Methyldopa in Hypertension Treatment During Pregnancy
Methyldopa is a safe and effective first-line antihypertensive agent for pregnant women with chronic or gestational hypertension, with the longest safety record and long-term infant follow-up data, though labetalol and extended-release nifedipine are now often preferred in high-income countries due to superior efficacy in preventing severe hypertension. 1, 2
First-Line Status and Clinical Role
The American College of Obstetricians and Gynecologists recommends methyldopa as one of three first-line antihypertensive medications for pregnant women, alongside labetalol and extended-release nifedipine. 1
Methyldopa is the only antihypertensive with adequate long-term infant follow-up data (7.5 years), establishing its safety profile over three decades of use. 3, 1
The drug works by converting to alpha-methylnorepinephrine, which stimulates central inhibitory alpha-adrenergic receptors, reducing blood pressure without directly affecting cardiac function or reducing glomerular filtration rate. 4
Dosing and Administration
Standard dosing ranges from 250-1000 mg/day (or up to 750 mg to 4 g per day in divided doses), typically given in three or four divided doses, with dose adjustments often needed as pregnancy advances. 2, 5, 6
Maximum blood pressure reduction occurs 4-6 hours after oral dosing, with smooth blood pressure control achieved in 12-24 hours once effective dosage is established. 4
The plasma half-life is 105 minutes, with approximately 70% excreted in urine as methyldopa and its conjugates, and excretion essentially complete in 36 hours. 4
Efficacy and Safety Profile
Methyldopa significantly reduces the frequency of severe hypertension occurring antenatally and during labor, with effective blood pressure control comparable to its action in non-pregnant individuals. 6
Treatment with methyldopa was associated with significantly improved fetal outcomes in controlled trials, including reduced mid-pregnancy abortions (1 fetal loss in treated group versus 9 pregnancy losses including 4 mid-pregnancy abortions in controls). 7
First trimester exposure to methyldopa does not increase the risk of major birth defects (3.7% versus 2.5% in controls; adjusted odds ratio 1.24,95% CI 0.4-4.0). 8
Methyldopa crosses the placental barrier and appears in cord blood and breast milk. 4
Important Limitations and Side Effects
Methyldopa should be avoided or switched in the postpartum period due to increased risk of postnatal depression. 1, 2, 5
Common side effects include peripheral edema, dry mouth, lightheadedness, lack of energy, and dizziness, with approximately 14.5% of patients requiring transfer to another drug due to minor side effects. 5, 6
High-dose methyldopa (1.25-2.0 g/day) may be associated with lower birth weight and can interfere with cerebral monoamine metabolism in neonates, causing dose-dependent increases in prolactin, thyrotropin, and triiodothyronine levels. 9
Beta-blockers and calcium channel blockers appear superior to methyldopa for preventing severe hypertension and preeclampsia in pregnancy. 2, 5
Comparative Effectiveness
Labetalol has efficacy comparable to methyldopa and can be administered intravenously for severe hypertension, making it often preferred in current practice. 3, 1
Nifedipine and labetalol are currently preferred as first-line agents in high-income countries, though methyldopa remains an important option when other agents are contraindicated or unavailable. 2, 5
Oxprenolol showed greater fetal growth compared to methyldopa in head-to-head trials, though this difference diminished after 10 weeks of treatment. 10
Critical Contraindications to Remember
ACE inhibitors, angiotensin receptor blockers, and direct renin inhibitors are strictly contraindicated during pregnancy due to severe fetotoxicity, particularly in the second and third trimesters. 3, 1, 2
If these contraindicated medications are taken inadvertently during the first trimester, immediate switching to methyldopa or another safe alternative with close monitoring including fetal ultrasound is necessary. 3
Treatment Algorithm
For pregnant women with confirmed blood pressure ≥140/90 mmHg, initiate methyldopa as a first-line option, particularly when labetalol or nifedipine are contraindicated or unavailable. 1, 5
Target blood pressure should be 110-135/85 mmHg, avoiding diastolic blood pressure below 80 mmHg to prevent impaired fetal growth while reducing maternal hypertension risk. 1
Monitor for side effects, particularly mood disturbances and lack of energy, which may require switching to alternative agents. 5, 6
Plan to discontinue or switch methyldopa in the postpartum period due to depression risk, with most patients able to stop treatment by six weeks after delivery. 1, 5, 6