What are the risks of using bupropion during pregnancy?

Bupropion Use During Pregnancy

Bupropion does not appear to significantly increase the overall risk of major congenital malformations during pregnancy, though there may be a small absolute increase in specific cardiovascular defects that requires careful consideration. 1, 2

Overall Malformation Risk

The most recent 2024 guidelines from the American Journal of Obstetrics and Gynecology clearly state that bupropion does not seem to be associated with major congenital malformations or other significant adverse obstetrical outcomes, although data are limited 1. This is corroborated by FDA labeling, which notes that epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall 2.

Large-scale data supports this reassuring finding:

• International Bupropion Pregnancy Registry: 675 first-trimester exposures showed no increased overall malformation risk 2
• United Healthcare database: 1,213 first-trimester exposures similarly showed no increased overall risk 2
• Meta-analysis pooled estimate: 1.0% congenital malformations among live-born infants (95% CI = 0.0%-3.0%) 3

Specific Cardiovascular Concerns

The evidence regarding specific cardiac defects is mixed and requires nuanced interpretation:

Left Ventricular Outflow Tract Obstruction (LVOTO)

• One study found increased risk (incidence 0.279% vs 0.07% with other antidepressants) 1
• National Birth Defects Prevention Study: adjusted OR 2.6 (95% CI 1.2-5.7) 2, 4
• However, confounding by indication cannot be ruled out, and other studies have not replicated this finding 1, 2
• The United Healthcare database lacked sufficient power to evaluate this association 2

Ventricular Septal Defects (VSD)

• Slone Epidemiology Study: adjusted OR 2.9 (95% CI 1.5-5.5) for first-trimester exposure 1
• When bupropion used alone (not combined with other antidepressants): adjusted OR 2.5 (95% CI 1.3-5.0) 5
• However, the NBDPS and United Healthcare studies did not find this association 2

Critical caveat: The absolute risk remains small even if these associations are real, and the FDA notes that findings are inconsistent and do not allow definitive conclusions 2.

Other Pregnancy Outcomes

Spontaneous Abortion

• Possible increased risk, but confounding by indication (depression itself, smoking) cannot be excluded 1

Diaphragmatic Hernia

• One study suggested possible increased risk (adjusted OR 2.77; 95% CI 1.34-5.71) 1
• However, the absolute risk is extremely small given the rarity of this defect (population prevalence 0.012%-0.031%), and other studies have not confirmed this 1

Poor Neonatal Adaptation

• Only one case report of seizures due to prolonged hypoglycemia from severe hyperinsulinism 1
• This is not a consistent finding

Birth Weight and Gestational Age

• Meta-analysis shows reassuring outcomes:
  • Mean birthweight: 3305.9 g (95% CI 3173.2-3438.7 g) 3
  • Mean gestational age: 39.2 weeks (95% CI 38.8-39.6 weeks) 3

Long-Term Neurodevelopmental Outcomes

A recent, large, well-controlled study demonstrated no increased risks for long-term neurodevelopmental outcomes including psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment 1. Further research is needed to clarify a possible increased risk for ADHD in offspring, though confounding by indication is likely 1.

Clinical Decision-Making Algorithm

When considering bupropion in pregnancy:

1. Weigh maternal risk of untreated depression - Women who discontinue antidepressants during pregnancy are more likely to experience relapse of major depression 2

2. Consider the indication:

   • For depression alone: Evaluate if other antidepressants with more robust pregnancy data might be preferable
   • For depression + smoking cessation: Bupropion may offer dual benefits that outweigh theoretical risks 6

3. First-trimester exposure requires specific counseling:

   • Overall malformation risk: Not increased
   • Specific cardiac defects: Small absolute risk increase possible but inconsistent across studies
   • If cardiac defects are a particular concern, consider fetal echocardiography

4. Document the risk-benefit discussion including:

   • Risks of untreated maternal depression
   • Inconsistent evidence for specific cardiac defects
   • Overall reassuring data for major malformations
   • Lack of long-term neurodevelopmental concerns

Important Caveats

• Caution is advised per current guidelines 1
• Data remain limited in quality and quantity 1, 3
• Confounding by indication (depression, smoking) is a persistent limitation across studies 1, 2, 4
• The small number of exposed cases in individual studies limits definitive conclusions 2, 5
• Animal studies showed fetal malformations in rabbits at doses equivalent to or greater than human doses, though not in rats 2