Treatment of hypertension in pregnancy

Kidney International, Vol. 18 (1980), pp. 267-2 78

Treatment of hypertension in pregnancy C. W. G. REDMAN Nuffield Department of Obstetrics and Gynaecoiogy, John Radcliffe Hospital, Oxford, England

The specific treatment of hypertension in preg-

probably lower in previously normotensive than it is for chronically hypertensive individuals in whom the arterioles have adapted structurally to higher pressures [8]. The same processes extending over longer periods of time are thought to cause cerebral microaneurysms, which in turn can rupture to cause cerebral hemorrhage. Thus, it is possible to explain why high blood pressure causes cerebral hemorrhage, why very high blood pressure causes acute cerebral dysfunction, and why both problems are prevented by adequate hypotensive treatment. In pregnancy, previously normotensive women may rapidly develop extreme hypertension to levels where all the clinical and experimental evidence would suggest that arterial and arteriolar damage should acutely ensue. Nevertheless, eclampsia is not simply a variant of malignant hypertension. The two conditions are similar in that they can include convulsions, death from cerebral hemorrhage, heart failure, hypovolemia, proteinuria, progressive uremia, disseminated intravascular coagulation, and microangiopathic hemolysis [10, 1.1]. But there are differences. In eclampsia, cerebral edema is not a notable autopsy feature [12]. The liver is peculiarly a target organ for the preeclamptic process, showing periportal hemorrhages and infarcts [12]. The arterial intimal proliferation of malignant hy-

nancy is still a matter of dispute. In the United Kingdom, some obstetricians never use antihypertensive treatment in the management of even severe preeclampsia [1]. Instead, emphasis is given to the use of anticonvulsants such as diazepam or chlormethiazole. In the United States, parenteral magnesium sulphate, which has no hypotensive action, is the first line of treatment [2]. Treatment of extreme hypertension in pregnancy

Rationale for treatment. There is considerable evidence to demonstrate the deleterious effects of sudden increments in blood pressure (above a critical value) in nongravid humans and experimental animals. In rats, acute increases to values above a mean pressure of 150 mm Hg rapidly cause focal arteriolar damage [3]. Experimentally, this is well seen in the mesenteric arterioles of the rat, which develop alternating constrictions and dilatations, resembling a string of beads [4]. The damaged areas

are confined to the dilated segments, where there are endothelial tears that allow plasma to track into and disrupt the media [5]. At these points, the arterioles are both abnormally permeable and unable to maintain their normal tone. The critical feature is the speed with which hypertensive damage evolves:

histologic abnormalities are detectable within 10 mm and have become extensive after 1 hour [3]. The malignant phase of hypertension may be solely explicable by this sequence of hypertensive arteriolar injury [6], although it has been claimed

pertension [13] is not a feature of preeclampsia [14], although it is seen in the separate syndrome of post-

partum renal failure [15]. This difference may be simply a function of the brevity of most eclamptic illnesses in that intimal proliferation is a secondary response taking time to develop after primary arte-

that the augmenting action of humoral factors, such as antidiuretic hormone, is also necessary [7]. The functional effect of pressure-forced dilatation of arterioles is a loss of autoregulatory control with exposure of more peripheral vessels to high-pressure hyperperfusion. Experimentally and clinically, this has been demonstrated in the brain [8] and is the cause of hypertensive encephalopathy and retinopathy [9]. The threshold for forced dilatation is

rial injury [16]. The retinal fundal changes of malig-

nant hypertension are usually not seen in eclampReceived for publication January 18, 1980

0085-2538/80/0018-0267 $02.40

© 1980 by the International Society of Nephrology

267

Redman

268

sia. Careful examination of the retinal arterioles will nevertheless reveal the alternating segments of constriction and dilatation that are characteristic of hypertensive injury [3, 17]. Therefore, even if eclampsia is not malignant hypertension, there is considerable evidence that it is a form of hypertensive encephalopathy. The only

other explanation for the convulsions is that they

result from ischemic injury caused by microvascular thrombosis [18]. This would categorize eclampsia nearer to thrombotic thrombocytopenic purpura, with which it may be confused diagnostically [19].

An increasing proportion of women who succumb to eclampsia die of cerebral hemorrhage (Table 1). At autopsy, there are petechiae in the cortex, white matter, and midbrain, associated with capillary thrombi. Larger hemorrhages, which may rupture into the subarachnoid space, are found in the white matter, basal ganglia, and pons [12]. They are similar to those seen in older hypertensive individuals and are associated with arterial wall necrosis [20].

The autopsy evidence is consistent with hypertensive cerebrovascular injury as the prime causes of eclampsia. Claims that hypertension is not always a feature of eclampsia may result from problems of blood pressure measurement [21] or from a failure to recognize that hypertensive injury may precede rather than coincide with eclamptic convulsions. Although activation of the clotting system is not simply secondary to vascular injury, in that it can be detected before extreme hypertension has developed [22], it is also possible to have eclampsia without coagulation abnormalities [23]. This argues

against a thrombotic etiology for eclampsia. It must therefore be concluded that unless pregnant women have arterial systems totally unlike nonpregnant individuals and experimental animals, the sudden in-

creases of blood pressure characteristic of preeclampsialeclampsia are the most likely cause of the neurologic features and the cerebral pathology. Principles of treatment of extreme hypertension in pregnancy. Blood pressures of 170 to 180/1 10 to 120 represent mean arterial pressures of 130 to 140 mm Hg. These are close to the limits where experimental hypertensive vascular damage begins. Thus,

on general principle, blood pressures at or above 170/110 should be treated. The decision to treat is based on the maximum blood pressures recorded in any period. The diagnosis of extreme hypertension in pregnancy is nearly always preeclampsia, which may be superimposed on chronic vascular or renal disease. In general, the basic management of preeclampsia hinges around two issues: detection (by screening the asymptomatic patient) and timely delivery. The former demands that antenatal care facilities be provided and used; the latter guarantees a cure for all preeclamptic hypertension and is, where possible, preferable to any system of medical treatment. The possible methods of management have been recently reviewed by several authors [24—3 1].

Arteriolar constriction, of unknown origin,

causes preeclamptic hypertension. It is probably not mediated through the sympathetic nervous system. Whether or not angiotensin is involved is disputed (reviewed in Ref. 11). Despite fluid retention, there is plasma volume depletion and reduced renal and placental perfusion [11].

The vasospasm responds best to the drugs that directly relax vascular smooth muscle, namely Table 1. Maternal deaths in England and Walesa

All maternal deaths 1961-63

692

Due to eclampsia % of all deaths

40 (5.8%)

579

40

1967-69

455

(6.9%) 41 (9.0%)

1970—72

355

29

1973—75

235

(8.2%) 21 (8.9%)

1964—66

Due to eclampsia and cerebral hemorrhage % of all eclamptic deaths 13 (32.5%) 14 (36.0%) 10

(24.4%) 16 (55.2%) 11

(52.4%)

a Data from Reports on Confidential Enquiries into Maternal

Deaths in England and Wales. London, HMSO, 1966, 1969, 1972, 1975, 1979

diazoxide and hydralazine. These are the agents of choice for acute hypertensive emergencies in pregnancy. Both are usually used in the immediate penpartum period. Neither has been tested in adequately controlled trials. Hydralazine has probably been used more extensively in pregnancy than has diazoxide [32-34]. It is best reserved for transient rises in blood pressure,

which are treated with intermittent i.m. or s.c. administration of 10 to 20 mg. Side effects are more likely to be troublesome with continuous i.v. infusion, and because they comprise headaches, vomiting, shakiness, and even hyperreflexia, they can mimic impending eclampsia. Hydralazine has a weak and transient action. Its effectiveness is

enhanced by concurrent sympathetic inhibition,

Treatment of hypertension in pregnancy

269

which blocks the reflex tachycardia that develops as

healthy human placenta must have a capacity to

the blood pressure falls. In pregnancy, this is

function normally over a range of different maternal blood pressures, including the 15% drop in mean arterial pressure that occurs at night during sleep [46].

achieved if the patient is already on methyldopa. Fetal side effects have not been reported. Some of the hydralazine metabolites are, however, poten-

But in preeclampsia, placental blood flow is re-

tially very toxic, and therefore it should not be used indiscriminately or at levels exceeding 300 mg in 24 hours. Diazoxide has mainly been used for intrapartum hypertensive emergencies [35—38]. Its ability to re-

duced [11] because of gross obstructive changes in the spiral arteries [47], which in themselves could limit the effectiveness of any mechanism of autoregulation of blood flow.

duce the blood pressure within minutes has been amply confirmed. The standard dose of 300 mg by rapid i.v. injection is excessive and can cause seri-

causes reduced placental perfusion cannot be answered directly. Neither do clinical studies of fetal morbidity or mortality after treatment provide useful information, because there are no controlled observations. It is general experience, however, that therapeutic reduction of maternal pressure does not cause apparent fetal problems and may be compati-

ous hypotension [38]. The tendency to hypotension is probably aggravated by the plasma volume depletion of preeclampsia and is more likely if the patient is already on sympathetic blocking drugs. Titration by intermittent administration of small boluses of 30 to 60 mg is preferable and effective [24, 39]. Diazoxide relaxes uterine muscle and usually inhibits labor [40, 41]. The advantages of using diazoxide have recently been queried [42]. There is no doubt that it is

a drug to be reserved for the most extreme situations (in our practice less than 0.05% of all maternities). Apart from hypotension and shock, neonatal hyperglycemia after acute administration in la-

bor has been reported [38]. The same is seen in utero in fetal lambs from sheep given 15 mg/kg/day of i.v. diazoxide for 100 hours (more than should be used clinically). After delivery, fetal pancreatic beta cell destruction was seen, as well as cataracts and muscle abnormalities in one animal [43]. On the oth-

er hand, diazoxide is the most likely drug to successfully control dangerous hypertension, and if used cautiously, is probably the safest option in these circumstances. If the renin-angiotensin system causes the hypertension of preeclampsia, then agents that inhibit its action might, in the future, be a useful part of treatment. In the immediate postpartum period, a converting enzyme inhibitor (SQ 20,881) did not lower the blood pressure of five preeclamptic women [44]. Experimentally, the angiotensin antagonist saralasin reduces the blood pressure of the pregnant ewe in a dose-dependent fashion [45]. Clinical studies of its use have not been reported. Lowering the blood pressure and placental per-

fusion. How perfusion of the human placenta is controlled is poorly understood because of the obvi-

ous ethical problems of measurement and experimentation. Moreover, animal observations are frequently limited to measurement of uterine artery flow, which may not reflect placental flow. The

Whether or not acute hypotensive treatment

ble with a continuing intrauterine existence over pe-

riods of weeks. Controlled clinical studies have demonstrated that long-term hypotensive treatment

does not retard fetal growth despite significant blood pressure reduction [48, 49]. In some vascular beds, blood flow increases after

hypotensive treatment, demonstrated in the preeclamptic myometrium after i.v. hydralazine [50]. Likewise in the pregnant ewe, with renal artery clip hypertension, hydralazine increases uterine artery flow—a change mediated by the reflex sympathetic increase in cardiac output [51]. Diazoxide in the hy-

pertensive or normotensive ewe reduces uterine perfusion [51-53]. The increased uterine flow in pregnant monkeys after angiotensin II infusion is abolished by pretreatment with indomethacin, whereas the hypertensive response is augmented [54]. Here, prostaglandins are apparently the determinants of changes in uterine flow, not the arteri-

al pressure. Autoregulation of rabbit placental blood flow has been claimed [55], with a lower limit

of arterial pressure below which flow diminishes. Presumably this threshold explains the reduced placental flow after bethanidine-induced hypotension in rabbits, which has also been reported [56]. Whether or not these observations are relevant to the management of preeclamptic hypertension is arguable. If perfusion of a preeclamptic placenta can only be maintained by a blood pressure that directly threatens maternal well-being, then urgent delivery is the main priority. In practice this must, in my experience, be a rare circumstance. Conservative treatment of moderate and severe

preeclampsia. The earlier the presentation, the more justified it is to attempt conservative management of preeclampsia in order to allow fetal matura-

Redman

270

II

34 weeks

Methyl dopa dose (by mouth)

750mg 500mg

750mg

I

750mg

I

—o Methyl dopa,

750mg

750mg 24 weeks

180

No treatment

160

8-0 0 0. 0 o 0

140

rtJ

--1.-i

6 6 = 120

15.00 18.00

22.00

02.00

.00

Time, hours

Fig. 1. Control of preeclamptic hypertension using oral methyl dopa only. The patient was transferred from another unit at 28 weeks in her second pregnancy with progressive hypertension

and proteinuria. Her first pregnancy ended at 28 weeks with eclampsia, placental abruption, intrauterine death, and acute renal failure. With conservative management, this pregnancy

SleepEl

c::seep :

a 00 0 100

80

continued until delivery at 30 weeks of a healthy son weighing

Li

1020 g.

—-

8 12 tion and enhanced neonatal survival. The patient must be asymptomatic, have adequate renal function, and be under constant in-patient supervision. In these circumstances, parenteral therapy is in-

appropriate, and oral agents need to be used. Methyl dopa is the first choice. The safety of methyl dopa in pregnancy has been established by uncontrolled and controlled studies [48, 57—59]. No serious adverse fetal effects have yet been documented. its use not only relieves the patient of the problems of parenteral therapy, but if, at a later time, diazoxide or hydralazine is needed, their action is potentiated because the sympathetic reflex tachycardia, which these agents induce, is inhibited. Although methyl dopa can be given i.v., oral administration can achieve an adequate therapeutic response within 12 hours provided a large initial loading dose of 750 to 1000mg is used (Fig. 1). This can be followed by 1.0 to 2.0 g!day, which is rapidly adjusted to 3.0 to 4.0 g/day as needed. A satisfac-

tory drop in the blood pressure tends to provoke transient oliguria, which may cause anxiety about preeclamptic renal failure —a complication easily

discounted by measuring the plasma urea and

'----'

L

16

I 20 24 Time, hours

4

8

12

Fig. 2. Two 24-hour blood pressure records on the same patient, the first at 24 weeks and the second at 34 weeks when she had

proteinuric preeclampsia treated with oral methyl dopa. The re-

versal of the normal circadian pattern of blood pressure is shown. (See Ref. 46)

suppressing one dangerous manifestation of the disorder. Nocturnal hypertension preeclampsia. The blood pressure normally falls during sleep, both in pregnant and nonpregnant subjects. In preeclampsia, the nocturnal fall is at first lost [60], and later the circadian pattern is reversed with the appearance of nocturnal hypertension [46] (Fig. 2). Any treatment regimen of hypertension in preeclampsia may need to anticipate nocturnal hypertension by a variable schedule, with the largest doses at night. Escape from blood pressure control. While pregnancy continues, preeclampsia is a relentlessly pro-

gressive disorder, so that sooner or later escape from blood pressure control can be expected. In general, the maternal and fetal condition deteriorate together, and it is not difficult to see when the limits

creatinine. Despite good blood pressure control, the

of conservative management have been reached and delivery is indicated. Oral vasodilators, how-

other changes of preeclampsia (abnormalities of renal, coagulation, and placental function) remain unchanged. Thus, hypotensive treatment is merely

ever, may be usefully added to the medical regime to prevent loss of blood pressure control. Oral hydralazine, which on its own is a weak hypotensive

Treatment of hypertension in pregnancy

271

2090 g, who developed transient hyperglycemia in the neonatal period (Fig. 3).

Other measures that have been used. Hyporo-

15

lemia is a well-documented feature of preeclampsia [11, 63], and it has been claimed [64], and disputed [65], that plasma volume expansion is beneficial. Other workers have tried hemodialysis [66], heparinization [67], or plasmapheresis [68], with varying

'1

0 0 0

claims of success. Diuretics are frequently used, but with what objectives (given the plasma volume depletion of most preeclamptic women) is not clear. All the reports are uncontrolled and, therefore, of limited value.

-D

0 0

5-

o

S

• Insulin 0.5 U iv. -

50 Age, hours

100

Fig. 3. Infant delivered at 36 weeks' gestation to a mother with

moderate preeclampsia superimposed on severe hypertension complicated by disseminated lupus erythematosus. For the last 47 days of pregnancy, oral diazoxide (150 mg daily) had been given. Transient hyperglycaemia treated by i.v. insulin was the only neonatal complication.

agent, effectively augments methyl dopa given at doses of 25 to 75 mg every 6 hours. The long-term use of oral diazoxide has been tried in four pregnancies for 19 to 69 days [61]. Two

of the patients were diabetic, of whom one could have been suffering from diabetic nephropathy, rather than preeclampsia. Diazozide was detected in cord blood and amniotic fluid and excreted in the neonates' urine for the first week of life. No effect of diazoxide was discernible on the neonatal blood pressure or blood sugar levels, although the two off-

spring of diabetic mothers had abnormal glucose tolerance at 24 hours of age. All the babies devel-

oped some degree of alopecia; and one, hypertrichosis lanuginosa. In other respects, the neonates developed normally except that one had a retarded bone-age at 1 year [62]. In Oxford, we have used oral diazoxide in four pregnant patients, of whom three had severe preeclampsia. One of the three in-

fants survived and is normal at the age of 1 year. The fourth patient had disseminated lupus erythematosus with milder superimposed preeclampsia. Treatment with methyl dopa and diazoxide was started at 202 and 206 days' gestation, respectively. Delivery was at 253 days, of a live male weighing

Treatment of mild to moderate hypertension in pregnancy

Rationale for treatment. In medical practice, the objectives of treating moderate hypertension span a decade or more of the middle and later parts of an

individual's life, and the success of treatment is

measured by the prevention of heart failure, aortic dissection, coronary vascular disease, and stroke. The same aims are not necessarily transferable to young women for the brief period of pregnancy; nor do nonobstetric studies provide any

guidelines as to how treating moderate hypertension might affect the fetus. In general, moderate hypertension in pregnancy (140 to 170/90 to 110) has three inherent risks: it precipitates complications of other maternal disorders; it is the precursor of more severe (preeclamptic) hy-

pertension; and it implies decreased perinatal survival. Aortic dissection occurs more commonly in preg-

nancy [69], particularly in association with hypertension [70]. It is thought that hypertension interacts with an underlying abnormality, such as with Marfan's syndrome [71], but that pregnancy itself does not cause predisposing intrinsic aortic changes [72]. Pedowitz reported a maternal mortality of 93%

[70]. Myocardial infarction complicates about 0.01% of maternities, occurring particularly and not surprisingly in older women [73]. It may be associated with hypertension, especially in the 3rd trimes-

ter [74]. The lesion is not always coronary artery thrombosis; periarteritis and dissecting hematomas of the coronary arteries have been documented [7577]. In pregnancy, hypertension increases the risk of bleeding from cerebral aneurysm but not cerebral angioma [78]. Pregnancy itself predisposes to carotid artery occlusion superimposed on atheromatous

disease, but hypertension does not seem to be a relevant factor [79]. These are all very rare complications and cannot in themselves justify the treat-

272

Redman

ment of all cases of moderate hypertension in pregnancy. The risks in pregnancy of a moderately elevated blood pressure in terms of later severe hypertension or perinatal death are closely linked and related to

20th week and later became hypertensive, treatment seemed to confer no benefit. But in those whose hypertension antedated the 20th week, active treatment was associated with a significantly -better fetal outcome with no losses in the treated

the further question of how chronic hypertension predisposes to preeclampsia. The likelihood of developing proteinuric preeclampsia increases two-

group and five losses, including three midtrimester abortions, in the control group (Table 2). Comparable results were reported in a similar but larger controlled trial of treatment with methyl dopa [48, 49] in which diuretics were not used. Patients with severe hypertension were excluded because hypotensive treatment could not be ethically withheld. A specific purpose of this trial was to inquire if

fold to sevenfold if there is preexisting maternal hypertension [80-841. Consequently, at every stage of gestation, a raised blood pressure augments the risk

of later more severe hypertension or of perinatal death, either directly or indirectly. Most of the specific obstetric risks of chronic hypertension appear to be mediated through superimposed preeclamp-

sia: without this complication, pregnancies with chronic hypertension have a similar or even better perinatal mortality than do normal pregnancies [85]. These associations do not demonstrate that the hypertension causes the problems. That hypotensive treatment may not prevent them is an obvious corollary. In preeclampsia, the uterine spiral arterioles are blocked by accumulations of lipophages, fibrin, and platelet aggregates —so-called acute atherosis"

early control of long-standing maternal hypertension prevented later superimposition of preeclampsia. The diagnosis of preeclampsia had to be made using new criteria because the use of hypotensive drugs nullified the usual definitions based on blood pressure levels. Proteinuria occurred so infrequently as not to be a useful indicator. Therefore, changes in plasma urate were used. A rising plasma urate is an early feature of preeclampsia [91] and is caused by a reduced renal urate clearance occurring independently of changes in the GFR (reviewed in

Ref. 11). It correlates well with the renal biopsy

[86]. These lesions account for the reduced uteroplacental blood flow of preeclampsia, as well as the increased incidence of placental infarcts [87], and the placental dysfunction that causes intrauterine asphyxia or growth retardation. Despite claims to the contrary [88], there is evidence that

changes of the disorder [14] and is associated with an increased perinatal mortality [92], Serial measurements of plasma urate clearly demonstrated no differences between the two groups (Table 3). This confirmed the analysis of fetal outcome: although it was significantly better with active treat-

these are not exclusive to hypertensive pregnancies [89]. In particular, placental infarcts are relatively common in normotensive pregnancies [87], and presumably share the same vascular pathology. There-

ment, the benefit could not be attributed to prevention or control of hypertensive complications. In particular, as in the earlier trial, midtrimester abortions were confined to the control group, and none of them were apparently directly caused by

fore, it is unlikely that they are caused or exacerbated by high blood pressure, but possibly have an immune etiology [90]. There is a parallel, in that the vascular lesions of renal allograft rejection were originally ascribed to hypertension before their immune basis was established. Therefore, neither on maternal or fetal grounds is there compelling background evidence that mild to moderate maternal hypertension should be treated. Evidence from clinical studies. After it had been shown that the treatment of severe hypertension in pregnancy with methyl dopa was compatible with a successful outcome [57, 58], the first controlled trial of its use for mild hypertension in pregnancy was reported [59]. One hundred women (diastolic blood pressure 90 mm Hg) were randomly allocated to no treatment, or methyl dopa combined with a diuretic. In women who were normotensive before the

maternal hypertensive disease. The improved pennatal outcome therefore remains unexplained but could be a consequence of some other action of methyl dopa. The obvious hypothesis is that it is Table 2. Perinatal outcome in two controlled trials of antihypertensive treatment in pregnancy

Total patients Leather eta! (1968) [591 Control

Treata Redman eta! (1976) [48] Control Treath

Midpregnancy Perinatal abortions

deaths

48

3

6

52

0

6

125

4

5

117

0

1

a Methyl dopa and bendrofluazide

Methyl dopa and other hypotensive agents if needed, but no diuretics

Treatment of hypertension in pregnancy Table 3. Incidence of superimposed preeclampsia in trial of methyl dopa for chronic hypertension in pregnancy.a

Control

Rise in uric acid

None, no. of patients Moderate, no. of patients Mean time of rise, days Severe,no. of patients Mean time of rise, days

(N =

103)

44 (42.7%)

57(55.3%)

Treat (N = 101) 39(38.6%) 59(58.4%)

25

240 24

2(1.9%)

3 (3.0%) 232

241

208

a A moderate rise in plasma urate was defined as increases of 30 to 120 iM at each of three successive followups. A severe rise in plasma urate was defined as an increase of more than 120 /SM between two successive followups. See Refs. 48 and 49.

affecting myometrial activity. This is supported by the observation that treated women labored less ef-

fectively. There were more emergency Cesarean sections for failure to progress, which was statistically significant for those women who had a combined medical and surgical induction [24]. The other main benefit of treatment was the re-

duction, but not abolition, of severe hypertensive episodes [49]. Blood pressure control and side effects with methyl dopa, using 0.75 to 4.0 g!day, were as would be predicted from medical experience. Methyl dopa could not be tolerated by 14.5% of women, and they were transferred to debrisoquine, clonidine, or bethanidine. Oral hydralazine was the most commonly used agent to augment the action of methyl dopa, but was never used on its own. The birth weights of the surviving babies were similar. The conclusion that hypotensive treatment had not altered fetal growth was confirmed by multivariate analysis and is consistent with similar incidence of superimposed preeclampsia in the two groups. The condition of the neonates at birth, the need for resuscitation, neonatal complications, and progress is the first year of life were also all similar in the two groups [93, 94].

The average head circumference of the treated

273

reassuring in terms of overall growth and develop-

ment. The subset of treated babies with smaller head circumferences have developed normally and do not differ either from the rest of the treated group or the control infants. Furthermore, average agestandardized scores of developmental attainment with respect to gross motor, fine motor, visuomotor functions, language, and comprehension have been systematically better in all categories, in girls and

boys separately, in treated compared with untreated children [96]. This assessment was done at the age of 4 years and is being repeated with the 7 year olds. This is a unique long-term pediatric followup of a controlled trial of hypotensive treatment in pregnancy. It therefore is the only information available concerning possible long-term adverse fe-

tal effects of treatment. The use of methyl dopa seems to be free of frequent or major problems, except that treatment should not be started between 16 and 20 weeks' gestation to avoid possible effects on fetal head growth.

A recent small controlled trial using a diuretic combined with methyl dopa or hydralazine for chronic hypertension in multiparas claimed that treatment prevented "pregnancy-aggravated" hypertension [97]. It is not clear if this means prevention of superimposed preeclampsia or merely that the hypotensive treatment exerted its intended effect. The perinatal outcomes were similar in the two groups.

Other measures for the prevention of preeclampsia. Diet, salt restriction, bedrest, and nonspecific sedation have all had their advocates. For

severe recurrent preeclampsia, long-term anticoagulation has been tried [98]. But diuretics remain the most extensively investigated.

Diuretics. All the adequately controlled trials agree with each other that neither perinatal mortality nor the incidence of proteinuric preeclampsia is modified by the prophylactic use of diuretics [99104]. Where this benefit has been claimed, edema

neonates, however, was reduced by a small but significant amount: treated, 34.2 1.7 cm; untreated, 34.6 1.3 cm (averages 1 SD). This difference was not associated with the total amount of methyl

has been included as a diagnostic sign of pre-

dopa prescribed, the duration of treatment, or the

natal mortality was associated with diuretic therapy [107]. But the treatment group was heavily biased

average daily doses. But the neonates involved were born to those mothers who started treatment between 16 and 20 weeks' gestation [95]. This is a period when intrauterine brain growth is particularly rapid, so that it is possible that the onset of treatment at this time affected head growth. The followup of these children, however, has been completely

eclampsia, and the outcome merely reflects the capacity of the diuretics to clear edema [105, 106]. In

one other study, a massive improvement in penby a composition in favor of the better perinatal mortality that was observed. Two high-risk groups were selectively removed from the treated category

only—that is, women with asymptomatic bacteriuria and treatment defaulters. The latter were transferred to the control group for analyzing the

274

Redman

results which, because they do not represent the outcome of true randomisation, need to be discounted. There is no evidence that diuretics are beneficial

for the treatment of established preeclampsia either, although their use is still strongly advocated [30, 108]. They will aggravate the hypovolemia of the disorder and in these circumstances can precipi-

tate iatrogenic renal failure [109]. The fetal consequences of the diabetogenic effects of thiazide compounds are not defined. Diuretics have caused maternal deaths from pancreatitis [110], electrolyte disturbances [11 1], and excessive ingestion [112]. They cause hyperuricemia, which obscures what is one of the most useful signs of early preeclampsia. Neonatal thrombocytopenia and hemolysis associated with their antenatal use have been documented [113, 114].

It cannot be concluded that there is an absolute contraindication to diuretics in pregnancy. But giv-

en their many disadvantages and the absence of clear evidence in favor of their use, there seem to be good reasons for avoiding them. The only exception is for the treatment of left ventricular failure, a rare complication of severe preeclampsia. Beta-adrenoceptor blocking agents. These drugs

There are only two controlled studies. A small randomized trial of i.v. propranolol to prevent acute

hypertension during induction of anesthesia for Caesarean section clearly implicated propranolol as a cause of neonatal respiratory depression [134]. In the second study a significantly improved fetal out-

come was observed in 26 hypertensive patients treated with long-term oxprenolol compared with 27 patients treated with methyl dopa [115]. The investigators claimed that oxprenolol not only controlled

maternal hypertension but promoted plasma volume expansion causing the apparently better fetal growth in the oxprenolol-treated group. Neonatal bradycardia and hypoglycemia were not observed. A feature of this trial is the unusually poor outcome of the methyl-dopa-treated group given the selection criteria. It is possible that the benefit attributed to oxprenolol represents inherent pretreatment differences between the two groups despite adequate randomization. Adrenergic control of uterine activity is well established. Beta-adrenergic blockade enhances uter-

ine activity in experimental animals, and in pregnant women in the second and third trimesters [135137]. Premature or precipitate labor might therefore

be a complication of treatment [123, 133], but the

have been used in pregnancy for the treatment of

larger series are reassuring on this point. Beta-

hypertension [115—122], cardiac dysrythmias [123— 127], thyrotoxic symptoms [118, 123, 128, 129], and

blockers cross the placenta with a speed dependent

hypertrophic obstructive cardiomyopathy [130133]. At present their safety in terms of adverse reactions of the fetus is not established. The available

prenolol have a long half-life in the fetal lamb [138]. Acute experiments in the ewe suggest that propranolol reduces umbilical blood flow [139] and impairs

information is confusing, because it chiefly comprises uncontrolled case reports or series, in which it is impossible to separate fetal problems ascribable to treatment from those ascribable to the condition

the fetal lamb's ability to withstand acute anoxic stress. If these data can be applied to the human situation, then fetal problems might only be expected when there is already compromise in terms

for which the treatment is given. Intrauterine

of preexisting placental inadequacy. Until more information is available, beta-adrenoceptor blocking agents should not be used routinely in pregnancy. Conclusions. (1) Extreme hypertension in pregnancy is as dangerous as it is in other medical situations and demands urgent treatment. (2) The treat-

growth retardation, respiratory difficulties at birth, neonatal bradycardia, and hypoglycemia have all been reported as possible problems after long-term propranolol at levels of 20 to 240 mg/day [116, 118, 121, 123—125, 131]. The largest series (uncontrolled)

is of 101 mothers treated for hypertension with metroprolol in various combinations with hydralazine or diuretics [122], with a perinatal mortality of 1.9% and with 11.7% of the infants "small for dates" to

an undefined extent. Neonatal hypoglycemia or bradycardia were not noted. This lack of complications agrees with one other smaller but similar series [117], but not with that of Lieberman eta! [120] who identified propranolol as a factor possibly con-

tributing to fetal demise in 9 patients with severe hypertension and renal disease.

on lipid-solubility, and both propranolol and ox-

ment of mild chronic hypertension in pregnancy does not prevent the later superimposition of preeclampsia. The perinatal advantages of such treatment cannot be attributed to the hypotensive action of the drugs. (3) Methyl dopa is the most thoroughly tested hypotensive agent in pregnancy. Apart from a possible effect on fetal head growth, if treatment is started between 16 and 20 weeks' gestation, no significant adverse reactions have been observed. (4) Beta adrenoceptor antagonists may be safe to use in

275

Treatment of hypertension in pregnancy

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