What are the effects of bupropion (Wellbutrin) on fertility and early pregnancy?

Bupropion Effects on Fertility and Early Pregnancy

Bupropion does not appear to increase the risk of major congenital malformations above baseline, though there is a small absolute increased risk of specific cardiovascular defects (left ventricular outflow tract obstruction and ventricular septal defects) with first-trimester exposure. 1

Impact on Fertility

• No evidence of impaired fertility was found in animal studies at doses up to 300 mg/kg/day (approximately 7 times the maximum recommended human dose). 2
• There are no human studies specifically examining bupropion's effects on fertility or conception rates.

Effects on Early Pregnancy and Fetal Development

Major Malformations

• The overall rate of major congenital malformations does not appear elevated above the general population baseline. 1, 3
• A meta-analysis found the pooled estimated proportion of congenital malformations among live-born infants was 1.0% (95% CI = 0.0%-3.0%), which is within normal population rates. 4

Specific Cardiovascular Defects

• First-trimester exposure is associated with a small absolute increased risk of two specific cardiac malformations:
  • Left ventricular outflow tract obstruction heart defects (adjusted odds ratio 2.9; 95% CI, 1.5-5.5) 1
  • Ventricular septal defects (adjusted odds ratio 2.9; 95% CI, 1.5-5.5) 1
• Despite the elevated odds ratio, the absolute risk remains relatively low given the baseline rarity of these conditions. 1

Other Structural Defects

• A possible increased risk for diaphragmatic hernia exists (adjusted odds ratio 2.77; 95% CI, 1.34-5.71), though the absolute risk is extremely small given the population prevalence of only 0.012%-0.031%. 1

Pregnancy Loss

• There is a possible increased risk for spontaneous abortion. 1
• One prospective study found significantly more spontaneous abortions in the bupropion group (20 out of 136 pregnancies) compared to controls (P = .009), though this rate is similar to other antidepressants. 3
• The spontaneous abortion rate remained within ranges observed with other antidepressant medications during pregnancy. 3

Placental Transfer and Fetal Exposure

• Bupropion and its active metabolites (hydroxybupropion and threohydrobupropion) cross the placenta to the fetal circulation. 5
• Umbilical cord venous plasma concentrations are 30%-60% lower than maternal plasma concentrations, suggesting the placenta provides a partial barrier with possible placental efflux transport. 6
• The median umbilical cord to maternal plasma ratios are: bupropion 0.53, hydroxybupropion 0.21, and threohydrobupropion 0.61. 5
• Fetal exposure to the active metabolites (particularly hydroxybupropion and threohydrobupropion) may be higher than exposure to the parent drug. 5
• Threohydrobupropion concentrations in amniotic fluid are higher than in umbilical cord venous plasma, suggesting fetal enzymes are active in metabolizing bupropion. 5

Birth Outcomes

• Mean birth weight following bupropion exposure was 3305.9 g (95% CI = 3173.2-3438.7 g), which is within normal range. 4
• Mean gestational age at delivery was 39.2 weeks (95% CI = 38.8-39.6 weeks), indicating no increased risk of preterm birth. 4
• One case report documented poor neonatal adaptation with seizures due to prolonged hypoglycemia from severe hyperinsulinism, though this is an isolated report. 1

Pharmacokinetic Changes During Pregnancy

• No clinically meaningful dose adjustments are necessary during pregnancy. 6
• Pregnancy does not significantly alter the steady-state plasma concentrations, metabolite-to-parent ratios, formation clearances, or renal clearance of bupropion or its metabolites. 6
• The stereoselective disposition of bupropion remains unchanged during pregnancy compared to postpartum. 6

Critical Caveats and Confounding Factors

• Confounding by indication cannot be ruled out in most studies—the underlying conditions (depression or smoking) may independently contribute to observed risks rather than the medication itself. 1, 7
• Women using bupropion for smoking cessation represent a particularly complex population where separating drug effects from smoking effects is challenging. 7
• The absolute risk of cardiovascular defects, even if increased, remains relatively low in the context of treating maternal depression or supporting smoking cessation. 1

Clinical Decision-Making Framework

• If already taking bupropion before pregnancy, engage in a risk-benefit discussion regarding continuing at the current effective dose versus considering alternatives. 1
• The benefits of treating maternal depression or supporting smoking cessation may outweigh the small absolute increased risks of specific cardiac defects in many clinical scenarios. 1, 7
• Monitor pregnancy carefully with attention to fetal growth, maternal blood pressure, and appropriate weight gain. 1
• All medications for weight management, including combination products containing bupropion, are contraindicated in individuals who are or may become pregnant. 8