Is there a risk associated with using trimethoprim (antibiotic) in women who are pregnant or planning to conceive?

Trimethoprim Use Around Conception: Significant Risks Requiring Caution

Trimethoprim carries substantial risks when used around conception and during pregnancy, including a doubled risk of miscarriage in the first trimester and increased congenital malformations (particularly cardiac and limb defects) when used in the 12 weeks before conception, and should be avoided unless the maternal infection poses greater risk than the medication itself. 1, 2, 3

Risk Profile by Timing of Exposure

Preconception Period (12 weeks before conception)

• Exposure to trimethoprim during the 12 weeks before conception is associated with a doubled risk of major congenital malformations (adjusted OR 1.87,95% CI 1.25-2.81). 3
• Specific malformations include:
  • Heart defects: 2.5-fold increased risk (OR 2.49,95% CI 1.18-5.26). 3
  • Limb defects: 2.2-fold increased risk (OR 2.18,95% CI 1.13-4.23). 3

First Trimester

• Trimethoprim exposure in the first trimester doubles the hazard of miscarriage (adjusted HR 2.04,95% CI 1.43-2.91). 2
• The mechanism involves folate antagonism, which interferes with DNA synthesis in rapidly dividing trophoblasts. 2
• Trimethoprim-sulfamethoxazole may increase risk of congenital abnormalities including urinary tract and cardiovascular abnormalities due to antifolate effects. 1
• The FDA classifies trimethoprim as Pregnancy Category C, stating it may interfere with folic acid metabolism and should only be used if potential benefits justify risks to the fetus. 1, 4

Second and Third Trimesters

• Trimethoprim-sulfamethoxazole can be used with more confidence during the second and third trimesters when the risk of neural tube defects is lower. 5
• For specific serious infections like Q fever, long-term cotrimoxazole therapy throughout pregnancy significantly decreases adverse fetal outcomes (from 81% untreated to 40% treated), with benefits clearly outweighing risks. 1, 5

Near Term and Delivery

• Clinicians should be aware of the risk for neonatal hyperbilirubinemia and kernicterus when cotrimoxazole is prescribed in the third trimester. 5
• Sulfonamides may cause kernicterus in neonates by displacing bilirubin from plasma proteins. 1

Risk Mitigation Strategies

Folic Acid Supplementation

• All women of childbearing potential taking trimethoprim should consume at least 400 μg of folic acid daily from supplements or fortified foods to reduce the risk of neural tube defects. 1, 5
• Concomitant folic acid use is specifically recommended when trimethoprim-sulfamethoxazole is used during pregnancy. 1

Clinical Decision Algorithm

When trimethoprim is being considered around conception or during pregnancy:

1. Avoid if possible, especially:

   • During the 12 weeks before planned conception 3
   • Throughout the first trimester 1, 2
   • Near term or at delivery 5

2. Consider use only when:

   • Safer alternatives (penicillins, cephalosporins, macrolides) have failed or are contraindicated 5
   • The maternal infection poses greater risk than the medication (e.g., Q fever, which can cause intrauterine fetal death) 1, 5
   • Use is during the second trimester when neural tube defect risk is lower 5

3. If trimethoprim must be used:

   • Prescribe high-dose folic acid supplementation (at least 400 μg daily) 1, 5
   • Monitor for adverse pregnancy outcomes including preeclampsia, placental abruption, and fetal growth restriction 6
   • Avoid use near term to minimize neonatal hyperbilirubinemia risk 5

Placenta-Mediated Complications

Maternal exposure to folic acid antagonists like trimethoprim increases risks of multiple placenta-mediated adverse outcomes: 6

• Preeclampsia (adjusted OR 1.52,95% CI 1.39-1.66) 6
• Severe preeclampsia (OR 1.77,95% CI 1.38-2.28) 6
• Placental abruption (OR 1.32,95% CI 1.12-1.57) 6
• Fetal growth restriction <10th percentile (OR 1.07,95% CI 1.01-1.13) 6
• Fetal growth restriction <3rd percentile (OR 1.22,95% CI 1.11-1.34) 6
• Fetal death (OR 1.35,95% CI 1.07-1.70) 6

Safer Alternative Antibiotics During Pregnancy

When treating infections in pregnant women or those planning conception, prioritize: 5

• Oral cephalexin (FDA Category B, compatible with pregnancy) 5
• Azithromycin (safer alternative for penicillin-allergic patients) 5
• Clindamycin (acceptable alternative) 5
• Amoxicillin/clavulanic acid (FDA Category B) 5

Common Pitfalls to Avoid

• Do not assume trimethoprim is safe simply because it is commonly prescribed for urinary tract infections. The antifolate mechanism creates specific pregnancy risks. 2
• Do not prescribe trimethoprim without concurrent folic acid supplementation in women of childbearing potential. 1
• Do not overlook preconception exposure. Risks extend to the 12 weeks before conception, not just during pregnancy. 3
• Do not use near term without considering neonatal kernicterus risk. 1, 5