Bupropion and possible increased risk of congenital cardiovascular malformations

HSA would like to inform healthcare professionals of the potential risk of congenital cardiovascular malformations associated with the use of bupropion during the first trimester of pregnancy.

Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines, dopamine and noradrenaline, and is indicated for the treatment of depressive illness (Wellbutrin SR®, GlaxoSmithKline Pte Ltd), as well as an adjunct in smoking cessation (Zyban®, GlaxoSmithKline Pte Ltd).

Potential risk of congenital cardiovascular malformations

Data from a recent epidemiological study,¹ along with findings from other studies, showed a possible increased risk of congenital cardiovascular malformations following bupropion exposure during pregnancy. However, the findings and types of cardiovascular defects observed across the studies were not consistent. One study reported a potential increased risk of certain congenital cardiovascular malformations such as ventricular septal defects and left outflow tract heart defects following maternal exposure to bupropion in the first trimester of pregnancy,² while other published data did not find an increased risk when all types of congenital cardiovascular malformations were considered as a group.³

The results of these studies are summarised below.

• An analysis of case-controlled data from the Slone Epidemiology Center Birth Defects Study (7,913 infant cases of cardiac defects and 8,611 controls) did not find a statistically significant increased risk of left outflow tract heart defects with maternal bupropion use (n=2; adjusted odds ratio [AOR]=0.4; 95% CI=0.1, 1.6). However, a statistically significant association was observed for ventricular septal defects (n=17; AOR=2.5; 95% CI=1.3, 5.0) following the use of bupropion alone during the first trimester.¹

• In a retrospective case-control analysis using data from the National Birth Defects Prevention Study (12,383 case infants and 5,869 control infants), a statistically significant association was observed between the occurrence of a left outflow tract heart defects in the infant and self-reported maternal bupropion use in early pregnancy (n=10; AOR=2.6; 95% CI=1.2, 5.7). However, no association was observed between maternal bupropion use and any other type of cardiac defects or with all categories of heart defects combined.²

• A retrospective, managed-care database study (7,005 infants) using United Healthcare data showed that infants exposed to bupropion during the first trimester were not at greater risk for all forms of congenital malformations (AOR=0.95; 95% CI=0.62, 1.45) or cardiovascular malformations (AOR=0.97; 95% CI=0.52, 1.80) when compared to infants exposed to other antidepressants during the first trimester. There was also no increased risk observed for all forms of congenital malformations (AOR=1.00; 95% CI=0.57, 1.73) or cardiovascular malformations (AOR=1.07; 95% CI=0.48, 2.40) in infants exposed to bupropion during the first trimester as compared to those exposed to bupropion outside the first trimester.³

HSA's advisory

To date, HSA has not received any local reports of congenital cardiovascular malformations associated with the use of bupropion.

HSA is working with the company to strengthen the precautions on its use in pregnancy and updating the pre-clinical safety data sections of the local package inserts for all bupropion-containing products to warn of the potential risk of congenital cardiovascular malformations following bupropion exposure. A Dear Healthcare Professional Letter has been issued in December 2012 to highlight the potential risk of congenital cardiovascular malformations associated with the use of bupropion during pregnancy.⁴

Healthcare professionals are advised to be aware of this potential risk when prescribing bupropion to women who are planning to become pregnant or who are pregnant, and to weigh the option of alternative treatments. Should bupropion be considered the treatment of choice in women of child-bearing potential, healthcare professionals are encouraged to inform patients of the potential risk of congenital cardiovascular malformations associated with its use and to emphasise the importance of using an effective birth control method.Healthcare professionals are encouraged to report adverse reactions associated with the use of bupropion to the Vigilance Branch of HSA.

References

1. GSK Protocol 115433. Bupropion and Cardiac Birth Defects (Slone Epidemiology Centre).

2. Am J Obstet Gynecol 2010; 203: e1-6

3. Pharmacoepidemiol Drug Saf 2007; 16: 474-84

4. GSK Dear Healthcare Professional Letter: Zofran (ondansetron) causes dose-dependent QT prolongation, dated 3 Dec 2012.