Bupropion therapy in pregnancy and the occurrence of cardiovascular malformations in infants

Bupropion is an aminoketone marketed as an oral antidepressant and non-nicotine smoking cessation aid.1,2 It is listed by the United States Food and Drug Administration as a pregnancy category C medication. A retrospective cohort study of maternal first trimester bupropion use and the occurrence of congenital malformations in infants previously published by Cole et al. (2007)3 showed that the prevalence of all congenital and all cardiovascular malformations among infants born to women exposed to first trimester bupropion therapy, regardless of concurrent exposure to other antidepressants, was comparable with infants born to women exposed to all other antidepressants in the first trimester or to bupropion outside of the first trimester. A subsequent article by Alwan et al. (2010)4 described the association between maternal bupropion treatment in early pregnancy and congenital heart defects in infants from National Birth Defects Prevention Study (NBDPS) data. They reported an approximately two and a half-fold increase in left ventricular outflow tract obstruction (LVOTO) defects with bupropion use in early pregnancy (crude odds ratio [OR]: 2.2, 95% confidence interval [CI]: 1.0–4.8; adjusted OR: 2.6, 95% CI: 1.2–5.7). Alwan et al. (2010)4 also calculated a crude risk ratio (RR) using the Cole et al. (2007)3 published data and found an approximately threefold increase in LVOTO with first trimester bupropion exposure compared with other antidepressant use (RR: 3.2; 95% CI: 1.0–10.6). 4 Given the findings of Alwan et al. (2010)4 using both NBDPS and the published Cole et al. (2007)3 data, we refined the original analysis of the Cole et al. (2007)3 data to examine specific cardiovascular malformations, in particular LVOTO. To validate the findings of Alwan et al. (2010)4 using the Cole et al. (2007)3 data, we refined the exposure categories to include monotherapy cohorts and clinically categorized the specific cardiovascular malformations using the same system employed by Alwan et al. (2010)4 and described in detail by Botto et al. (2007). 5 This classification system, based on developmental and epidemiologic considerations, is designed to facilitate the assessment of isolated cardiac defects. We utilized the same study population identified from an administrative claims database for the Cole et al. (2007)3 study of bupropion use during pregnancy, which consisted of women aged 12–49 years at the time of delivery with at least one dispensing of bupropion or another antidepressant from pharmacy claims between 1 January 1995 and 30 September 2004. Methods for dataset development are described in detail elsewhere.3 The three following exposure cohorts originally created in Cole et al. (2007)3 included: maternal first trimester exposure to bupropion, regardless of other antidepressant exposure (‘bupropion first trimester monotherapy or polytherapy’), maternal first trimester exposure to antidepressants other than bupropion (‘other antidepressants first trimester monotherapy or polytherapy’), and maternal exposure to bupropion outside the first trimester, regardless of other antidepressant exposure (‘bupropion outside first trimester monotherapy or polytherapy’). For the current analysis, the following monotherapy cohorts were also subsetted from the original cohorts: maternal first trimester exposure to only bupropion (‘bupropion first trimester monotherapy’), maternal first trimester exposure to only one type of antidepressant other than bupropion, (‘other antidepressants first trimester monotherapy’), and maternal exposure to only bupropion outside the first trimester (‘bupropion outside first trimester monotherapy’). For this analysis, a pediatric cardiologist reviewed previously abstracted medical records from Cole et al. (2007)3 for specific cardiovascular malformations. The malformations were classified using the same categorizations used in Alwan et al. (2010)4 and described in detail by Botto et al. (2007). 5 To