fetal outcome in trial of antihypertensive treatment in pregnancy

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Saturday 9 October 1976 FETAL OUTCOME IN TRIAL OF ANTIHYPERTENSIVE TREATMENT IN PREGNANCY C. W. G. REDMAN Nuffield Department of Obstetrics and Gynœcology, John Radcliffe Hospital, Headington, Oxford OX3 9DU L. J. BEILIN Department of the Regius Professor of Medicine, Radcliffe Infirmary, Oxford J. BONNAR Department of Obstetrics and Gynœcology, Rotunda Hospital, Dublin M. K. OUNSTED Department of Pœdiatrics, John Radcliffe Hospital Summary 242 women completed a controlled trial of methyldopa (’Aldomet’) for moderate hypertension in pregnancy. Active treatment was associ- ated with a significantly improved fetal outcome, due in part to a reduced number of mid-pregnancy abortions. There were 9 pregnancy losses in the control group, which included 4 mid-pregnancy abortions, and 1 fetal loss in the treated group. The birthweight and maturity of viable infants were similar in treated and control groups, and a detailed multivariate analysis confirmed that hypotensive treatment had no effect on fetal growth in utero. The better outcome associated with treatment was not due to the prevention of pre-eclampsia, and may be partly due to a direct or indirect effect of methyldopa on uterine activity. Methyldopa is safe to use for the treatment of hypertension in pregnancy in the context of close medical and obstetric supervision. Introduction THE increased hazards of chronic maternal hyperten- in pregnancy are mostly due to a greater susceptibil- to superimposed pre-eclampsia,’ but because preg- nant women with chronic hypertension are older, creased age may be an independently associated risk :actor,2 Even if the hypertension is mild or moderate in pee and not in itself hazardous to the mother, fetal survival may be impaired. The cause of pre-eclampsia is unknown, but it is as- I Xmed with reduced uteroplacental blood-tlow3 and in- i creased placental infarction with underlying occlusion of the uterine spiral arteries by fat-laden cells and fibrin.4 If these lesions are a cause and not a consequence of the disorder, then the increased susceptibility of chronically hypertensive women to pre-eclampsia could be explained if chronic hypertension caused them. Such an hypotheti- cal chain of events might be slowed or stopped by the use of hypotensive drugs. It is not known if treatment of mild or moderate hypertension in pregnancy improves the fetal prognosis. Uncontrolled series have indicated that the use of methyl- dopa in pregnancy is safe.s 6 Despite the use of antihy- pertensive drugs in general clinical practice for 25 years, there has been only one controlled trial to assess their value in pregnancies complicated by early hypertension. In that trial, Leather et al. used methyldopa combined with a thiazide diuretic. They found that treatment was associated with fewer pregnancy losses (mid-trimester abortions and perinatal deaths) and heavier babies deli- vered at later gestations, especially when hypertension was recorded before the second half of pregnancy. The reasons for the better outcome were not defined, nor was the trial large enough to establish the results conclusi- vely. With these favourable reports concerning the use of methyldopa for the treatment of hypertension in preg- nancy a further evaluation of its use in pregnancy has been needed. This paper describes the effect of methyldopa on the outcome and the development of pre-eclampsia in hyper- tensive pregnancies in a large controlled trial. Because there is experimental evidence that hypotensive therapy may reduce placental perfusion,g a detailed analysis of fetal growth and birthweight is also presented. A second report will describe the blood-pressure control achieved with treatment and the side-effects. Patients and Methods Selection of Patients Patients in the routine antenatal clinics were referred for possible inclusion in the trial if their blood-pressures exceeded 140/90 mm Hg. Their blood-pressures were then checked on at least two further occasions by one of four trained midwives using a London School of Hygiene sphygmomanometer to minimise observer bias. Readings were taken in the right arm after 5 min rest on the left side, and after standing for 1 min. The diastolic end-point was phase iv of the Korotkoff sounds. Before 28 weeks, hypertension was confirmed if either the

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Saturday 9 October 1976

FETAL OUTCOME IN TRIAL OFANTIHYPERTENSIVE TREATMENT IN

PREGNANCY

C. W. G. REDMAN

Nuffield Department of Obstetrics and Gynœcology, JohnRadcliffe Hospital, Headington, Oxford OX3 9DU

L. J. BEILIN

Department of the Regius Professor of Medicine,Radcliffe Infirmary, Oxford

J. BONNAR

Department of Obstetrics and Gynœcology,Rotunda Hospital, Dublin

M. K. OUNSTED

Department of Pœdiatrics, John Radcliffe Hospital

Summary 242 women completed a controlled trialof methyldopa (’Aldomet’) for moderate

hypertension in pregnancy. Active treatment was associ-ated with a significantly improved fetal outcome, due inpart to a reduced number of mid-pregnancy abortions.There were 9 pregnancy losses in the control group,which included 4 mid-pregnancy abortions, and 1 fetalloss in the treated group. The birthweight and maturityof viable infants were similar in treated and control

groups, and a detailed multivariate analysis confirmedthat hypotensive treatment had no effect on fetal growthin utero. The better outcome associated with treatmentwas not due to the prevention of pre-eclampsia, and maybe partly due to a direct or indirect effect of methyldopaon uterine activity. Methyldopa is safe to use for thetreatment of hypertension in pregnancy in the context ofclose medical and obstetric supervision.

Introduction

THE increased hazards of chronic maternal hyperten-in pregnancy are mostly due to a greater susceptibil-to superimposed pre-eclampsia,’ but because preg-nant women with chronic hypertension are older,creased age may be an independently associated risk:actor,2 Even if the hypertension is mild or moderate inpee and not in itself hazardous to the mother, fetalsurvival may be impaired.The cause of pre-eclampsia is unknown, but it is as-

I Xmed with reduced uteroplacental blood-tlow3 and in-

i

creased placental infarction with underlying occlusion ofthe uterine spiral arteries by fat-laden cells and fibrin.4If these lesions are a cause and not a consequence of thedisorder, then the increased susceptibility of chronicallyhypertensive women to pre-eclampsia could be explainedif chronic hypertension caused them. Such an hypotheti-cal chain of events might be slowed or stopped by the useof hypotensive drugs.

It is not known if treatment of mild or moderate

hypertension in pregnancy improves the fetal prognosis.Uncontrolled series have indicated that the use of methyl-dopa in pregnancy is safe.s 6 Despite the use of antihy-pertensive drugs in general clinical practice for 25 years,there has been only one controlled trial to assess theirvalue in pregnancies complicated by early hypertension.In that trial, Leather et al. used methyldopa combinedwith a thiazide diuretic. They found that treatment wasassociated with fewer pregnancy losses (mid-trimesterabortions and perinatal deaths) and heavier babies deli-vered at later gestations, especially when hypertensionwas recorded before the second half of pregnancy. Thereasons for the better outcome were not defined, nor wasthe trial large enough to establish the results conclusi-vely.

With these favourable reports concerning the use ofmethyldopa for the treatment of hypertension in preg-nancy a further evaluation of its use in pregnancy hasbeen needed.

This paper describes the effect of methyldopa on theoutcome and the development of pre-eclampsia in hyper-tensive pregnancies in a large controlled trial. Becausethere is experimental evidence that hypotensive therapymay reduce placental perfusion,g a detailed analysis offetal growth and birthweight is also presented. A secondreport will describe the blood-pressure control achievedwith treatment and the side-effects.

Patients and Methods

Selection of Patients

Patients in the routine antenatal clinics were referred forpossible inclusion in the trial if their blood-pressures exceeded140/90 mm Hg. Their blood-pressures were then checked onat least two further occasions by one of four trained midwivesusing a London School of Hygiene sphygmomanometer to

minimise observer bias. Readings were taken in the right armafter 5 min rest on the left side, and after standing for 1 min.The diastolic end-point was phase iv of the Korotkoff sounds.Before 28 weeks, hypertension was confirmed if either the

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systolic or diastolic pressures equalled or exceeded 140 or 90mm Hg, respectively, on two occasions separated by at least 24h. After 28 weeks, the limits were 150 or 95 mm Hg, respec-tively. Thus patients were separated into "early" and "late"groups according to the time of presentation. No patient wasadmitted after 36 weeks, and this upper limit was reduced to32 weeks within the first year of the trial.When hypertension was confirmed, patients were admitted

for a baseline assessment before allocation of treatment. Stan-dard clinical and laboratory investigations were completed butno attempt was made to distinguish between pregnancy-in-duced hypertension and hypertension antedating pregnancy.

Allocation of Treatment and Exclusions

Treatment was allocated randomly at the end of the baselineinpatient assessments to "early" and "late" entries separately.Placebo tablets were not used. Active treatment was with

methyldopa (’Aldomet’). If necessary, other drugs, such as

hydrallazine, were added to achieve good blood-pressure con-trol. When side-effects were troublesome, debrisoquine, beth-anidine, or clonidine were substituted. Diuretics and beta-ad-renergic blockers were not used.

Patients who had "severe" hypertension beforerandomisation of treatment were excluded from the controlledtrial because of the risks of withholding treatment. "Severe"hypertension was defined as systolic or diastolic pressureswhich equalled or exceeded 170 or 110 mm Hg, respectively,on two occasions more than 4 h apart; or 180 or 120 mm Hg,respectively, on two occasions more than 5 min apart. If pa-tients developed "severe" hypertension after being assigned tothe "no treatment" group, long-term antihypertensive treatsment was started, but the patients were not withdrawn fromthe control group. Therefore, the trial compares early treat-ment of moderate hypertension with either no specific treat-ment or late treatment limited to patients with severe hyper-tension.

Patients with other major independent obstetric risk factors(diabetes, multiple pregnancy, rhesus immunisation) were alsoexcluded from random allocation of treatment.

Patients attended a special antenatal hypertension clinicafter treatment had been allocated. Except for the differencesin treatment allocation, treated and control patients weresupervised in exactly the same way both antenatally and inlabour. No attempt was made to substitute outpatient for inpa-tient management of hypertension, although most patientswere managed as outpatients. Decisions about admission weremade by experienced obstetricians who were aware of thetreatment group to which each patient belonged.

Diagnosis of Pre-eclampsiaThe incidence of pre-eclampsia was assessed in three ways.

Hypertension itself could not be used as a sign of the disorder.Oedema of the face, hands, and ankles was scored separatelyby one observer on a scale 0-3, corresponding to "no oedema"through to "severe cedema". At each visit a carefully super-vised midstream specimen of urine was taken and treated forprotein by standard turbidometric methods. Positive readingsare reported only in the absence of infection after routine cul-ture.

Increases in plasma-urate during pregnancy are ascribable topre-eclampsia and are sensitive and objective measurements ofthe development of the condition.9 10 Increases in plasma-ureatend to occur later and reflect a more advanced stage of thedisorder. For this reason, plasma urate and urea were mea-sured monthly until 32 weeks’ gestation, then at least every 2weeks until delivery, and finally 6 weeks after delivery. In thisway, increases due to pre-eclampsia were documented.

Assessment of Outcome and Management of DeliveryAll fetal losses at or after 24 weeks were further investigated

at necropsy.

At the time of the trial, routine induction at 38 weeks’ ges-tation was the standard management for patients with hyper-tension. The trial patients were delivered electively at this t1l!1eunless there were signs at an earlier time to indicate that con.tinuation of pregnancy was too hazardous for either mother orfetus. At delivery the condition of the baby was recorded indetail and the neonate was later examined for possible congeni-tal malformation and assessment of gestational maturity. Theprogress of the neonate, any special management required, andthe condition of the baby at discharge have all been recordedand these observations will be reported elsewhere.

Statistical Methods

Fisher’s chi square test was used for the analysis of the out-come of the trial. Differences between means were tested byStudent’s t test.

Results

Recruitment

In four years more than 1000 patients were referredfor examination and 277 were identified as havinghypertension severe enough for potential inclusion in thetrial. 30 of these patients were not entered in the trial(for the reasons shown in table in, of which the com-monest was a blood-pressure too high to be able to with-hold treatment). The remaining 247 were accepted forrandom allocation to the trial groups, most of them inthe early entry group. 5 patients failed to complete thetrial, all from the early treated group. 2 of these left thearea and 3 were excluded because of a later diagnosis oftwins. Subsequent data relate only to the 242 womenwho completed the trial.

Treated and control patients were similar with respectto social and obstetric characteristics (table I). During

TABLE I-SOCIAL AND OBSTETRIC CHARACTERISTICS

the trial treatment significantly lowered the blood-pres.sures, and these are analysed elsewhere." The durationsof treatment were similar in the two groups, as were thenumber of follow-ups. In the early entry group, treatedand control patients were admitted to hospital for vensimilar reasons and for similar lengths of time. However,the late control group spent more time in hospital.almost entirely due to an excess of admissions for man-agement of high blood-pressure.

11 control patients later developed severe hyperter.-sion and were started on hypotensive treatment. In aLbut 2 of the patients, this happened antenatally.

Outcome of PregnancyThere were 9 pregnancy losses in the control gro

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spared with 1 in the treated group-a significantreduction associated with active treatment significantr,duction associated with active treatment (P=0.013,Fisher’s exact test, table it). 4 of the losses in the controlgroup occurred in the second trimester as mid-preg-nancy abortions. 4 perinatal deaths were due to pre-ec-lampsia (table iv), 3 in the control group and 1 in thetreated group. The other causes of death are listed. Twobabies had significant congenital abnormalities (nos. 1and 3, table iv). The first patient began antihypertensivetreatment at 19 weeks’ gestation, which cannot there-fore have caused the abnormalities. The second was deli-vered to a patient in the control group. 2 deaths (nos.2 and 5) were from pregnancies where severe maternalhypertension demanded antenatal treatment in patientsassigned to the control group. In 1, treatment continuedfor the last 6 days of a total of 9 weeks in the trial. Inthe other, treatment began 9 days after entering the trialand intrauterine death occurred 5 days later.The highest perinatal mortality of nearly 60% was in

the severely hypertensive group excluded from the trial

TABLE II-OUTCOME OF TRIAL

TABLE III-PATIENTS EXCLUDED FROM ENTRY TO TRIAL

’Includes 3 women withdrawn from the early treated group.7Heno,ch-Sch6nleln nephntis, disseminated lupus erythematosus, middle-cer-

:2ral-artery thrombosis, bicornuate uterus.

table in). Here the main cause of death was pre-eclamp-sia,

Fetal Growth and BirthweightThe mean length of gestation at delivery, birth-

,1 eights, and placental weights of viable pregnancieswere similar in the early entry group (table v). For thelate entry group, the treated pregnancies resulted in hea-vier infants. Although the differences were not statisti-callv significant, they were ascribable to more advancedpregnancies at delivery (P<0.05). The birthweights inthe early entry group were analysed further by multi-ariate regression in an attempt to uncover any smalleffect of antihypertensive treatment on intrauterinegrowth. Two linear regression equations were computed: *hich the treatment group of each patient and the:lration of treatment were included as independent’,a!1ables. Parity, initial plasma-urate, and initial mater-- .a; weight were the most important predictors of uncor-

TABLE IV-DETAILS OF THE PERINATAL DEATHS

rected birthweight. The number of cigarettes smokedand initial hoematocrit were the most important pre-dictors of birthweight corrected for time of deliveryand sex of baby. In both equations, these and allother variables contributing significantly to the reductionof variance were included. Further inclusion of thetreatment group and duration of treatment showedno effect of either on the two measures of fetal growth.

Incidence of Pre-eclampsiaThe treated and control groups did not differ with re-

TABLE V-BIRTHWEIGHT, PLACENTAL WEIGHT, AND GESTATION ATDELIVERY

*Excluding 4 mid-trimester miscarriages.tt (D.F.=32)=1.94 P<0.05.tt (D.F.=32)=1.51 P>0.05, not significant.

TABLE VI-MAXIMUM INCREASE IN PLASMA-URATE

756

spect to changes in oedema scores or weight gain. Pro-teinuria in excess of 100 mg/dl in a midstream urinespecimen or 1.0 g/24 h appeared in 6 treated womenand 5 control women: similarly, there were no dif-ferences in the frequency of lesser amounts of pro-teinuria. The maximum antenatal changes in plasma-urate measured from the baseline established at entryare shown in table vi. There was no tendency for thetreated group to show consistently smaller or greater in-creases of plasma-urate. A further analysis showed thatthese changes did not appear at a consistently earlier orlater stage of pregnancy. Similar changes were observedwith plasma-urea.

Discussion

In a similar but smaller controlled trial’ there were 9

perinatal losses in the control group, including 3 mid-tri-mester abortions, and 6 in the treated group, with noabortions. The survivors in the treated group were hea-vier and born at a later gestation, but only if the hyper-tension was of early onset.

This trial was organised differently; nevertheless, theresults are in many respects comparable but more clear-cut. One similarity is the excess of mid-pregnancy abor-tions in the control group. None occurred in the treatedwomen in either trial. The excess could account for the

significantly improved fetal outcome in this trial. Other-wise there is a small excess of perinatal deaths notascribable to any one cause. There were not enoughdeaths to judge the effect of treatment on the develop-ment of pre-eclampsia. In the whole series, severe pre-ec-lampsia was rare but the renal consequences of themilder forms of the disorder (hyperuricaemia, uraemia,proteinuria) occurred to a similar degree in both groups.

(Edema is known to be an unreliable sign of pre-ec-lampsia as it is also present in normal pregnancies. Sincemethyldopa may cause fluid retention, it is relevant thatthis was not demonstrated in this trial. Although theconcentrations of proteinuria reported are low, consider-able care was given to avoiding contaminated or infectedurine specimens. The proteinuria, therefore, is likely tobe renal in origin, although not all of it may have beencaused by pre-eclampsia. The most reliable indicators ofpre-eclampsia in this trial are undoubtedly the changesof renal function. A raised plasma-urate is invariable inpre-eclampsia,9 and the fact that the trial groups showedremarkably similar patterns of change is evidence thatthe incidence of pre-eclampsia was unaltered by treat-ment. Therefore this cannot explain the improved prog-nosis of the treated group.

There is little information as to whether or not mid-

pregnancy abortion is a specific problem of hypertensivepregnancies. None of the 4 that occurred in the controlgroup showed any features of atypical early pre-eclamp-sia. It is possible that control of the blood-pressure insome way prevented mid-pregnancy abortion in thetreated group. However, because it seems likely that al-terations in uterine motility or cervical competence aremajor factors in determining mid-pregnancy abortion,"we may be observing an unexpected pharmacologicaleffect of methyldopa, either directly on the myometriumor mediated indirectly by endocrine changes. The fetaladrenal and pituitary are thought to influence myome-trial activity, especially at parturition,12 and methyldopa

has powerful effects on the central nervous system andcrosses the placental barrier. It could therefore affec;fetal pituitary and adrenal function, possibly by actingon the hypothalamus. In non-pregnant adults, ahypothalamic action of methyldopa can induceexcessive prolactin release,13 although this does not

occur in pregnancy.14In the trial reported by Leather et al.’ antihyperten-

sive treatment prolonged gestation, but it was not clearif this was a real benefit or an artefact generated by thestandard obstetric practice of using the level of blood-pressure as a guide to early intervention. With very care-ful control over the conditions of intervention, we wereunable to show the same change, except for treatedwomen in the small late-entry group. But we were notobserving the natural length of gestation as the pregnan-cies were ended deliberately at about the 38th week ofgestation. The differences in birthweight reported byLeather et al., due to differences in the length of preg-nancy, were not apparent in this trial except, again, inthe smaller late-entry groups.

Blood-pressures were significantly reduced in thetreated patients." It has been suggested that chroniclowering of blood-pressure in pregnancy may cause pla-cental underperfusion and fetal deprivation. The multi-variate analysis of fetal growth showed no effect, favour-able or unfavourable, which could be ascribed to

treatment, despite effective reduction of blood-pressure.The use of methyldopa for chronic maternal hyper-

tension is therefore safe for mother and fetus. Apartfrom the beneficial effects on blood-pressure control,methyldopa may have a separate effect in preventingmid-trimester abortions. This possibility needs to be in-vestigated by further studies and, if confirmed, to beexplained. Until this issue is resolved, we recommendthat the use of methyldopa be reserved for maternal in-dications which, for this trial, meant blood-pressures inexcess of 170/110mm Hg. We emphasise that antihyper-tensive treatment should always be given in associationwith careful antenatal management, and that anywoman so treated must be frequently reviewed at a

specialist unit.We thank Professor Sir Richard Doll, F.R.s., Professor Sir John

Stallworthy, and Prof. A. C. Turnbull for help and advice; the consul-tant staff of the John Radcliffe Hospital whose patients participatedin the trial; and Mr U. Abdulla, Mr D. Hunter, and Mr C. Mantellfor much expert clinical assistance. Financial aid was given by Merek.Sharp and Dohme Ltd.

Requests for reprints should be addressed to C. W. G. R.

REFERENCES

1. Butler, N. R., Bonham, D. G. Perinatal Mortality: First Report of BritishPerinatal Mortality Survey. Edinburgh, 1963.

2. Butler, N. R., Alberman, E. D. Perinatal Problems: Second Report of 1958British Perinatal Mortality Survey. Edinburgh, 1969.

3. Morris, N., Osborne, S. B., Wright, H. P. Lancet, 1955, i, 323.4. Dixon, H. G., Robertson, W. B. J. Obstet. Gyn&oelig;c. Br. Commonw. 1958, 65,

803.

5. Kincaid-Smith, P., Bullen, M., Mills, J. Br. med. J. 1966, i, 274.6. Hans, S. F., Kopelman, H. ibid. 1964, i, 736.7. Leather, H. M., Baker, P., Humphreys, D. M., Chadd, M. A Lancet, 1968,

ii, 488.8. de Swiet, M., Hoffbrand, B. I. Am. J. Obstet. Gynec. 1971, 111 374.9. Redman, C. W, G., Beilin, L. J., Bonnar, J. J. clin. Path. (in the press).

10. Redman, C. W. G., Beilin, L. J., Bonnar, J. Lancet, 1976, i, 1370.11. Cavanagh, D., Talisman, M. R. Prematurity and the Obstetrician. New

York, 1969.12. Challis, J. R. G., Thorburn, G. D. Br. med. Bull. 1975, 31, 57.13. Steiner, J., Cassar, J., Mashiter, K., Dawes, I., Russell Fraser, T., Brecken-

ridge, A. Br. med. J. 1976, i, 1186.14. Redman, C. W. G., Bonnar, J., Beilin, L. J., McNeilly, A S ibid 1975, i, 304.15. Redman, C. W. G., Berlin, L. J., Bonnar, J. Unpublished.