What are the risks of using ACE (Angiotensin-Converting Enzyme) inhibitors, Angiotensin Receptor Blockers (ARBs), and Spironolactone (Aldosterone Antagonist) during pregnancy?

Side Effects of ACE Inhibitors, ARBs, and Spironolactone in Pregnancy

ACE inhibitors, ARBs, and spironolactone are absolutely contraindicated throughout pregnancy due to severe fetotoxicity and must be discontinued immediately upon pregnancy planning or confirmation. 1

Specific Fetal Complications

ACE Inhibitors and ARBs

These medications cause a constellation of severe fetal abnormalities when used during pregnancy:

Second and Third Trimester Exposure:

• Renal tubular dysgenesis (abnormal kidney development leading to permanent renal failure) 2, 3
• Anuria-oligohydramnios (absent or severely reduced amniotic fluid) 3, 4
• Profound fetal hypotension (due to disruption of the renin-angiotensin system) 3, 4
• Pulmonary hypoplasia (underdeveloped lungs secondary to oligohydramnios) 5, 3
• Intrauterine growth restriction 2, 6
• Hypocalvaria (incomplete skull bone formation) 3, 4
• Intrauterine fetal death 2, 3

First Trimester Exposure:

• Recent high-quality data from the ESC Registry of Pregnancy and Cardiac Disease (5,739 pregnancies) demonstrates that ACE inhibitor use during the first trimester increases the risk of congenital anomalies 3.2-fold (odds ratio 3.2,95% CI 1.0-9.6) 7
• This finding contradicts older assumptions that first-trimester exposure was safe 7

Spironolactone

Spironolactone causes anti-androgenic effects on the developing fetus:

• Feminization of male fetuses when exposed during late embryogenesis 8
• Abnormal sex differentiation in male fetuses due to testosterone antagonism 8
• Endocrine dysfunction in female fetuses including enlarged ovaries and uteri 8
• Decreased weights of male reproductive organs (ventral prostate, seminal vesicles) that persist into adulthood 8

Critical Timing Considerations

The evidence clearly shows:

• All three trimesters are dangerous - ACE inhibitors should be avoided even in the first trimester based on the most recent 2024 data 7
• Discontinue immediately upon pregnancy planning - there is no need to stop months in advance, but switching must occur before conception 5, 7
• Women of childbearing potential taking these medications require preconception counseling about switching to safe alternatives 1, 5

Safe Alternative Medications

First-line alternatives recommended by multiple guidelines:

For Acute/Severe Hypertension in Pregnancy:

• Labetalol IV: 20 mg initial bolus, then 40 mg after 10 minutes, then 80 mg every 10 minutes (maximum 220 mg) 9
• Hydralazine IV: 5 mg bolus, then 10 mg every 20-30 minutes (maximum 25 mg) 9
• Nifedipine (long-acting oral): 10 mg orally, repeat every 20 minutes (maximum 30 mg) if IV access unavailable 9

For Chronic Hypertension Management:

• Long-acting nifedipine: 30 mg once daily, titrate up to 90 mg daily as needed 5
• Methyldopa: 250-500 mg twice daily (longest safety record in pregnancy) 1, 9, 5
• Labetalol (oral): 100-400 mg twice daily 5

Important: Never use immediate-release nifedipine due to risk of precipitous hypotension 5

Blood Pressure Targets During Pregnancy

Target BP: 110-135/85 mmHg 1, 5

• This range reduces maternal hypertensive complications while minimizing fetal growth impairment 1
• Lower targets may improve long-term maternal outcomes but risk fetal growth restriction 1

Clinical Management Algorithm

For women currently taking ACE inhibitors/ARBs/spironolactone:

1. If planning pregnancy: Switch immediately to methyldopa, labetalol, or long-acting nifedipine 5
2. If pregnancy confirmed: Discontinue ACE-I/ARB/spironolactone the same day and substitute safe alternative 1
3. Follow-up within 2-4 weeks after medication switch to ensure adequate BP control 5
4. Monitor for dose-related pedal edema with nifedipine (more common in women) 5

Case example from the literature: A woman taking losartan throughout pregnancy developed oligohydramnios at 24 weeks. When losartan was discontinued at 32 weeks and replaced with nifedipine, amniotic fluid normalized within 8 days, and a healthy infant was delivered at 35 weeks 10

Common Pitfalls to Avoid

• Never continue ACE-I/ARB/spironolactone once pregnancy is planned or confirmed - switch immediately 1, 5
• Avoid diuretics during pregnancy (except late-stage for volume control) as they reduce uteroplacental perfusion 1, 5
• Avoid atenolol specifically among beta-blockers as it may particularly impair fetal growth 6
• Do not use immediate-release/short-acting nifedipine - only long-acting formulations 5

Regulatory Classification

• ACE inhibitors and ARBs: FDA Category D (positive evidence of human fetal risk) 2
• Spironolactone: FDA warning to avoid in pregnancy due to anti-androgenic properties and animal data showing feminization 8

Postpartum Considerations

After delivery, ACE inhibitors, ARBs, and spironolactone can be resumed if clinically indicated, though spironolactone's active metabolite (canrenone) appears in breast milk in low amounts 8