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072596 treatment of hypertension in pregnant womenD R U G T H E R A PY
The rates are higher in older women, obese women,and black women.8 The diagnosis is usually based oneither a history of hypertension before pregnancy or A L A S T A I R J . J . W O O D , M . D . , Editor blood-pressure elevations to at least 140/90 mm Hgbefore 20 weeks’ gestation.1 It is difficult to diagnose chronic hypertension in TREATMENT OF HYPERTENSION
pregnant women in whom the blood pressure beforepregnancy is not known. In such cases, the diagnosis IN PREGNANT WOMEN
is usually based on the presence of hypertension be-fore 20 weeks’ gestation. In some women, however, hypertension before 20 weeks’ gestation may be thefirst 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 pres- nancy and are an important cause of mater- nal and perinatal morbidity and mortality world- In nonpregnant women and in men, hypertension wide.1 During normal pregnancy, systolic pressure is often classified as mild, moderate, severe, or very changes little; however, diastolic pressure decreases severe on the basis of either the systolic or the dia- by an average of 10 mm Hg early in gestation (13 stolic blood pressure. During pregnancy, chronic to 20 weeks) and rises again to prepregnancy levels hypertension is considered either mild or severe. Al- in the third trimester. The term “hypertension in though there is no widely accepted definition of mild pregnancy” describes a broad spectrum of condi- hypertension, there is agreement that a diastolic tions in which blood pressure varies widely. In re- blood pressure of 110 mm Hg or higher (Korotkoff viewing the literature on this subject, one is faced phase V) constitutes severe hypertension.
with difficulties regarding the definitions and classi- In babies born to pregnant women with chronic hy- fications used to categorize hypertension in preg- pertension, perinatal outcome is poor, mostly because nant women,2-6 including which Korotkoff sound (phase IV or phase V) should be used to measure di- diagnose superimposed preeclampsia vary, however; astolic blood pressure.1,5 All current definitions and they have included exacerbation of hypertension, ede- classification schemes have certain pitfalls as they re- ma, proteinuria, hyperuricemia, or a combination of late to clinical diagnosis and management. Neverthe- these factors. Neither the exacerbation of hyperten- less, a recent report by the Working Group on High sion nor edema is a reliable indicator of superimposed Blood Pressure in Pregnancy recommended using preeclampsia. In the absence of renal disease, the onset the classification system proposed by the American of proteinuria (at least 300 mg per 24 hours) is the College of Obstetricians and Gynecologists in 1972,2 best indicator of superimposed preeclampsia.
even though this classification is not accepted in many Risks to the Mother and Fetus
countries outside the United States.7 In this review,hypertensive disorders of pregnancy will be divided Pregnant women with chronic hypertension are at into three categories: chronic hypertension, gestation- increased risk for superimposed preeclampsia and al hypertension, and preeclampsia (Table 1).
abruptio placentae, and their babies are at increasedrisk for perinatal morbidity and mortality.8 The like- CHRONIC HYPERTENSION
lihood of these complications is particularly increased The incidence of chronic hypertension in preg- in women with long-standing severe hypertension nant women ranges from 1 percent to 5 percent.1 and those with preexisting cardiovascular or renaldisease.13-16 In addition, fetal and maternal morbidi-ty and mortality are higher than normal when preg-nant women have a diastolic pressure of 110 mm Hgor higher during the first trimester.14,15 Converse- From the Division of Maternal–Fetal Medicine, Department of Obstet- ly, the outcomes of women with mild, uncomplicat- rics and Gynecology, University of Tennessee, 853 Jefferson Ave., Rm.
ed chronic hypertension during pregnancy and of E102, Memphis, TN 38103, where reprint requests should be addressedto Dr. Sibai.
their babies are similar to those of normal pregnant 1996, Massachusetts Medical Society.
T h e New E n g l a n d Jo u r n a l of Me d i c i n e TABLE 1. HYPERTENSIVE DISORDERS OF PREGNANCY.
*Defined as у1ϩ by dipstick testing on two occasions or у300 mg in a 24-hour urine collection.
ed in only three trials,22,23,26 was not reduced by The results of two retrospective studies of preg- treatment. Abruptio placentae was mentioned in only nant women13,17 and randomized trials involving non- one trial,26 in which there was no difference in fre- pregnant women18 indicate that antihypertensive quency between the treated and untreated groups therapy decreases the incidence of stroke and cardio- (1 percent in each group). In the two largest tri- vascular complications among pregnant women with als,21,26 the incidence of perinatal death was less than diastolic blood-pressure values above 110 mm Hg.
2 percent in the untreated groups. Demonstrating a There is general agreement that pregnant women 50 percent reduction in the frequency of either with severe hypertension should receive pharmaco- abruptio placentae or perinatal death would have re- logic treatment,1,8,19 but whether it is beneficial to quired the enrollment of approximately 2000 wom- lower blood pressure in pregnant women with mild en in each group. Therefore, the continued uncer- essential hypertension is not known.1,8,19 tainty about the benefits of lowering blood pressure The cardiovascular benefits of long-term therapy in pregnant women who have mild chronic hyper- to lower blood pressure in nonpregnant, middle- tension is mainly due to the fact that all published aged, and elderly subjects with diastolic pressures of trials have been too small to detect moderate reduc- less than 110 mm Hg (mild hypertension) are well tions in the rates of obstetrical complications. established.12,18 These benefits were most evident af- Other trials have evaluated the benefits of lower- ter four to six years of treatment in men who were ing blood pressure in pregnant women with mild older than 50 and those with risk factors for cardio- chronic or gestational hypertension.27-36 Some have vascular disease or stroke.12,18 However, most preg- compared two different antihypertensive drugs; others nant women with mild chronic hypertension are less have involved a combination of drugs or compared than 40 years old and have uncomplicated mild hy- treatment with no treatment or a placebo (Table 3).
pertension. Therefore, treating mild chronic hyperten-sion in pregnant women is unlikely to be beneficial.
Risks of Pharmacologic Treatment
In order to improve perinatal outcomes, therapy Antihypertensive drugs have potential adverse ef- to lower the blood pressure in pregnant women fects on the mother and the fetus or neonate,37 and with mild hypertension must reduce the incidence some of the latter may not become evident until of preeclampsia, abruptio placentae, preterm deliv- childhood. Antihypertensive drugs can affect the fe- ery, and fetal or neonatal death. In the past 30 years, tus either indirectly, by lowering uteroplacental blood at least seven studies have compared antihyperten- flow, or directly, by influencing the umbilical or fetal sive therapy with either no medication or a placebo in pregnant women with mild chronic hypertension Methyldopa is the drug most often used to treat (Table 2).20-26 There was a higher rate of fetal loss chronic hypertension in pregnant women and has during the second trimester among untreated wom- been used most commonly in randomized trials en in several early trials,20,21 but this finding was not (Tables 2 and 3). Short-term treatment with meth- confirmed in later studies.22-26 There was no decrease yldopa (for an average of 24 days) during the third in the frequency of superimposed preeclampsia in trimester does not affect uteroplacental or fetal he- five trials.21-24,26 The rate of preterm delivery, report- modynamics.38 Furthermore, neither short-term ef- D R U G T H E R A PY
TABLE 2. RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY IN PREGNANT WOMEN WITH MILD CHRONIC HYPERTENSION.
MEAN WK OF
in whom severe hypertension devel-oped despite treatment fects on the fetus or neonate26 nor long-term effects treated with diuretics; whether therapy should be during infancy39 have been reported after the long- continued during pregnancy is controversial.1,14,26 term use of methyldopa in pregnancy. In contrast, The working group concluded that therapy to con- atenolol has definite adverse effects on uteropla- trol blood pressure should be continued in women cental and fetal hemodynamics,40 as well as on fetal who are already receiving a diuretic or in those treat- growth.25 The data concerning the potential adverse ed before 20 weeks’ gestation.1 Diuretic therapy is effects of other beta-adrenergic–antagonist drugs particularly useful in pregnant women with salt-sen- during pregnancy are conflicting.26-28,30-36 Moreover, sitive hypertension or with left ventricular diastolic there are no studies of the long-term effects on the dysfunction; however, it should be discontinued infant of beta-adrenergic–antagonist drugs during if preeclampsia develops or there is evidence of re- duced fetal growth.1 Early initiation of prenatal care A meta-analysis of nine randomized trials compar- and close medical supervision are the keys to a suc- ing diuretic therapy with no treatment in a total of cessful outcome of pregnancy in such cases.1,13,26 7000 normotensive pregnant women found no dif- The decision to initiate drug therapy in a woman ference in the incidence of adverse effects on the with chronic hypertension should take into account mother or neonate between the two groups.41 This the severity of the hypertension, the potential risk of overview did not evaluate the effects of diuretics on damage to target organs, and the presence or ab- fetal growth. Diuretic therapy in pregnant women sence of preexisting cardiovascular disease.8,12 The with mild chronic hypertension is associated with a initial drug of choice is methyldopa. If there are con- lower-than-normal degree of plasma volume expan- traindications to its use (such as drug-induced liver sion, which may be detrimental to fetal growth.23 damage) or if it is ineffective or cannot be tolerated, Administration of drugs that inhibit angioten- labetalol or nifedipine can be given.
sin-converting enzyme during pregnancy is contrain-dicated because these drugs are associated with fe- GESTATIONAL HYPERTENSION
tal growth retardation, oligohydramnios, congenital Gestational hypertension is defined as the develop- malformations, neonatal renal failure, and neonatal ment of high blood pressure without other symptoms death.42 There is little experience with the long-term of preeclampsia after 20 weeks’ gestation in a previ- administration of calcium-channel–blocking drugs to ously normotensive woman. In some women, gesta- pregnant women with hypertension.8,36 Therefore, tional hypertension may be an early manifestation of their effects on the fetus and neonate are unknown.
preeclampsia, whereas in others it may be an earlysign of unrecognized chronic hypertension.1,3,5 Gen- Management of Chronic Hypertension
erally, the outcome of pregnancy in women with ges- Women with chronic hypertension should be eval- tational hypertension is good without drug therapy.
uated before conception so that drugs that may haveadverse effects on the fetus (such as angiotensin- PREECLAMPSIA
converting–enzyme inhibitors and atenolol) can be Preeclampsia has traditionally been described as the replaced by other drugs such as methyldopa or la- occurrence of hypertension, edema, and proteinuria betalol. Many women with chronic hypertension are after 20 weeks’ gestation in a previously normoten- T h e New E n g l a n d Jo u r n a l of Me d i c i n e TABLE 3. RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY IN PREGNANT WOMEN WITH ALL FORMS OF MILD HYPERTENSION.*
NO. OF OF GESTATION
Fewer side effects in combined-treatment Fewer cesarean sections in treatment group Less proteinuria and lower birth weights in More admissions to neonatal intensive care *These trials included women with chronic hypertension, gestational hypertension only, or preeclampsia.
sive woman. The differences between preeclampsia These changes result in reduced perfusion of the and gestational hypertension are summarized in Ta- placenta, kidneys, liver, and brain. Endothelial dys- ble 1. In general, preeclampsia is defined as hyper- function (resulting in vasospasm, altered vascular tension plus hyperuricemia or proteinuria, and it is permeability, and activation of the coagulation sys- categorized as mild or severe primarily on the basis tem) could explain many of the clinical findings in of the degree of elevation in blood pressure, the women with preeclampsia.4 Indeed, many of the ab- degree of proteinuria, or both. At present, there is normalities described in such women are due pri- no consensus regarding the definition of mild hyper- marily to reduced perfusion rather than to hyper- tension, severe hypertension, or severe proteinuria.1-6 Nonetheless, emphasis on either hypertension or pro-teinuria may minimize the clinical importance of Risks of Preeclampsia to the Mother and Fetus
a number of other disturbances in various organ The chief risks to the woman entailed by pre- systems.4 For example, some women with the syn- eclampsia are convulsions, cerebral hemorrhage, drome of hemolysis, elevated serum liver-enzyme abruptio placentae with disseminated intravascular concentrations, and low platelet counts (HELLP) coagulopathy, pulmonary edema, renal failure, liver have life-threatening complications (pulmonary ede- hemorrhage, and death. The risks to the fetus in- ma, acute renal failure, or liver rupture) but little or clude severe growth retardation, hypoxemia, acido- no hypertension and minimal proteinuria.43 In ad- sis, prematurity, and death. The frequency of these dition, among women with preeclampsia who later complications depends on the duration of gestation have convulsions (eclampsia), 20 percent have a at the onset of preeclampsia, the presence or absence diastolic blood pressure below 90 mm Hg or no of associated medical complications, the severity of proteinuria.44 Some women with preeclampsia have the preeclampsia, and the quality of medical man- symptoms and signs that are mistakenly thought to agement. In women with mild preeclampsia who are indicate the presence of other disorders (Table 4).
closely followed,45-48 the risk of convulsions is 0.2percent, that of abruptio placentae is 1 percent, and Pathophysiology
that of fetal or neonatal death is less than 1 percent.
One of the earliest abnormalities noted in women The incidence of fetal growth retardation (birth in whom preeclampsia later develops is the failure weight, Ͻ10th percentile) is 5 to 13 percent, and of the second wave of trophoblastic invasion into that of preterm delivery ranges from 13 percent to the spiral arteries of the uterus. As a result of this 54 percent — depending on the duration of gesta- defect in placentation, there is failure of the cardio- tion at onset and the presence or absence of pro- vascular adaptations (increased plasma volume and teinuria.45-48 Conversely, maternal and fetal or neo- reduced systemic vascular resistance) that are char- natal morbidity and mortality are substantial among acteristic of normal pregnancy. In preeclampsia, both women with eclampsia,44,49,50 those with the HELLP cardiac output and plasma volume are reduced, syndrome,43,51 and those in whom preeclampsia oc- whereas systemic vascular resistance is increased.1 D R U G T H E R A PY
preeclampsia and a cervix favorable for induction at TABLE 4. CONDITIONS SOMETIMES
term (Bishop’s score, Ͼ6), delivery should be induced to avoid possible maternal and fetal complications.1,3 In contrast, there is no agreement about the managementof mild preeclampsia earlier in pregnancy. In particular, there is disagreement about the need for bed rest, pro- longed hospitalization, antihypertensive drug therapy, Bed rest, whether at home or in the hospital, is commonly recommended for women with mild pre- eclampsia.55 The purported benefits of bed rest in- clude the reduction of edema, improved fetal growth, Exacerbation of systemic lupus erythematosus prevention of progression to severe preeclampsia, and improved outcomes of pregnancy.45-47 In three ran- domized 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 hospi-talization.56-58 In one trial, however, more womentreated at home had progression to severe diseaseand needed preterm delivery.58 Moreover, none ofthese trials were large enough to evaluate the risks Management of Preeclampsia
of eclampsia, abruptio placentae, and fetal or neona- Early diagnosis, close medical supervision, and timely delivery are the cardinal requirements of the At least 10 randomized trials evaluating drug treat- management of preeclampsia; delivery is the ulti- ment in women with mild gestational hypertension mate cure.1,3 Once the diagnosis is established, sub- or preeclampsia remote from term have been report- sequent management should be based on the initial ed (Table 5).40,46,47,59-66 In eight of these trials, anti- evaluation of maternal and fetal well-being. On the hypertensive drug therapy was compared with either basis of the results of this evaluation, a decision is no medication or a placebo, and in two trials dif- then made regarding hospitalization, expectant man- ferent antihypertensive drugs were compared.40,62 In agement, or delivery, with the following factors tak- some trials,59,63-65 the frequency of proteinuria, pro- en into account: the severity of the disease process, gression to severe disease, and neonatal respiratory the status of mother and fetus, and the length of distress syndrome was higher when the women were gestation. Irrespective of the management strategy not treated, but these findings were not confirmed chosen, the ultimate goal must first be the safety of in other trials.46,47,60 The effects of treatment on the the mother and, second, the delivery of a live infant length of pregnancy, on fetal growth, and on the in- who will not require intensive and prolonged neona- cidence of preterm delivery varied. Therefore, there is no clear benefit to drug treatment in women withmild gestational hypertension or preeclampsia.
Women with preeclampsia require close observa- Severe Preeclampsia
tion because the disorder may worsen suddenly. The Severe preeclampsia may be rapidly progressive, presence of symptoms (such as headache, epigastric resulting in sudden deterioration in the status of pain, and visual abnormalities) and proteinuria both mother and fetus, so that prompt delivery is rec- increases the risks of both eclampsia and abruptio ommended regardless of the duration of gestation.3,67 placentae; women with these findings require close Prompt delivery is clearly indicated when there is im- observation in the hospital.45-47 Outpatient manage- minent eclampsia, multiorgan dysfunction, or fetal ment may be considered if compliance is expected to distress or when severe preeclampsia develops after be good, hypertension is mild, and the fetus is nor- 34 weeks.68 Early in gestation, however, prolonga- mal. The management should include close monitor- tion of pregnancy with close monitoring may be in- ing of the mother’s blood pressure, weight, urinary dicated in order to improve neonatal survival and protein excretion, and platelet count, as well as of fe- reduce short-term and long-term neonatal morbid- tal status.1 In addition, the woman must be informed ity.9,53,54,69 In three recent clinical trials in women about the symptoms of worsening preeclampsia.48 If with severe preeclampsia remote from term, neona- there is evidence of disease progression, hospitaliza- tal morbidity and mortality were reduced with con- servative management.53,54,69 Nevertheless, because There is general agreement that in women with mild only 116 women were assigned to conservative man- T h e New E n g l a n d Jo u r n a l of Me d i c i n e TABLE 5. RANDOMIZED TRIALS OF ANTIHYPERTENSIVE DRUG THERAPY IN WOMEN
WITH GESTATIONAL HYPERTENSION OR PREECLAMPSIA.
MEAN WK OF
MEAN WK OF
agement in these trials, and because such manage- distress with hydralazine, several investigators have ment entails risk to the mother and fetus, conserva- recommended using other drugs to treat severe pre- tive management must be considered only at tertiary eclampsia (Table 6).69,70,72-79 In nine randomized tri- perinatal centers and must include very close moni- als in which hydralazine (or dihydralazine) was com- pared with another drug, only one found that side The primary objective of treatment in women with effects and treatment failure were more frequent in severe hypertension and preeclampsia is to prevent cerebral complications such as encephalopathy andhemorrhage. The threshold for treatment is usually Anticonvulsant Drug Therapy
a sustained diastolic blood pressure of 110 mm Hg Women with preeclampsia have an increased risk or higher.3,67-70 Some experts recommend initiating of convulsions.1,80 The degree of risk depends on the treatment at diastolic blood-pressure values of 105 severity of the preeclampsia and on the characteris- mm Hg or even lower,1 whereas others use mean ar- tics of the woman.80 For many years, authorities in terial pressure greater than 125 mm Hg as the thresh- the United States have recommended that magne- sium sulfate be given prophylactically during labor The aim of therapy is to keep the mean arterial and post partum to all women with preeclampsia.80,81 pressure below 126 mm Hg (but not less than 105 In contrast, authorities in other countries consider mm Hg) and the diastolic pressure below 105 lowering the maternal blood pressure to be adequate mm Hg (but not less than 90 mm Hg).1,71 The ini- prophylaxis.82-84 This controversy is not surprising, tial treatment of choice in women who have severe since the incidence of eclampsia in women with pre- hypertension during the peripartum period is hy- eclampsia is extremely low and varies greatly among dralazine given intravenously in 5-mg bolus dos- different groups of women.80-85 For example, in two es.1,3,71 The dose may be repeated as needed every 20 large, observational studies in the United States, the minutes up to a cumulative total of 20 mg. If this average rate of eclampsia among 13,924 women with amount of hydralazine does not achieve the desired preeclampsia who received prophylaxis with magne- therapeutic response, or if the mother has side ef- sium sulfate was 0.26 percent,80 which does not dif- fects such as tachycardia, headache, or nausea, labet- fer substantially from the rate of 0.18 percent among alol (20 mg intravenously) or nifedipine (10 mg 3885 women with preeclampsia who did not receive orally) may be given. Because of concern about fetal D R U G T H E R A PY
TABLE 6. RANDOMIZED TRIALS OF ANTIHYPERTENSIVE-DRUG THERAPY IN PREGNANT WOMEN
More effective blood-pressure control in More effective blood-pressure control in Similar effects on placental and umbilical Similar effects on placental flow-velocity *Severe hypertension was defined as a diastolic blood pressure у110 mm Hg.
†Single values are means; inclusive values are ranges.
‡Inclusive values are ranges; plus–minus values are means ϮSD; single values are means.
§The value was not reported.
Two randomized trials have evaluated prophylaxis sions in women with eclampsia.87 All women with with magnesium sulfate in women with preeclamp- eclampsia should therefore receive magnesium sul- sia.81,84 In one trial of an antihypertensive drug plus fate during labor and delivery and for at least 24 magnesium sulfate in 112 women with severe pre- eclampsia and antihypertensive therapy alone in 116,84there was one case of eclampsia in the magnesium Prevention of Preeclampsia
sulfate group and none in the other group. In the For many years, salt restriction and diuretic drugs other trial,81 magnesium sulfate and phenytoin were have been used to prevent preeclampsia. It is now compared for the prevention of eclampsia in 2137 known that dietary sodium restriction during preg- women with mild preeclampsia. There were 10 cases nancy reduces blood volume without reducing the of eclampsia (1 percent) in the phenytoin group and frequency of hypertension.88 The results of a review none in the magnesium sulfate group.
of early studies of women at risk for preeclampsia The routine use of magnesium sulfate prophylaxis suggested that low doses of aspirin reduced the in- in all women with preeclampsia has been ques- cidence and severity of preeclampsia.89 However, the tioned.85,86 Nevertheless, if a decision is made to treat results of two large, multicenter, randomized trials such women prophylactically during labor and deliv- in nulliparous women90 and women at various de- ery, magnesium sulfate is the ideal therapy.1,80,81 More- grees of risk for preeclampsia91 do not support the over, in a recent large-scale trial, magnesium sulfate use of aspirin in pregnancy. The results of epidemi- was superior to both phenytoin and diazepam for ologic studies have suggested an inverse association the treatment and prevention of recurrent convul- between dietary calcium intake, on the one hand, T h e New E n g l a n d Jo u r n a l of Me d i c i n e and maternal blood pressure and the incidence of 19. Redman CWG. Controlled trials of antihypertensive drugs in pregnan-
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SUMMARY OF PRODUCT CHARACTERISTICS NAME OF THE MEDICINAL PRODUCT BETAC ® 20 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 20 mg betaxolol hydrochloride. Excipients: One tablet contains 100 mg lactose monohydrate. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL Film-coated tablet White, round, co