D R UG TH ER A PY

Review Article

Drug Therapy
A L A S T A I R J . J . W O O D , M. D . , Editor

T REATMENT OF H YPERTENSION IN P REGNANT W OMEN

BAHA M. SIBAI, M.D.

YPERTENSIVE disorders are the most common medical complications of pregnancy and are an important cause of maternal and perinatal morbidity and mortality worldwide.1 During normal pregnancy, systolic pressure changes little; however, diastolic pressure decreases by an average of 10 mm Hg early in gestation (13 to 20 weeks) and rises again to prepregnancy levels in the third trimester. The term hypertension in pregnancy describes a broad spectrum of conditions in which blood pressure varies widely. In reviewing the literature on this subject, one is faced with difficulties regarding the definitions and classifications used to categorize hypertension in pregnant women,2-6 including which Korotkoff sound (phase IV or phase V) should be used to measure diastolic blood pressure.1,5 All current definitions and classification schemes have certain pitfalls as they relate to clinical diagnosis and management. Nevertheless, a recent report by the Working Group on High Blood Pressure in Pregnancy recommended using the classification system proposed by the American College of Obstetricians and Gynecologists in 1972,2 even though this classification is not accepted in many countries outside the United States.7 In this review, hypertensive disorders of pregnancy will be divided into three categories: chronic hypertension, gestational hypertension, and preeclampsia (Table 1).
CHRONIC HYPERTENSION

The rates are higher in older women, obese women, and black women.8 The diagnosis is usually based on either a history of hypertension before pregnancy or blood-pressure elevations to at least 140/90 mm Hg before 20 weeks gestation.1 It is difficult to diagnose chronic hypertension in pregnant women in whom the blood pressure before pregnancy is not known. In such cases, the diagnosis is usually based on the presence of hypertension before 20 weeks gestation. In some women, however, hypertension before 20 weeks gestation may be the first manifestation of preeclampsia.9 Furthermore, because of the normal physiologic decrease in blood pressure during the second trimester, many women with chronic hypertension have normal blood pressure before 20 weeks gestation.10,11 In nonpregnant women and in men, hypertension is often classified as mild, moderate, severe, or very severe on the basis of either the systolic or the diastolic blood pressure.12 During pregnancy, chronic hypertension is considered either mild or severe. Although there is no widely accepted definition of mild hypertension, there is agreement that a diastolic blood pressure of 110 mm Hg or higher (Korotkoff phase V) constitutes severe hypertension.1,8 In babies born to pregnant women with chronic hypertension, perinatal outcome is poor, mostly because of superimposed preeclampsia.11,13 The criteria used to diagnose superimposed preeclampsia vary, however; they have included exacerbation of hypertension, edema, proteinuria, hyperuricemia, or a combination of these factors.8 Neither the exacerbation of hypertension nor edema is a reliable indicator of superimposed preeclampsia. In the absence of renal disease, the onset of proteinuria (at least 300 mg per 24 hours) is the best indicator of superimposed preeclampsia.
Risks to the Mother and Fetus

The incidence of chronic hypertension in pregnant women ranges from 1 percent to 5 percent.1

From the Division of MaternalFetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, 853 Jefferson Ave., Rm. E102, Memphis, TN 38103, where reprint requests should be addressed to Dr. Sibai. 1996, Massachusetts Medical Society.

Pregnant women with chronic hypertension are at increased risk for superimposed preeclampsia and abruptio placentae, and their babies are at increased risk for perinatal morbidity and mortality.8 The likelihood of these complications is particularly increased in women with long-standing severe hypertension and those with preexisting cardiovascular or renal disease.13-16 In addition, fetal and maternal morbidity and mortality are higher than normal when pregnant women have a diastolic pressure of 110 mm Hg or higher during the first trimester.14,15 Conversely, the outcomes of women with mild, uncomplicated chronic hypertension during pregnancy and of their babies are similar to those of normal pregnant women.11
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TABLE 1. HYPERTENSIVE DISORDERS

CHRONIC HYPERTENSION

OF

PREGNANCY.

CLINICAL FINDING

GESTATIONAL HYPERTENSION

PREECLAMPSIA

Time of onset of hypertension Degree of hypertension Proteinuria* Serum urate 5.5 mg/dl (0.33 mmol/liter) Hemoconcentration Thrombocytopenia Hepatic dysfunction *Defined as 1

20 Weeks of gestation Mild or severe Absent Rare Absent Absent Absent

Usually in third trimester Mild Absent Absent Absent Absent Absent

20 Weeks of gestation Mild or severe Usually present Present in almost all cases Present in severe disease Present in severe disease Present in severe disease

by dipstick testing on two occasions or

300 mg in a 24-hour urine collection.

Pharmacologic Treatment

The results of two retrospective studies of pregnant women13,17 and randomized trials involving nonpregnant women18 indicate that antihypertensive therapy decreases the incidence of stroke and cardiovascular complications among pregnant women with diastolic blood-pressure values above 110 mm Hg. There is general agreement that pregnant women with severe hypertension should receive pharmacologic treatment,1,8,19 but whether it is beneficial to lower blood pressure in pregnant women with mild essential hypertension is not known.1,8,19 The cardiovascular benefits of long-term therapy to lower blood pressure in nonpregnant, middleaged, and elderly subjects with diastolic pressures of less than 110 mm Hg (mild hypertension) are well established.12,18 These benefits were most evident after four to six years of treatment in men who were older than 50 and those with risk factors for cardiovascular disease or stroke.12,18 However, most pregnant women with mild chronic hypertension are less than 40 years old and have uncomplicated mild hypertension. Therefore, treating mild chronic hypertension in pregnant women is unlikely to be beneficial. In order to improve perinatal outcomes, therapy to lower the blood pressure in pregnant women with mild hypertension must reduce the incidence of preeclampsia, abruptio placentae, preterm delivery, and fetal or neonatal death. In the past 30 years, at least seven studies have compared antihypertensive therapy with either no medication or a placebo in pregnant women with mild chronic hypertension (Table 2).20-26 There was a higher rate of fetal loss during the second trimester among untreated women in several early trials,20,21 but this finding was not confirmed in later studies.22-26 There was no decrease in the frequency of superimposed preeclampsia in five trials.21-24,26 The rate of preterm delivery, report258
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ed in only three trials,22,23,26 was not reduced by treatment. Abruptio placentae was mentioned in only one trial,26 in which there was no difference in frequency between the treated and untreated groups (1 percent in each group). In the two largest trials,21,26 the incidence of perinatal death was less than 2 percent in the untreated groups. Demonstrating a 50 percent reduction in the frequency of either abruptio placentae or perinatal death would have required the enrollment of approximately 2000 women in each group. Therefore, the continued uncertainty about the benefits of lowering blood pressure in pregnant women who have mild chronic hypertension is mainly due to the fact that all published trials have been too small to detect moderate reductions in the rates of obstetrical complications. Other trials have evaluated the benefits of lowering blood pressure in pregnant women with mild chronic or gestational hypertension.27-36 Some have compared two different antihypertensive drugs; others have involved a combination of drugs or compared treatment with no treatment or a placebo (Table 3).
Risks of Pharmacologic Treatment

Antihypertensive drugs have potential adverse effects on the mother and the fetus or neonate,37 and some of the latter may not become evident until childhood. Antihypertensive drugs can affect the fetus either indirectly, by lowering uteroplacental blood flow, or directly, by influencing the umbilical or fetal cardiovascular circulation. Methyldopa is the drug most often used to treat chronic hypertension in pregnant women and has been used most commonly in randomized trials (Tables 2 and 3). Short-term treatment with methyldopa (for an average of 24 days) during the third trimester does not affect uteroplacental or fetal hemodynamics.38 Furthermore, neither short-term ef-

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TABLE 2. RANDOMIZED TRIALS

OF

ANTIHYPERTENSIVE DRUG THERAPY

MEAN DIASTOLIC BLOOD PRESSURE AT ENTRY
mm Hg

IN

PREGNANT WOMEN

WITH

MILD CHRONIC HYPERTENSION.

STUDY

NO. OF WOMEN

MEAN WK OF GESTATION AT ENTRY

TREATMENT

KEY FINDINGS

Leather et al. Redman21

20

47 208 58

20 21 and 22 limit, 15 and 16 limit, (upper 28) (upper 20)

107 88 and 90 90 to 99

Methyldopa diuretic hydralazine vs. no drug Methyldopa hydralazine vs. no drug Methyldopa, diuretic, and hydralazine vs. no drug Diuretic vs. no drug Double-blind: methyldopa vs. placebo Double-blind: atenolol vs. placebo Methyldopa vs. labetalol vs. no drug

Arias and Zamora22

Sibai et al.23 Weitz et al.24 Butters et al.25 Sibai et al.26

20 25 29 263

9 to 13 34 16 (range, 1224) 11 (range, 613)

93 90 86 91 and 92

Longer gestation and fewer perinatal deaths in treatment group Fewer mid-pregnancy losses in treatment group Compromised infants born to women in whom severe hypertension developed despite treatment Lower plasma volume in treated group No difference in outcomes Poor fetal growth in treatment group No difference in outcomes

fects on the fetus or neonate26 nor long-term effects during infancy39 have been reported after the longterm use of methyldopa in pregnancy. In contrast, atenolol has definite adverse effects on uteroplacental and fetal hemodynamics,40 as well as on fetal growth.25 The data concerning the potential adverse effects of other beta-adrenergicantagonist drugs during pregnancy are conflicting.26-28,30-36 Moreover, there are no studies of the long-term effects on the infant of beta-adrenergicantagonist drugs during pregnancy. A meta-analysis of nine randomized trials comparing diuretic therapy with no treatment in a total of 7000 normotensive pregnant women found no difference in the incidence of adverse effects on the mother or neonate between the two groups.41 This overview did not evaluate the effects of diuretics on fetal growth. Diuretic therapy in pregnant women with mild chronic hypertension is associated with a lower-than-normal degree of plasma volume expansion, which may be detrimental to fetal growth.23 Administration of drugs that inhibit angiotensin-converting enzyme during pregnancy is contraindicated because these drugs are associated with fetal growth retardation, oligohydramnios, congenital malformations, neonatal renal failure, and neonatal death.42 There is little experience with the long-term administration of calcium-channelblocking drugs to pregnant women with hypertension.8,36 Therefore, their effects on the fetus and neonate are unknown.
Management of Chronic Hypertension

treated with diuretics; whether therapy should be continued during pregnancy is controversial.1,14,26 The working group concluded that therapy to control blood pressure should be continued in women who are already receiving a diuretic or in those treated before 20 weeks gestation.1 Diuretic therapy is particularly useful in pregnant women with salt-sensitive hypertension or with left ventricular diastolic dysfunction; however, it should be discontinued if preeclampsia develops or there is evidence of reduced fetal growth.1 Early initiation of prenatal care and close medical supervision are the keys to a successful outcome of pregnancy in such cases.1,13,26 The decision to initiate drug therapy in a woman with chronic hypertension should take into account the severity of the hypertension, the potential risk of damage to target organs, and the presence or absence of preexisting cardiovascular disease.8,12 The initial drug of choice is methyldopa. If there are contraindications to its use (such as drug-induced liver damage) or if it is ineffective or cannot be tolerated, labetalol or nifedipine can be given.
GESTATIONAL HYPERTENSION

Women with chronic hypertension should be evaluated before conception so that drugs that may have adverse effects on the fetus (such as angiotensinconvertingenzyme inhibitors and atenolol) can be replaced by other drugs such as methyldopa or labetalol. Many women with chronic hypertension are

Gestational hypertension is defined as the development of high blood pressure without other symptoms of preeclampsia after 20 weeks gestation in a previously normotensive woman. In some women, gestational hypertension may be an early manifestation of preeclampsia, whereas in others it may be an early sign of unrecognized chronic hypertension.1,3,5 Generally, the outcome of pregnancy in women with gestational hypertension is good without drug therapy.
PREECLAMPSIA

Preeclampsia has traditionally been described as the occurrence of hypertension, edema, and proteinuria after 20 weeks gestation in a previously normotenVol ume 335 Numbe r 4

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TABLE 3. RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY IN PREGNANT WOMEN WITH ALL FORMS OF MILD HYPERTENSION.*
MEAN WK MEAN DIASTOLIC GESTATION PRESSURE AT ENTRY AT ENTRY
mm Hg

STUDY

NO. OF WOMEN

OF

OF

AT

MEAN WK GESTATION DELIVERY

TREATMENT

KEY FINDINGS

Fidler et al. Gallery et al.28 Horvath et al.29 Rosenfeld et al.30

27

100 183 100 44 176 155 36 114 100

30 to 31 29 to 30 31 to 32 25 26 28 32 to 35 29 to 30

98 and 100 92 and 94 85 97 and 100 90 91 101 and 104 94 and 96 94 and 96

38 38 37 38 38 37 to 38 37 to 38 38

Plouin et al.31 Plouin et al.32 Blake and MacDonald33 Cruickshank et al.34,35 Jannet et al.36

Methyldopa vs. oxprenolol Methyldopa vs. oxprenolol Methyldopa vs. clonidine Hydralazine vs. hydralazine plus pindolol Methyldopa vs. labetalol Oxprenolol hydralazine vs. placebo Atenolol methyldopa diuretic vs. no drug Labetalol vs. no drug Nicardipine vs. metoprolol

More fetal bradycardia with oxprenolol Higher birth weights with oxprenolol Similar pregnancy outcomes Fewer side effects in combined-treatment group Similar pregnancy outcomes Fewer cesarean sections in treatment group Less proteinuria and lower birth weights in treatment group More admissions to neonatal intensive care unit in labetalol group Similar pregnancy outcomes The value was not reported.

*These trials included women with chronic hypertension, gestational hypertension only, or preeclampsia.

sive woman. The differences between preeclampsia and gestational hypertension are summarized in Table 1. In general, preeclampsia is defined as hypertension plus hyperuricemia or proteinuria, and it is categorized as mild or severe primarily on the basis of the degree of elevation in blood pressure, the degree of proteinuria, or both. At present, there is no consensus regarding the definition of mild hypertension, severe hypertension, or severe proteinuria.1-6 Nonetheless, emphasis on either hypertension or proteinuria may minimize the clinical importance of a number of other disturbances in various organ systems.4 For example, some women with the syndrome of hemolysis, elevated serum liver-enzyme concentrations, and low platelet counts (HELLP) have life-threatening complications (pulmonary edema, acute renal failure, or liver rupture) but little or no hypertension and minimal proteinuria.43 In addition, among women with preeclampsia who later have convulsions (eclampsia), 20 percent have a diastolic blood pressure below 90 mm Hg or no proteinuria.44 Some women with preeclampsia have symptoms and signs that are mistakenly thought to indicate the presence of other disorders (Table 4).
Pathophysiology

These changes result in reduced perfusion of the placenta, kidneys, liver, and brain. Endothelial dysfunction (resulting in vasospasm, altered vascular permeability, and activation of the coagulation system) could explain many of the clinical findings in women with preeclampsia.4 Indeed, many of the abnormalities described in such women are due primarily to reduced perfusion rather than to hypertensive vascular injury.
Risks of Preeclampsia to the Mother and Fetus

One of the earliest abnormalities noted in women in whom preeclampsia later develops is the failure of the second wave of trophoblastic invasion into the spiral arteries of the uterus. As a result of this defect in placentation, there is failure of the cardiovascular adaptations (increased plasma volume and reduced systemic vascular resistance) that are characteristic of normal pregnancy. In preeclampsia, both cardiac output and plasma volume are reduced, whereas systemic vascular resistance is increased.1
260
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The chief risks to the woman entailed by preeclampsia are convulsions, cerebral hemorrhage, abruptio placentae with disseminated intravascular coagulopathy, pulmonary edema, renal failure, liver hemorrhage, and death. The risks to the fetus include severe growth retardation, hypoxemia, acidosis, prematurity, and death. The frequency of these complications depends on the duration of gestation at the onset of preeclampsia, the presence or absence of associated medical complications, the severity of the preeclampsia, and the quality of medical management. In women with mild preeclampsia who are closely followed,45-48 the risk of convulsions is 0.2 percent, that of abruptio placentae is 1 percent, and that of fetal or neonatal death is less than 1 percent. The incidence of fetal growth retardation (birth weight, 10th percentile) is 5 to 13 percent, and that of preterm delivery ranges from 13 percent to 54 percent depending on the duration of gestation at onset and the presence or absence of proteinuria.45-48 Conversely, maternal and fetal or neonatal morbidity and mortality are substantial among women with eclampsia,44,49,50 those with the HELLP syndrome,43,51 and those in whom preeclampsia occurs before 34 weeks gestation.52-54

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TABLE 4. CONDITIONS SOMETIMES CONFUSED WITH PREECLAMPSIA OR ECLAMPSIA.

Viral hepatitis Acute fatty liver of pregnancy Acute pancreatitis Gallbladder disease Appendicitis Kidney stones Glomerulonephritis Hemolyticuremic syndrome Exacerbation of systemic lupus erythematosus Autoimmune thrombocytopenia Thrombotic thrombocytopenic purpura Cerebral venal thrombosis Encephalitis of various causes Cerebral hemorrhage

Management of Preeclampsia

Early diagnosis, close medical supervision, and timely delivery are the cardinal requirements of the management of preeclampsia; delivery is the ultimate cure.1,3 Once the diagnosis is established, subsequent management should be based on the initial evaluation of maternal and fetal well-being. On the basis of the results of this evaluation, a decision is then made regarding hospitalization, expectant management, or delivery, with the following factors taken into account: the severity of the disease process, the status of mother and fetus, and the length of gestation. Irrespective of the management strategy chosen, the ultimate goal must first be the safety of the mother and, second, the delivery of a live infant who will not require intensive and prolonged neonatal care.45-48
Mild Preeclampsia

preeclampsia and a cervix favorable for induction at term (Bishops score, 6), delivery should be induced to avoid possible maternal and fetal complications.1,3 In contrast, there is no agreement about the management of mild preeclampsia earlier in pregnancy. In particular, there is disagreement about the need for bed rest, prolonged hospitalization, antihypertensive drug therapy, or anticonvulsant prophylaxis.1 Bed rest, whether at home or in the hospital, is commonly recommended for women with mild preeclampsia.55 The purported benefits of bed rest include the reduction of edema, improved fetal growth, prevention of progression to severe preeclampsia, and improved outcomes of pregnancy.45-47 In three randomized trials, however, there were no benefits to bed rest at home or in the hospital among women with mild gestational hypertension,56-58 although bed rest at home reduced the number of days of hospitalization.56-58 In one trial, however, more women treated at home had progression to severe disease and needed preterm delivery.58 Moreover, none of these trials were large enough to evaluate the risks of eclampsia, abruptio placentae, and fetal or neonatal death. At least 10 randomized trials evaluating drug treatment in women with mild gestational hypertension or preeclampsia remote from term have been reported (Table 5).40,46,47,59-66 In eight of these trials, antihypertensive drug therapy was compared with either no medication or a placebo, and in two trials different antihypertensive drugs were compared.40,62 In some trials,59,63-65 the frequency of proteinuria, progression to severe disease, and neonatal respiratory distress syndrome was higher when the women were not treated, but these findings were not confirmed in other trials.46,47,60 The effects of treatment on the length of pregnancy, on fetal growth, and on the incidence of preterm delivery varied. Therefore, there is no clear benefit to drug treatment in women with mild gestational hypertension or preeclampsia.
Severe Preeclampsia

Women with preeclampsia require close observation because the disorder may worsen suddenly. The presence of symptoms (such as headache, epigastric pain, and visual abnormalities) and proteinuria increases the risks of both eclampsia and abruptio placentae; women with these findings require close observation in the hospital.45-47 Outpatient management may be considered if compliance is expected to be good, hypertension is mild, and the fetus is normal. The management should include close monitoring of the mothers blood pressure, weight, urinary protein excretion, and platelet count, as well as of fetal status.1 In addition, the woman must be informed about the symptoms of worsening preeclampsia.48 If there is evidence of disease progression, hospitalization is indicated. There is general agreement that in women with mild

Severe preeclampsia may be rapidly progressive, resulting in sudden deterioration in the status of both mother and fetus, so that prompt delivery is recommended regardless of the duration of gestation.3,67 Prompt delivery is clearly indicated when there is imminent eclampsia, multiorgan dysfunction, or fetal distress or when severe preeclampsia develops after 34 weeks.68 Early in gestation, however, prolongation of pregnancy with close monitoring may be indicated in order to improve neonatal survival and reduce short-term and long-term neonatal morbidity.9,53,54,69 In three recent clinical trials in women with severe preeclampsia remote from term, neonatal morbidity and mortality were reduced with conservative management.53,54,69 Nevertheless, because only 116 women were assigned to conservative manVol ume 335 Numbe r 4

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TABLE 5. RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY WITH GESTATIONAL HYPERTENSION OR PREECLAMPSIA.
MEAN WK OF GESTATION AT ENTRY MEAN DIASTOLIC PRESSURE AT ENTRY
mm Hg

IN

WOMEN

STUDY

NO. OF WOMEN

MEAN WK OF GESTATION AT DELIVERY

TREATMENT

KEY FINDINGS

Rubin et al.59 Wichman et al.60 Hogstedt et al.61 Ellenbogen et al.62 Sibai et al.46 Pickles et al.63,64 Phippard et al.65 Sibai et al.47 Montan et al.40 Ismail et al.66

85 52 161 32 186 144 52 200 29 30

34 33 29 to 31 30 to 32 32 34 31 to 32 33 35 Third trimester

94 80 to 87 91 97 and 98 91 and 94 93 82 to 84 94 90 101 to 107

39 38 38 36 to 37 35 38 * 36 to 37 39 *

Atenolol vs. placebo Metoprolol vs. placebo Metoprolol plus hydralazine vs. no drug Pindolol vs. methyldopa Labetalol vs. no drug Labetalol vs. placebo Clonidine vs. placebo Nifedipine vs. no drug Atenolol vs. pindolol Nifedipine vs. placebo

Less proteinuria and fewer hospital admissions in atenolol group Lower umbilical-blood lactate level in metoprolol group Similar pregnancy outcomes Better renal function in pindolol group More fetal growth retardation in labetalol group Less proteinuria and fewer preterm deliveries in labetalol group Fewer preterm deliveries in clonidine group Similar pregnancy outcomes Lower placental weight in atenolol group Improved renal function in nifedipine group

*The value was not reported.

agement in these trials, and because such management entails risk to the mother and fetus, conservative management must be considered only at tertiary perinatal centers and must include very close monitoring of both mother and fetus.68 The primary objective of treatment in women with severe hypertension and preeclampsia is to prevent cerebral complications such as encephalopathy and hemorrhage. The threshold for treatment is usually a sustained diastolic blood pressure of 110 mm Hg or higher.3,67-70 Some experts recommend initiating treatment at diastolic blood-pressure values of 105 mm Hg or even lower,1 whereas others use mean arterial pressure greater than 125 mm Hg as the threshold.71 The aim of therapy is to keep the mean arterial pressure below 126 mm Hg (but not less than 105 mm Hg) and the diastolic pressure below 105 mm Hg (but not less than 90 mm Hg).1,71 The initial treatment of choice in women who have severe hypertension during the peripartum period is hydralazine given intravenously in 5-mg bolus doses.1,3,71 The dose may be repeated as needed every 20 minutes up to a cumulative total of 20 mg. If this amount of hydralazine does not achieve the desired therapeutic response, or if the mother has side effects such as tachycardia, headache, or nausea, labetalol (20 mg intravenously) or nifedipine (10 mg orally) may be given. Because of concern about fetal
262
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distress with hydralazine, several investigators have recommended using other drugs to treat severe preeclampsia (Table 6).69,70,72-79 In nine randomized trials in which hydralazine (or dihydralazine) was compared with another drug, only one found that side effects and treatment failure were more frequent in the hydralazine group.69
Anticonvulsant Drug Therapy

Women with preeclampsia have an increased risk of convulsions.1,80 The degree of risk depends on the severity of the preeclampsia and on the characteristics of the woman.80 For many years, authorities in the United States have recommended that magnesium sulfate be given prophylactically during labor and post partum to all women with preeclampsia.80,81 In contrast, authorities in other countries consider lowering the maternal blood pressure to be adequate prophylaxis.82-84 This controversy is not surprising, since the incidence of eclampsia in women with preeclampsia is extremely low and varies greatly among different groups of women.80-85 For example, in two large, observational studies in the United States, the average rate of eclampsia among 13,924 women with preeclampsia who received prophylaxis with magnesium sulfate was 0.26 percent,80 which does not differ substantially from the rate of 0.18 percent among 3885 women with preeclampsia who did not receive prophylaxis in a Scottish study.82

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TABLE 6. RANDOMIZED TRIALS

OF ANTIHYPERTENSIVE-DRUG THERAPY IN WITH SEVERE HYPERTENSION.*

PREGNANT WOMEN

STUDY

WK OF GESTATION AT ENTRY

DIASTOLIC PRESSURE AT ENTRY

mm Hg

TREATMENT FAILURE

FETAL DISTRESS

COMMENTS

number (%)

Fenakel et al.69 Nifedipine (n 24) Hydralazine (n 25) Mabie et al.70 Labetalol (n 40) Hydralazine (n 20) Garden et al.72 Labetalol (n 6) Dihydralazine (n 6) Michael73 Labetalol (n 45) Diazoxide (n 45) Ashe et al.74 Labetalol (n 10) Dihydralazine (n 20) Seabe et al.75 Nifedipine (n 17) Dihydralazine (n 16) Moodley and Gouws76 Epoprostenol (n 22) Hydralazine (n 25) Martins-Costa et al.77 Nifedipine (n 20) Hydralazine (n 17) Rossouw et al.78 Ketanserin (n 10) Hydralazine (n 10) Duggan et al.79 Nifedipine (n 5) Hydralazine (n 4)

32.4 32.3 35.6 34.5 3035 3438 2538 2637 38.5 38.5 31.1 31.5 36.0 36.0 36.0 36.0 3141 3039

110 110 110 110 115130 110130 105140 105120 118 8 117 5 116 7 116 9 112 27 117 12 119 6 118 8 110 110 110 110

1 (4) 8 (32) 4 (10) 0 2 (33) 5 (83) 3 (7) 14 (31) 6 (60) 4 (20) 1 (6) 4 (25) 0 2 (8) 0 0 0 1 (10) 0 0

1 (4) 11 (44)

Nifedipine was more effective and had fewer side effects than hydralazine

0 of 13 Considerable variability in the dose of 2 of 6 (33) labetalol 0 of 3 0 of 3 0 3 (7) 1 (10) 0 1 (6) 0 0 2 (8) 0 0 0 1 (10) 0 0 More effective blood-pressure control in labetalol group Smoother control of blood pressure in labetalol group More effective blood-pressure control in dihydralazine group Similar maternal and fetal effects Similar maternal and fetal effects Similar maternal and fetal effects Similar effects on placental and umbilical flow-velocity wave forms Similar effects on placental flow-velocity wave forms

*Severe hypertension was defined as a diastolic blood pressure Single values are means; inclusive values are ranges. Inclusive values are ranges; plusminus values are means The value was not reported.

110 mm Hg.

SD; single values are means.

Two randomized trials have evaluated prophylaxis with magnesium sulfate in women with preeclampsia.81,84 In one trial of an antihypertensive drug plus magnesium sulfate in 112 women with severe preeclampsia and antihypertensive therapy alone in 116,84 there was one case of eclampsia in the magnesium sulfate group and none in the other group. In the other trial,81 magnesium sulfate and phenytoin were compared for the prevention of eclampsia in 2137 women with mild preeclampsia. There were 10 cases of eclampsia (1 percent) in the phenytoin group and none in the magnesium sulfate group. The routine use of magnesium sulfate prophylaxis in all women with preeclampsia has been questioned.85,86 Nevertheless, if a decision is made to treat such women prophylactically during labor and delivery, magnesium sulfate is the ideal therapy.1,80,81 Moreover, in a recent large-scale trial, magnesium sulfate was superior to both phenytoin and diazepam for the treatment and prevention of recurrent convul-

sions in women with eclampsia.87 All women with eclampsia should therefore receive magnesium sulfate during labor and delivery and for at least 24 hours post partum.44,67
Prevention of Preeclampsia

For many years, salt restriction and diuretic drugs have been used to prevent preeclampsia. It is now known that dietary sodium restriction during pregnancy reduces blood volume without reducing the frequency of hypertension.88 The results of a review of early studies of women at risk for preeclampsia suggested that low doses of aspirin reduced the incidence and severity of preeclampsia.89 However, the results of two large, multicenter, randomized trials in nulliparous women90 and women at various degrees of risk for preeclampsia91 do not support the use of aspirin in pregnancy. The results of epidemiologic studies have suggested an inverse association between dietary calcium intake, on the one hand,
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and maternal blood pressure and the incidence of preeclampsia and eclampsia, on the other.92 A metaanalysis of six randomized trials that included 1700 pregnant women found calcium supplementation during pregnancy to be effective in reducing the risk of hypertension,93 but its effects on preeclampsia (defined as hypertension plus proteinuria) were small.
CONCLUSIONS

In caring for pregnant women with hypertension, it is important to differentiate among chronic hypertension, gestational hypertension, and preeclampsia. Maternal and neonatal outcomes are usually good among pregnant women who have either mild chronic hypertension or gestational hypertension. In addition, antihypertensive drug therapy may permit such women to continue their pregnancies to term. In contrast, preeclampsia is a unique syndrome of pregnancy that is potentially dangerous for both mother and fetus; it does not respond well to the conventional antihypertensive therapy used in nonpregnant patients. Close medical supervision and timely delivery are the keys to the treatment of preeclampsia.
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