discontinue paroxetine, the drug should be slowly tapered off over a number of weeks.

Lee S. Cohen, MD
Ruta Nonacs, MD PhD

“Dear Doctor” Letters from GlaxoSmithKline: September 2005 and December 2005

New FDA Guidelines concerning paroxetine during pregnancy (Issued September 2005)

Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005; 14(12 ): 823-827.

Alwan S, Reefhuis J, Rasmussen S, et al. Maternal use of selective serotonin re-uptake inhibitors and risk for birth defects, (abstract). Birth Defects Research (Part A): Clinical and Molecular Teratology 2005;73:291.

Hallberg P, Sjoblom V. The use of selective serotonin reuptake inhibitors during pregnancy and breast- feeding: a review and clinical aspects. Journal of Clinical Psychopharmacology 2005; 25 (1): 59-73

Wogelius P, Norgaard M, Muff Munk E, et al. Maternal use of selective serotonin reuptake inhibitors and risk of adverse pregnancy outcomes, (abstract). Pharmacoepidemiology and Drug Safety 2005;14:S143.

Kulin NA, Pastuszak A, Sage S, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors – A prospective controlled multicenter study. JAMA 1998;279:609-610.

*This post was originally published as an article in the December 2005 newsletter.

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