What are the effects of less than 50 mg/day of Spironolactone (aldosterone antagonist) on fetal development in a woman in her 2nd trimester?

Effects of Spironolactone During Second Trimester Pregnancy

Spironolactone should be avoided during the second trimester of pregnancy due to potential risks of feminization of male fetuses and other adverse fetal outcomes, even at doses less than 50 mg/day. 1, 2

Mechanism and Risks to Fetal Development

Spironolactone poses significant risks during pregnancy through several mechanisms:

• Anti-androgenic activity: Spironolactone antagonizes androgen receptors and can interfere with normal male fetal development 1
• Placental crossing: The medication crosses the placenta and can directly affect the developing fetus 2
• Feminization risk: Animal studies have shown feminization of male fetuses when exposed to spironolactone in utero 1
• Dose-independent risk: Even at doses below 50 mg/day, the anti-androgenic effects remain a concern for fetal development 2

Evidence from Human and Animal Studies

The FDA drug label clearly states that spironolactone should be avoided during pregnancy based on:

• Animal studies showing feminization of male fetuses when administered at 200 mg/kg/day between gestation days 13-21 1
• Documented changes in reproductive tract development including decreased weights of ventral prostate and seminal vesicle in males 1
• Enlarged ovaries and uteri in females with persistent endocrine dysfunction into adulthood 1

Human data is limited but concerning:

• Case reports show one case of ambiguous genitalia in a newborn whose mother was treated with spironolactone until week 5 of gestation 2
• Five other cases resulted in normal male genital development, but long-term effects remain unknown 2

Pregnancy Classification and Recommendations

• The FDA classifies spironolactone as Pregnancy Category C 2, indicating potential risks based on animal reproduction studies
• The drug label explicitly recommends avoiding spironolactone in pregnant women or advising pregnant women of the potential risk to male fetuses 1
• All major dermatology guidelines contraindicate the use of spironolactone during pregnancy 2

Alternative Treatments During Pregnancy

For conditions typically treated with spironolactone during pregnancy:

• For hypertension: Other antihypertensives considered safer in pregnancy should be used 2
• For heart failure: Hydralazine, nitrates, and certain beta-blockers (metoprolol) are preferred alternatives 2
• For acne/hormonal conditions: Treatment should be postponed until after delivery or safer alternatives should be considered 2

Clinical Decision Algorithm

1. Immediately discontinue spironolactone if discovered during pregnancy
2. Assess fetal development with detailed ultrasound to evaluate for any genital abnormalities
3. Monitor pregnancy closely for any complications
4. Consider alternative treatments based on the condition being treated
5. Provide genetic counseling regarding potential risks to the fetus

Key Considerations for Healthcare Providers

• Even short-term exposure during critical periods of fetal development may pose risks 3
• The second trimester is a particularly sensitive period for genital development in male fetuses 1
• The risk appears to be dose-dependent in animal studies, but any exposure should be considered potentially harmful 1
• Patients should be counseled about the potential risks and need for close monitoring of fetal development 2

While one recent case report described normal development in a male infant after brief maternal exposure to spironolactone at 16 weeks gestation 3, this single case does not outweigh the substantial evidence from animal studies and the clear FDA warnings against use during pregnancy.