Antihypertensive Drugs

Chronic hypertension is defined as hypertension predating pregnancy or diagnosed before 20 weeks of gestation (systolic at or above 140 or diastolic at or above 90 millimeters of mercury). It affects approximately 1 to 5 percent of pregnancies in the United States. Patients with chronic hypertension carry a 20 to 25 percent risk of superimposed preeclampsia — substantially higher than the 3 to 5 percent baseline risk in normotensive women. Blood pressure often falls physiologically in the second trimester, which may allow dose reduction of antihypertensive medications. All antihypertensive medications must be switched to pregnancy-safe agents before or immediately upon confirmed pregnancy.

Gestational hypertension is new-onset hypertension at or after 20 weeks of gestation without proteinuria or other features of preeclampsia. It accounts for approximately 6 percent of pregnancies and resolves within 12 weeks postpartum by definition. Women with gestational hypertension have a 15 to 25 percent risk of progressing to preeclampsia and approximately 50 percent develop chronic hypertension within 10 years — making gestational hypertension a marker of long-term cardiovascular risk.

Preeclampsia is new-onset hypertension at or after 20 weeks accompanied by one or more of: proteinuria at or above 300 mg per 24 hours; thrombocytopenia (platelet count below 100,000 per microliter); renal insufficiency (creatinine above 1.1 mg/dL or doubling without other explanation); impaired liver function (transaminases twice the upper limit of normal with or without right upper quadrant pain); pulmonary edema; or new-onset headache unresponsive to acetaminophen or visual disturbances. Critically, proteinuria is no longer required for diagnosis when other severe features are present.

The pathophysiology begins with abnormal placentation — failure of trophoblastic invasion of the spiral arteries causes placental ischemia, which drives release of anti-angiogenic factors (soluble fms-like tyrosine kinase-1) that inhibit vascular endothelial growth factor. Systemic endothelial dysfunction follows: vasoconstriction, increased vascular permeability, platelet activation, and coagulation cascade activation. Severe features of preeclampsia (any one qualifies for the severe designation) include systolic at or above 160 or diastolic at or above 110 millimeters of mercury on two readings at least 4 hours apart, thrombocytopenia, creatinine above 1.1 mg/dL, transaminases above twice the upper limit of normal, pulmonary edema, or new-onset headache unresponsive to acetaminophen.

HELLP syndrome is a severe variant of preeclampsia characterized by hemolysis (microangiopathic hemolytic anemia with elevated lactate dehydrogenase and schistocytes on smear), elevated liver enzymes (above twice the upper limit of normal), and low platelets (below 100,000 per microliter; severe below 50,000). An important diagnostic caveat: blood pressure may be only mildly elevated or even normal in 15 to 20 percent of HELLP cases — diagnosis requires vigilance beyond blood pressure measurement. Delivery is the definitive treatment.

Eclampsia is new-onset grand mal seizure in a woman with preeclampsia without another identifiable cause. It can occur antepartum, intrapartum, or postpartum — up to 48 hours after delivery in most cases, and rarely up to 4 weeks postpartum. Magnesium sulfate is the agent of choice for both seizure prophylaxis in severe preeclampsia and for treatment of eclamptic seizures. It is not an antihypertensive — blood pressure management with appropriate agents must proceed in parallel.

Intravenous labetalol: 20 mg over 2 minutes; if inadequate, 40 mg after 10 minutes, then 80 mg every 10 minutes (maximum cumulative dose 300 mg per episode). Onset 5 to 10 minutes; duration 3 to 6 hours. Advantages include titratable response, no reflex tachycardia, extensive obstetric experience. Avoid in asthma, significant bradycardia, and decompensated heart failure; monitor to avoid maternal heart rate below 60 beats per minute.

Oral nifedipine (immediate-release, swallowed — not sublingual): 10 mg orally, repeated in 20 to 30 minutes if blood pressure remains severe, to a maximum of 30 mg per episode. Onset 20 to 30 minutes. The critical distinction: this is immediate-release nifedipine given by mouth and swallowed — sublingual administration produces a precipitous, unpredictable blood pressure drop and is contraindicated. Concurrent magnesium sulfate use may enhance hypotension.

Intravenous hydralazine: 5 to 10 mg bolus, repeated every 20 to 30 minutes (maximum 20 mg per episode). Onset is variable and less predictable (10 to 30 minutes). Associated with more adverse effects including reflex tachycardia, headache, and flushing. Considered third-line when labetalol and nifedipine are unavailable or contraindicated. American College of Obstetricians and Gynecologists considers all three acceptable first-line options.

Magnesium sulfate is the cornerstone of seizure prophylaxis in severe preeclampsia and treatment of eclamptic seizures. Its anticonvulsant mechanism involves blockade of N-methyl-D-aspartate glutamate receptors, reduction of neuronal excitability, and cerebral vasodilation. It causes a modest secondary blood pressure reduction insufficient for antihypertensive management — dedicated antihypertensive therapy must proceed in parallel.

Dosing: loading dose of 4 to 6 g intravenous over 15 to 20 minutes, followed by maintenance of 1 to 2 g per hour continuous infusion, continued for 24 to 48 hours postpartum. The therapeutic window is narrow: therapeutic range 4 to 7 mEq/L; loss of deep tendon reflexes (patellar) occurs at 7 to 10 mEq/L (earliest clinical sign of toxicity); respiratory depression occurs at 10 to 13 mEq/L; cardiac arrest above 15 mEq/L. Monitoring requires hourly assessment of deep tendon reflexes, respiratory rate (maintain at or above 12 breaths per minute), and urine output (maintain at or above 25 mL per hour — magnesium is renally excreted and accumulates in renal impairment). The antidote is calcium gluconate 1 g intravenous (10 mL of 10 percent solution) over 3 minutes.

Blood pressure may surge in the first 3 to 5 days postpartum due to mobilization of extravascular fluid into the intravascular compartment (particularly pronounced after magnesium sulfate infusion) and loss of placental vasodilatory prostaglandins. Women with severe preeclampsia require blood pressure monitoring for at least 72 hours after delivery. Postpartum eclampsia can occur up to 4 weeks after delivery — patients must be educated to present immediately for severe headache, visual changes, or confusion.

Most antihypertensives used in pregnancy are compatible with breastfeeding. Preferred agents include labetalol (low breast milk transfer), long-acting nifedipine (low transfer, no adverse neonatal effects), and methyldopa. An important postpartum shift: captopril and enalapril specifically are compatible with breastfeeding in full-term neonates due to low breast milk transfer — avoid in premature neonates due to reduced renal clearance. Women who stopped angiotensin converting enzyme inhibitors during pregnancy can resume a breastfeeding-compatible agent postpartum if indicated for renoprotection. Angiotensin receptor blockers have insufficient breastfeeding safety data and are generally avoided while breastfeeding.