Hypertension in a Pregnant Patient: How I Treat

Introduction

Hypertension in pregnancy, defined as BP≥140/90 mm Hg, complicates 10%–15% of pregnancies. Preeclampsia is hypertension, after 20 weeks, with proteinuria (>300 mg/d) and/or maternal AKI, liver dysfunction, neurologic symptoms, hemolysis, or thrombocytopenia (1). Chronic hypertension is hypertension diagnosed prepregnancy or before 20 weeks, and is a strong risk factor for superimposed preeclampsia. Nephrologists are consulted to manage women with primary (essential) or secondary hypertension. The latter is most often associated with CKD, but occasionally adrenal, endocrine, or renovascular hypertension manifest during pregnancy.

Case

A 32-year-old woman with 7 years of hypertension was referred for pregnancy counseling. Her body mass index is 22 and her BP is 134/82 mm Hg on nifedipine and labetalol. Her kidney function and electrolytes are normal. She was advised that pregnancy is reasonable, and informed of increased risk for preeclampsia, preterm birth, cesarean section, fetal growth restriction, and abruptio placenta. Six months later she returns 14 weeks pregnant. Her BP is 140/90 mm Hg, and her BP is 140/90 mm Hg, and her labs are as follows: serum sodium 139 mmol/L, potassium 2.8 mmol/L, carbon dioxide 28 mmol/L, BUN 15 mg/dl, creatinine 0.72 mg/dl, and urinalysis normal. Her plasma renin activity (PRA) is 1.55 ng/ml per hour (0.25–5.82 ng/ml per hour) and her 24-hour urine aldosterone excretion is 282 µg per day (6–44 mcg/d) on nifedipine and labetalol.

Evaluation

BP decreases in early and midpregnancy because of hormonally mediated vasodilation and medications may be reduced. BP may increase closer to term, with or without other features of preeclampsia. A 7-year history of hypertension in a 32-year-old is uncommon and suggests possible secondary hypertension. Elevated BP despite two antihypertensive medications, at a gestational age where BP should be decreasing, is concerning. Biochemical profiling of blood and urine, not part of routine obstetric care, was performed.

Hypokalemia is not a feature of normal pregnancy, in the absence of hyperemesis, and is a clue that this patient has primary aldosteronism. This is supported by the low PRA and high 24-hour urine aldosterone excretion, tests that were ordered because of hypokalemia. PRA increases in normal pregnancy in the first trimester, in response to vasodilation and lower BP (2). Levels at the end of the first trimester average 6–12 ng/ml per hour, increase modestly until a few weeks before term, and then stabilize. Urine aldosterone excretion rises as well: 40–80 mcg/d in the first trimester and 100–150 mcg/d at term (2). Similar levels are observed in women with chronic hypertension; PRA remains elevated even when taking medications known to suppress renin (2). Hypertension, hypokalemia, suppressed PRA, and elevated aldosterone excretion in this case suggest primary aldosteronism. Computed tomography imaging of the adrenals was not done because of potential fetal radiation exposure. Magnetic resonance imaging (MRI) without gadolinium could be considered; however, BP is controlled, and even if the patient has surgically curable, unilateral hyperaldosteronism, it might be difficult to prove without adrenal vein sampling, a procedure requiring some radiation exposure. At this stage in pregnancy we thought it reasonable to manage BP medically, especially in view of evidence that high levels of progesterone during pregnancy have mineralocorticoid antagonist activity and may ameliorate hyperaldosteronism.

Other causes of secondary hypertension may be diagnosed preconception, or during pregnancy. Evaluation should be considered in younger women (<30 years) with hypertension requiring more than one medication, and suggestive clinical or laboratory features (3). CKD is ruled out with blood and urine tests, and kidney ultrasound. Kidney biopsy should be considered early in pregnancy with new onset of nephrotic syndrome, nephritis, or reduced GFR. Thyroid disease is easily ruled out and treated. Renovascular hypertension due to fibromuscular dysplasia is suggested by severe hypertension and high PRA (>15 ng/ml per hour). Duplex kidney artery dopplers may be useful, followed by an MRI without gadolinium if results are positive. Angiography is necessary to confirm the diagnosis. Successful angioplasty has been performed in the second trimester with appropriate shielding of the fetus. Pheochromocytoma has a high maternal and fetal mortality rate, especially when the diagnosis is missed. Early detection with plasma or urinary metanephrines and noncontrast MRI improves outcomes (4). α-Blockers can be used for BP management and surgery should be considered in the second trimester. Pheochromocytoma can mimic preeclampsia; hypertension often worsens as pregnancy progresses, and may be severe.

Antihypertensive Medication

The American College of Obstetricians and Gynecologists (ACOG) recommends treatment of hypertension in pregnancy only when BP reaches severe levels (≥160/105–110 mm Hg) because of concerns that aggressive therapy may cause placental ischemia and impaired fetal growth (5). However, we continued treatment with labetalol and nifedipine because it was likely that she had primary aldosteronism, her BP was increasing as pregnancy progressed, and she was at risk for severe hypertension. Indeed, a recent clinical trial supports the safety of treating to lower targets in pregnancy (6). Labetalol and nifedipine are widely used in pregnancy and considered safe. Methyldopa, rarely used outside of pregnancy, is safe and effective, but may cause fatigue or depression, especially postpartum. Diuretics are avoided in preeclampsia but can be continued in women with chronic hypertension who were taking them before pregnancy. We try to reduce the dose to limit hemodynamic and metabolic adverse effects. No antihypertensive has been shown to prevent preeclampsia. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and renin inhibitors are contraindicated because of fetal nephrotoxicity. Women with chronic hypertension are at increased risk for preeclampsia, and current practice, which we endorse, is to prescribe low-dose aspirin (75–150 mg) between 12 and 16 weeks of pregnancy until delivery, as there is considerable evidence that this reduces the risk of preeclampsia by 15%–25% (7).

Our patient’s BP increased, requiring increasing medication. Hypokalemia persisted despite potassium supplementation. The fetus was male, and mineralocorticoid receptor antagonists are not recommended in pregnancy because of potential antiandrogenic effects on male fetuses. Given the limited experience in pregnancy, we avoid these drugs. Amiloride is a consideration, but experience is limited. Despite nifedipine 90 mg XL (extended release) and labetalol 1200 mg daily, she developed severe hypertension and proteinuria. She was hospitalized at 32 weeks and delivered by cesarean section. She received intravenous magnesium sulfate to prevent convulsions.

Superimposed Preeclampsia

Women with chronic hypertension are five times more likely to develop preeclampsia; however, all guidelines acknowledge the difficulty making the diagnosis, especially in women with baseline proteinuria. Preeclampsia in a previous pregnancy, higher baseline BP, and decreased GFR increase risk (5). A late pregnancy increase in BP, especially with new onset proteinuria, thrombocytopenia and elevated liver enzymes after 20 weeks is suggestive. Circulating angiogenic factor levels may help distinguish superimposed preeclampsia from CKD progression (8). Treatment is guided by severity of hypertension, symptoms such as headache, abnormal laboratory results, fetal status, and gestational age. Delivery is the definitive cure and recommended >37 weeks. Before 37 weeks, careful consideration of maternal and fetal risks may necessitate preterm delivery. Uncontrolled severe hypertension should be treated with parenteral labetalol or hydralazine and is usually an indication for delivery. Oral nifedipine may be added; we use the long-acting preparation. Although short-acting nifedipine is endorsed by ACOG, rapid, large BP decreases are discouraged to avoid placental hypoperfusion and fetal distress. BP should be lowered <160/110 mm Hg in a short period of time; we aim for 130–150/80–100 mm Hg. Magnesium sulfate is prescribed to prevent eclampsia.

Postpartum

Immediately after delivery, BP may decrease because of anesthesia, blood loss, and modest antihypertensive effects of magnesium sulfate. By postpartum day 3, BP increases and may remain quite elevated in the first postpartum week, requiring increased medication. We recommend aggressive treatment of postpartum hypertension, as it may persist for weeks and the risk of stroke is increased postpartum (9). Although postpartum nonsteroidal anti-inflammatory drugs may be safe if used for <3 or 4 days, we avoid them in women with chronic hypertension and persistent postpartum hypertension, especially after cesarean section when prolonged analgesia may be required.

A 1590 g male infant was delivered. BP was 160–180/105–110 mm Hg immediately postpartum, requiring parenteral labetalol and hydralazine. She was discharged on nifedipine and spironolactone. A computed tomography scan showed a 1 cm right adrenal nodule. Laparoscopic adrenalectomy was performed 6 weeks later. Because of her young age and unequivocal hormonal and biochemical profile, adrenal vein sampling was not performed. She has been normotensive for 5 years and has had two normotensive pregnancies.

Conclusions

Secondary hypertension, although not common, presents diagnostic and therapeutic challenges that nephrologists can address because obstetricians are less familiar with these disorders. Secondary hypertension should be considered in young, nonobese women with significant hypertension and abnormal laboratory results, such as hypokalemia and elevated creatinine. Our patient’s hypokalemia and hypertension worsened during pregnancy, making the diagnosis of aldosteronism more obvious. A potential explanation for this may be the presence of a mutation in exon 3 of the CTNNB1 gene in the adenoma. This mutation is reported to be associated with high levels of receptors for pregnancy steroid hormones on the adenoma, leading to increased expression during pregnancy (10). Appropriate diagnosis, BP control with medications safe for pregnancy, low-dose aspirin, and treatment of postpartum hypertension are necessary for good outcomes in these complex patients.

Disclosures

Dr. August has nothing to disclose.