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Hypertension in Pregnancy: Diagnosis and Treatment

  • Vesna D. Garovic
    Correspondence
    Address reprint requests and correspondence to Vesna D. Garovic, MD, Division of Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905
    Affiliations
    Divisions of Hypertension and Nephrology, Department of Internal Medicine, and Pregnancy-Related Hypertension and Kidney Disease Clinic, Mayo Clinic, Rochester, Minn
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      Hypertension affects 10% of pregnancies in the United States and remains a leading cause of both maternal and fetal morbidity and mortality. Hypertension in pregnancy includes a spectrum of conditions, most notably preeclampsia, a form of hypertension unique to pregnancy that occurs de novo or superimposed on chronic hypertension. Risks to the fetus include premature delivery, growth retardation, and death. The only definitive treatment of preeclampsia is delivery. Treatment of severe hypertension is necessary to prevent cerebrovascular, cardiac, and renal complications in the mother. The 2 other forms of hypertension, chronic and transient hypertension, usually have more benign courses. Optimal treatment of high blood pressure in pregnancy requires consideration of several aspects unique to gestational cardiovascular physiology. The major goal is to prevent maternal complications without compromising uteroplacental perfusion and fetal circulation. Before an antihypertensive agent is prescribed, the potential risk to the fetus from intrauterine drug exposure should be carefully reviewed.
      ACE (angiotensin-converting enzyme), DBP (diastolic blood pressure), HELLP (hemolysis, elevated liver enzymes, low platelet count), NHBPEP (National High Blood Pressure Education Program), SBP (systolic blood pressure)
      Normal pregnancy is characterized by increases in cardiac output and blood volume, generalized vasodilatation, a decrease in blood pressure, and resistance to pressor agents such as norepinephrine and angiotensin II.
      • McLaughlin MK
      • Roberts JM
      Hemodynamic changes.
      Blood pressure achieves a nadir by midpregnancy, then returns to prepregnancy levels at term. Systolic blood pressure (SBP) is less affected than diastolic blood pressure (DBP) because of the increased cardiac output that offsets the vasodilatation. Further decline is noted during sleep, which follows the pattern of normal circadian rhythms observed in nonpregnant women.

      DEFINITION AND CLASSIFICATION

      Hypertension in pregnancy is defined as a blood pressure of 140/90 mm Hg or higher. Korotkoff phase V (disappearance) rather than Korotkoff phase IV (muffling of sounds) is used for the determination of DBP.
      • National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      In the outpatient setting, blood pressure should be measured in the sitting position, after a period of rest in a quiet environment. For hospitalized patients, the lateral recumbent position eliminates the effect of compression of the inferior vena cava by the enlarged uterus that impairs venous return and causes a decline in blood pressure. Regardless of posture, special care should be taken to ensure that the patient's arms are kept at the heart level; positioning the arms above the heart can spuriously reduce the blood pressure readings. In pregnancy, the lowest blood pressures are obtained by using the right arm while the patient is resting in the left lateral position.
      • Van Dongen PW
      • Eskes TK
      • Martin CB
      • Van't Hof MA
      Postural blood pressure differences in pregnancy: a prospective study of blood pressure differences between supine and left lateral position as measured by ultrasound.
      These blood pressure readings might merely reflect the changes in hydrostatic pressure caused by keeping the right arm above the heart. Therefore, the increases in blood pressure with a change from a lateral to a supine position may simply represent a postural phenomenon rather than positive results on a rollover test, once considered a predictor of preeclampsia.
      • Lindheimer MD
      • Roberts JM
      • Cunningham FG
      • Chesley L
      Introduction, history, controversies, and definitions.
      The Working Group of the National High Blood Pressure Education Program (NHBPEP) recently published a second report revising the classification of hypertensive disorders in pregnancy.
      • National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      The term transient hypertension was replaced by gestational hypertension, which is used only during pregnancy for a group of women who develop high blood pressure for the first time after 20 weeks' gestation in the absence of proteinuria. The rest of the classification remains unchanged (Table 1).
      Table 1Classification of Hypertensive Disorders in Pregnancy
      • National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      Preeclampsia-eclampsia
      Preeclampsia superimposed on chronic hypertension
      Chronic hypertension
      Gesiational hypertension

      Preeclampsia

      Preeclampsia is a multisystemic disease characterized by hypertension and proteinuria, a protein level of 300 mg or greater in a 24-hour urine specimen that roughly correlates with a qualitative measurement of 1+ (30 mg/dL) on dipstick urinalysis in the absence of urinary tract infection. Because of disagreement between random and 24-hour urinary protein determinations, the latter is recommended for diagnostic purposes. If this is not feasible, a timed urinary collection corrected for creatinine excretion is an acceptable alternative. The diagnosis of hypertension is supported by recording elevated blood pressure on 2 determinations performed 6 hours apart.
      An important feature of preeclampsia is its unpredictable clinical course; women with mild hypertension and minimal proteinuria can have rapid progression to the convulsive form of eclampsia. Thus, distinguishing between “mild” and “severe” forms is discouraged because it can be clinically misleading.
      • August P
      Preeclampsia: new thoughts on an ancient problem.
      However, certain symptoms and signs are considered markers of severe disease and necessitate close monitoring and, frequently, urgent delivery. These include an SBP of 160 mm Hg or higher and a DBP of 110 mm Hg or higher, nephrotic range proteinuria (protein level ≥3.5 g/24 h), renal functional impairment (serum creatinine level >1.2 mg/dL), thrombocytopenia (platelet count <100 × l0
      • Sibai BM
      • Anderson GD
      Pregnancy outcome of intensive therapy in severe hypertension in first trimester.
      /L), and/or evidence of microangiopathic hemolytic anemia, hepatocellular injury, pulmonary edema, and neurologic disturbances.
      Preeclampsia usually occurs after 20 weeks of gestation and traditionally is considered a disease of the first pregnancy. However, women with a history of preeclampsia have an increased risk during subsequent pregnancies. Other risk factors include extremes of reproductive age, multiple gestations (eg, twins), family history of preeclampsia, and the presence of trophoblastic disease, chronic hypertension, diabetes mellitus, connective tissue disease, and renal disease. The hemodynamic changes include decreased cardiac output relative to normal pregnancy, elevated peripheral vascular resistance,
      • Visser W
      • Wallenburg HC
      Central hemodynamic observations in untreated precclamptic patients.
      and loss or reversal of the normal diurnal rhythm, resulting in elevated nocturnal blood pressure readings.
      The hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome is a deceptive form of preeclampsia. It can rapidly evolve into a life-threatening syndrome of liver failure and worsening thrombocytopenia in the presence of only mild to moderate hypertension. The most severe complication of the HELLP syndrome is liver rupture, which has high maternal and fetal mortality rates.
      The cause and pathogenesis of preeclampsia remain elusive. Consequently, specific preventive and treatment options have not been developed. Ideally, high-risk patients should be evaluated early in pregnancy by an obstetrician with special expertise in this field. The baseline values for hemoglobin, hematocrit, platelet count, serum uric acid, creatinine, and protein excretion should be obtained because a comparison with values later in pregnancy may help in establishing the diagnosis of preeclampsia.
      Patients presenting with hypertension in the second half of pregnancy should be additionally monitored for hepatic involvement (serum transaminase levels), presence of hemolysis (lactic acid dehydrogenase level and blood smear), and degree of capillary leak (serum albumin level). These tests are particularly useful in monitoring disease severity and progression.
      • National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      If preeclampsia develops at less than 32 weeks' gestation, when the fetus is still immature, consideration should be given to postponing delivery.
      • Sibai BM
      • Mercer BM
      • Schiff E
      • Friedman SA
      Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks' gestation: a randomized controlled trial.
      This is a reasonable approach when hypertension is mild, and no renal, liver, or coagulation abnormalities are evident. Patients should be hospitalized and closely monitored for signs of fetal distress and symptoms of headache, visual disturbances, and right upper quadrant pain that may herald progression to more severe forms, including eclampsia. The threshold for initiation of antihypertensive therapy is the same as for severe preeclampsia, ie, DBP of 100 mm Hg or higher. An oral agent is preferred if delivery is not expected within 48 hours.
      • August P
      Preeclampsia: new thoughts on an ancient problem.
      Outpatient management can be considered for asymptomatic patients with treatment-responsive hypertension in the absence of marked proteinuria (protein level <1 g/24 h).
      Labor should be induced when pregnancies are at or near term and in women with severe hypertension persisting after 24 to 48 hours of treatment, HELLP syndrome, progressive renal failure, premonitory signs of eclampsia, and fetal distress.
      • Cunningham FG
      • Lindheimer MD
      Hypertension in pregnancy.
      Patients having severe preeclampsia at less than 34 weeks' gestation should receive corticosteroids to accelerate fetal lung development. Intravenous magnesium sulfate therapy has been shown to be more effective than either phenytoin or diazepam for seizure prophylaxis in women with severe preeclampsia and for prevention of recurrent seizures in those with eclampsia. Magnesium sulfate should be administered during labor and delivery and for at least 24 hours postpartum by con­tinuous intravenous infusion. To avoid magnesium toxicity in women with renal insufficiency, the maintenance dose should be reduced, and the serum magnesium levels should be monitored every 1 to 2 hours (compared to every 4-6 hours in women with normal renal function) until a steady state is reached. Effective therapy for magnesium toxicity is intravenous calcium gluconate, which should be available at the bedside.
      Studies have shown that pharmacological treatment of DBP of 110 mm Hg or greater decreases the incidence of acute maternal cardiac and cerebral insults.
      • Sibai BM
      • Anderson GD
      Pregnancy outcome of intensive therapy in severe hypertension in first trimester.
      Most investigators agree that antihypertensive therapy in the peripartum period should be initiated when the DBP approaches 100 mm Hg.
      • August P
      Preeclampsia: new thoughts on an ancient problem.
      The most important reason for treatment of hypertension is the prevention of maternal cerebrovasular and cardiac complications. Control of blood pressure does not prevent or cure preeclampsia. In fact, eclamptic seizures can occur when the blood pressure is only mildly elevated.

      Chronic Hypertension

      The hallmark of chronic hypertension is a blood pressure of 140/90 mm Hg or greater before pregnancy or before the 20th week of gestation. Most patients will have a benign course with an exaggerated decrease in DBP of as much as 20 mm Hg. This often leads to normalization of blood pressure in midpregnancy
      • Sibai BM
      • Abdella TN
      • Anderson GD
      Pregnancy outcome in 211 patients with mild chronic hypertension.
      and may mask the diagnosis of chronic hypertension if prepregnancy values are unknown. The blood pressure usually increases to pregnancy levels in the third trimester, frequently leading to diagnostic confusion with preeclampsia. Proteinuria is absent in uncomplicated chronic hypertension, and when it occurs for the first time in the third trimester, it is the best indicator of superimposed preeclampsia. Antihypertensive treatment is usually instituted for an SBP of 150 mm Hg or greater or a DBP of 100 mm Hg or greater, unless there is evidence of renal disease or other target organ complica­tions.
      • Cunningham FG
      • Lindheimer MD
      Hypertension in pregnancy.
      In these instances, antihypertensive therapy is initiated when the DBP is 90 mm Hg or greater. Women with chronic hypertension are at an increased risk for developing preeclampsia, particularly if the blood pressure does not decline in midgestation or if they have secondary hypertension. Ideally, they should be evaluated before pregnancy for end-organ damage, such as left ventricular hypertrophy, hypertensive nephropathy, and retinopathy. A work-up of secondary hypertension should be considered (eg, primary hyperaldosteronism, renovascular disease, pheochromocytoma), particularly in young patients with hard-to-control blood pressure requiring several antihypertensive agents. Medications prescribed before pregnancy can be continued during pregnancy except for angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. Women taking these medications who present for prepregnancy counseling should be told to use another agent (eg, methyldopa) before conception.
      The combination of hypertension and kidney disease is associated with increased risks of fetal loss, prematurity, and intrauterine growth retardation. Women with chronic renal diseases should be advised to plan their pregnancies while their renal function is relatively preserved (serum creatinine level ≤1.4 mg/dL)
      • National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      because fetal prognosis has improved with the neonatal care currently available. Such patients require the collaborative efforts of a multidisciplinary team, including high-risk obstetrics, nephrology, and hypertension, for optimal treatment.
      Women with preeclampsia superimposed on chronic hypertension are at particularly high risk for cerebral hemorrhage and placental abruption. It remains unclear whether early treatment of chronic hypertension in pregnancy prevents preeclampsia. Several randomized trials have failed to demonstrate that treatment of chronic hypertension reduces the incidence of superimposed preeclampsia.
      • Sibui BM
      Treatment of hypertension in pregnant women.
      The main criticism of these trials was inadequate sample size; moreover, only 1 trial
      • Weirz C
      • Khouzami V
      • Maxwell K
      • Johnson JW
      Treatment of hypertension in pregnancy with mcthyidopa: a randomized double blind study.
      was placebo-controlled. The continued uncertainty can be resolved only by carefully designed clinical trials, which are urgently needed.

      Gestational Hypertension

      Gestational hypertension is characterized by hypertension occurring for the first time in the second half of pregnancy in the absence of proteinuria. This category encompasses both women with preeclampsia who have not yet developed proteinuria and those with hypertension only. The differentiation between these 2 groups is possible only retrospectively, ie, postpartum. Transient hypertension (the term previously used for this category) refers to a subgroup of women in whom blood pressure returns to normal by 12 weeks' postpartum. The failure of blood pressure to normalize leads to the diagnosis of chronic hypertension. Transient hypertension has a benign course and good prognosis, with a tendency to recur in subsequent pregnancies. The blood pressure usually normalizes shortly after delivery, although the risk of developing hypertension later in life is increased.
      • Chesley LC
      • Sibai BM
      Clinical significance of elevated mean arterial pressure in the second trimester.

      TREATMENT

      Goals for the treatment of hypertension in pregnancy differ from those for the general hypertensive population. The benefit of treatment of mild diastolic hypertension, blood pressure of 90 to 99 mm Hg, has been clearly established and documented for the general population, while in pregnancy it remains an area of controversy in the absence of well-designed clinical trials.
      The choice of antihypertensive medication in pregnancy is limited by concerns for fetal safety. In addition to proven safety, an ideal antihypertensive agent should gradually reduce blood pressure without compromising uteroplacental blood flow to the fetus. If administered intravenously, a short-acting formulation that permits rapid reversal of hypotension is preferred. According to the Working Group report of the NHBPEP,
      • National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      first-line oral and intravenous treatment is methyldopa and hydralazine, respectively. Methyldopa is the only antihypertensive agent with a proven record of safety in pregnancy, established by follow-up studies of children exposed to the drug in utero.
      • Cockburn J
      • Moar VA
      • Ounsted M
      • Redman CW
      Final report of study on hypertension during pregnancy; the effects of specific treatment on the growth and development of the children.
      Because of its long history of efficacy and acceptable side-effect profile, intravenous hydralazine is recommended for the treatment of severe hypertension in women who are near term. Other antihypertensive medications are now being used more often, particularly if blood pressure control cannot be achieved with first-line agents or in the presence of intolerable adverse effects. Some of the newer agents have demonstrated efficacy and safety comparable to those of methyldopa and hydralazine.
      β-Blockers have demonstrated effective blood pressure control and a satisfactory safety profile when administered in the third trimester. Labetalol has been used with increasing frequency for the treatment of severe acute hypertension during pregnancy and has shown efficacy and tolerance equivalent to hydralazine.
      • Umans JG
      • Lindheimer MD
      Antihypertensive treatment.
      The main concerns about the use of β-blockers stem from evidence of intrauterine growth retardation and low placental weight documented when atenolol was used in the second trimester.
      • Butters L
      • Kennedy S
      • Rubin PC
      Atenolol in essential hypertension during pregnancy.
      β-Blockers can potentially cause additional adverse effects, such as fetal bradycardia, impaired fetal compensatory response to hypoxia, and neonatal hypoglycemia.
      Data on the safety and efficacy of calcium channel blockers, especially early in pregnancy, are limited. Calcium channel blockers are potent tocolytics and can affect the progression of labor. Another concern is the potential for profound hypotension and circulatory collapse when magnesium sulfate is used concurrently with calcium channel blockers for seizure prophylaxis. In pregnancy, calcium channel blockers are increasingly used for severe hypertension refractory to other drugs. Nifedipine has been studied most extensively and has been shown to decrease blood pressure and improve renal function without affecting blood flow in the umbilical artery.
      • Ismail AA
      • Mcdhat I
      • Tawfic TA
      • Kholeif A
      Evaluation of calcium-antagonist (Nifedipine) in the treatment of pre-eclampsiu.
      As in other settings, the availability of long-acting preparations has mitigated the risk of precipitous blood pressure decreases that can potentially compromise uteroplacental blood flow and fetal well-being.
      According to the Working Group report of the NHBPEP, diuretics can be continued during pregnancy if initiated before conception, especially in women with salt-sensitive chronic hypertension.
      • National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      Other indications for diuretic therapy are hypertension in the setting of renal failure and congestive heart failure. Possible adverse effects include electrolyte abnormalities such as hyponatremia, hypokalemia, and hyperuricemia. Diuretics can aggravate volume depletion and promote reactive vasoconstriction and should be avoided in women with preeclampsia.
      ACE inhibitors are contraindicated in pregnancy. They adversely affect the fetal renal system, causing anuria and oligohydramnios. Complications reported in newborns after in utero exposure during the second and third trimester include fetal limb abnormalities, lung hypoplasia, craniofacial deformities, and renal dysplasia.
      • Pryde PG
      • Sedman AB
      • Nugent CE
      • Ban Jr, M
      Angtotensin-con-vcrting enzyme inhibitor fetopathy.
      Angiotensin II receptor blockers exert a similar hemodynamic effect on fetal renal circulation and can potentially cause similar fetal malformations. Fetuses of women who take ACE inhibitors or angiotensin II receptor blockers during the first trimester are not considered at a higher risk for these malformations, and women exposed to such agents during this time do not need to terminate their pregnancy.
      Finally, direct vasodilators, other than hydralazine, may need to be considered for the rare patient with severe refractory hypertension. Direct vasodilators can cause severe complications, such as excessive hypotension (both sodium nitroprusside and diazoxide) and cyanide intoxication (sodium nitroprusside only), making them the agents of last resort.
      • Umans JG
      • Lindheimer MD
      Antihypertensive treatment.
      Nonpharmacological treatment consists mainly of bed rest, which has been shown not only to lower blood pressure but also to promote diuresis and reduce premature labor.
      • Papiemik E
      • Kaminski M
      Multifactorial study of the risk of prematurity at 32 weeks of gestation, I: a study of the frequency of 30 predictive characteristics.
      However, pregnant women with sodium-sensitive chronic hypertension should continue salt restriction during pregnancy. Salt restriction is not recommended for routine treatment of women with preeclampsia, who frequently are volume contracted.
      Prevention of preeclampsia has been attempted by using several strategies. Some have proved to be unsuccessful, such as salt restriction,
      • Steegers EA
      • Eskes TK
      • Jongsma HW
      • Hein PR
      Dietary sodium restriction during pregnancy: a historical review.
      magnesium,
      • Spatling L
      • Spatling G
      Magnesium supplementation in pregnancy: a double blind study.
      and fish oil supplementation
      • Salvig JD
      • Olsen SF
      • Secher NJ
      Effects of fish oil supplementation in late pregnancy on blood pressure: a randomised controlled trial.
      ; others are potentially dangerous (diuretics). The role of low-dose aspirin has been studied in several large trials, including the multicenter Collaborative Low-dose Aspirin Study in Pregnancy (CLASP)
      • CLASP (Collaborative Low dose Aspirin Study in Pregnancy) Collaborative Group
      CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-cclampsia among 9364 pregnant women.
      trial that failed to show a beneficial effect of aspirin in the prevention of preeclampsia. Although the study was designed to include women with a higher risk, the incidence of preeclampsia in the placebo group was only 7.6%, similar to that in the general population. Therefore, the issue of the role of aspirin in high-risk groups remained unclear. In 1998, the National Institutes of Health published the results of a double-blind, randomized, placebo-controlled trial of the role of low-dose aspirin in the prevention of preeclampsia in 2539 women at higher risk (history of chronic hypertension, insulin-treated diabetes mellitus, multifetal gestations, and preeclampsia in previous pregnancy).
      • Caritis S
      • Sibai B
      • Hauth J
      • et al.
      Low-dose aspirin to prevent preeclampsia in women at high risk.
      The demonstrated benefit was too small to justify routine prophylaxis: 38 women would need to be treated to prevent 1 case of preeclampsia. Similarly, low-dose aspirin did not improve perinatal outcomes in these women. Calcium supplementation, beyond the daily recommended level, also proved of no benefit in a large National Institutes of Health trial of 4589 healthy nulliparous women.
      • Levine RJ
      • Hauth JC
      • Curet LB
      • et al.
      National Institute of Child Health and Human Development Network of Matemal-Felal Medicine Units. Trial of calcium to prevent preeclampsia.
      The potential benefit of antioxidants, vitamins C and E, was recently investigated in women at increased risk.
      • Chappell LC
      • Seed FT
      • Briley AL
      • et al.
      Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.
      When initiated at 16 to 22 weeks' gestation at doses of 1000 mg and 400 IU daily, respectively, a reduction in plasma markers of endothelial injury and a decreased incidence were observed in the treated group compared with the placebo group. While the investigators recognized the need for multicenter trials to assess the effects in low-risk and high-risk patients from different populations, these studies should also address the issues of safety, particularly for the fetus, of vitamins C and E at the recommended doses.

      CONCLUSION

      The ultimate goal of treatment of hypertension in pregnancy is delivery of a healthy newborn without compromising maternal health. Early diagnosis and subsequent close monitoring of both mother and fetus are crucial. Elevated blood pressure without proteinuria usually has a benign course and can be managed on an outpatient basis. Antihypertensive medications should be used judiciously, and fetal risks from intrauterine exposure must be carefully evaluated. Severe preeclampsia (both pure and superimposed) represents an obstetrical emergency, with potential fatal outcomes for both fetus and mother. Optimally, such women should be hospitalized and treated with bed rest, antihypertensive medications, and magnesium sulfate for seizure prophylaxis. The definitive treatment of preeclampsia is delivery. For mild forms remote from term, postponing delivery is desirable and, if possible, can improve neonatal prognosis by decreasing prematurity.

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