Br. J. clin. Pharmac. (1979), 8, 211S-215S

USE OF LABETALOL IN THE TREATMENT OF SEVERE HYPERTENSION DURING PREGNANCY

C.A. MICHAEL Department of Obstetrics and Gynaecology, University of Western Australia, Western Australia 6008

1 Labetalol, a hypotensive agent combining a- and fl-adrenoceptor antagonist properties, was used to treat severe hypertensive disease complicating pregnancy. 2 Effective reduction in BP was achieved in all but 3 of the 25 patients treated. Careful monitoring of feto-placental function was undertaken to ensure the maintenance of fetal well-being. Maternal and fetal side-effects were minimal and it was not necessary to discontinue the drug in any patient. 3 Labetalol was estimated in the cord blood of the fetus at delivery as well as in the breast milk of mothers on day 3 post partum. There were no adverse effects of the drug on the infants and significant hypotension did not occur. 4 The results suggest that labetalol has a direct action on fetal lung maturation and this, together with its effective hypotensive effect, contributes to the low perinatal mortality (3.5%) observed. 5 Oculotoxicity due to the labetalol was not observed in the infants delivered. 6 It is concluded that the efficient hypotensive action of labetalol, together with apparent freedom from maternal and fetal side-effects, and consequent improved perinatal mortality, suggest that it is a suitable drug for use in pregnancy complicated by hypertension.

Introduction SEVERE hypertensive disease arising in pregnancy sion to convulsions. The fetus suffers nasal conges- remains a major cause of maternal and perinatal tion, lethargy, increased secretions in the respiratory morbidity and mortality. The place of hypotensive tract and an increased tendency to hypothermia. therapy in the control of hypertensive disorders in Methyldopa can cause excessive lethargy in the pregnancy has in the past been difficult to assess. This mother and may have an adverse effect on the was largely due to the reluctance of obstetricians to developing neural mechanisms of the fetus. A positive use antihypertensive drugs because of concern about Coomb's titre may occur in the mother and it causes their effects on the fetus. It is now accepted that the a reduction in cardiac output and sodium retention, control of hypertension with antihypertensive agents both undesirable in pregnancy. Bethanidine and is of unequivocal value in terms of fetal survival guanethidine cause troublesome postural hypoten- (Leather et al., 1968; Michael, 1975; Redman et al., sion and diarrhoea in the mother. 1976). Where hypertension arises in pregnancy and More recently, propranolol has been used. Fetal where the fetus is immature, it is possible with bradycardia and hypotension may occur and may treatment to allow the pregnancy to continue by aggravate fetal distress and mask the clinical preventing hypertensive sequelae in the mother. Fetal diagnostic features of fetal hypoxia. It may increase maturity is increased and fetal loss from prematurity neonatal hypoglycaemia. Myometrial irritability may because of premature induction of labour for be a problem and it may interfere with maternal maternal reasons is therefore reduced. bladder function in the puerperium. Caution should be exercised, however, in the use of The purpose of this study was to evaluate the antihypertensive drugs because of the risk of reduced effectiveness of labetalol, a combined a- and fi- placental perfusion. In the past many antihyperten- adrenoceptor antagonist, in patients with severe sive drugs have been used and side-effects from these hypertensive disease in pregnancy. The investigation drugs have been noted in both mother and fetus, includes those patients with severe pregnancy induced making them undesirable for use in pregnancy. hypertension or essential hypertension with or Reserpine may cause maternal depression and without exacerbation in pregnancy. increase the susceptibility of patients with hyperten- 0306-5251/79/170211-05 $01.00 00 Macmillan Journals Ltd 1979 212S C.A. MICHAEL

Methods and human placental lactogen), fetal growth esti- mations (serial fetal cephalometry and fetal girth using Selection of patients was restricted to those who, ultrasound) and fetal cardiotocography were carried during pregnancy, had a BP of 150/105 mm Hg or out. more with or without proteinuria, where the fetus was immature, and where it was desirable and safe to prolong pregnancy. Initially in the first five patients Results labetalol was administered only where other hypo- tensive agents were unsuccessful or were discontinued Satisfactory control was achieved in all but three because of side-effects or because of a poor effect on patients (at 26, 28 and 29 weeks of gestation, BP. The end point of treatment occurred when tests respectively). In these patients BP reduction occurred of feto-placental function demonstrated increasing only initially and was not maintained. In all but one fetal hypoxia, where the maternal hypertension was patient the proteinuria either improved significantly uncontrolled or associated with increasing pro- (11 patients) or disappeared (6 patients). Eclampsia teinuria, or where fetal pulmonary maturity was did not occur in any of the patients. attained. Twenty-five patients (three with twin pregnancy) were treated and delivered (Table 1). Six of these Side-effects patients were known to be hypertensive before week 20 of pregnancy, the remainder developed hyperten- Side-effects with the drug were not a significant sion for the first time after week 20. The longest problem. Postural hypotension occurred in two duration of treatment was 12 weeks and the shortest 6 patients, lethargy in one and scalp tingling in another. days. It was not necessary to discontinue the drug in any All patients were admitted to hospital for the patients. commencement of therapy. The initial dose of labetalol was 100 mg orally three times daily and this Lecithin: sphingomyelin ratio in amnioticfluid was increased at half-weekly intervals until control of BP was achieved. Diuretics were not prescribed. An The results indicate fetal lung maturity in all patients adequate reduction in BP was considered to be to except one. Increasing amounts of pulmonary levels of 90 mm Hg diastolic. It was thought surfactant were found from 31 weeks gestation and in undesirable to reduce BP below this level because of higher concentration than normally expected for the the risk of reduction in placental perfusion and gestational age of the fetus (Table 2). exacerbation of any existing placental insufficiency. When adequate reduction in BP was obtained, where the proteinuria did not increase and if other Renal and hepatic function adverse features were absent, the pregnancy was allowed to continue. Tests of renal and liver function In two patients an increase in the blood urea was were carried out weekly. In addition twice weekly noted and levels beyond the normal range were tests of placental function (plasma urinary oestrogens Table 2 Amniotic fluid lecithin/sphingomyelin ratio Table 1 Clinical data of patients treated with in patients treated with labetalol labetalol Respiratory Number of patients 25 Gestation L :S ratio Foam test Distress Primigravidae 19 28(1) Yes (not H MD) Age distribution 16-40 yr 29(1) - - No Multiple pregnancy 3 31 (5) 3.0-6.4 +++ No 1 mild RDS, BP range (mm Hg) 150/105-210/130* not HMD Proteinuria 18 32(1) 5.0 +++ No Underlying renal disease 4t 33(4) 3.4-7.0 +++ No Diabetes 1 (incl. twins, 1 set) 34(5) 8.4-9.5 +++ No *Only patients with severe hypertension arising 35(6) 6.0-8.6 +++ No during pregnancy were treated with labetalol. The first (incl. twins, 2 sets) five patients were treated with other hypotensive 36(4) 7.4-9.5 +++ No agents and labetalol was administered when these agents failed to control the hypertension or where *Number of patients in parenthesis. side-effects occurred. HMD, Hyaline membrane disease. t Including patient with diabetes. R DS, Respiratory distress syndrome. SEVERE HYPERTENSION DURING PREGNANCY 213S obtained. These returned to nonnal immediately Cord blood labetalol estimation following delivery. There was no alteration in hepatic function. Table 3 illustrates the mean cord blood levels of labetalol compared with the level reached in maternal plasma when related to the dose of the drug Feto-placental function administered to the mother. With the exception of the one patient receiving 1200 mg daily the levels of It was not necessary to deliver any patients for fetal labetalol reached were well below the therapeutic reasons before the development of fetal pulmonary levels obtained in each mother when related to the maturity. In two patients fetal cardiotocography total daily dose of labetalol. One of the infants was indicated the possibility of fetal hypoxia, and labour hypotensive at birth but none had bradycardia. was induced. In both cases fetal lung maturity had occurred. One patient showed a reduction of oestrogen Breast milk labetalol estimation below the tenth percentile at 32 weeks gestation and labour was induced. Five patients The concentration of labetalol in breast milk is shown showed evidence of reduced fetal growth on in Table 3 and was related to dose of the drug and ultrasound. Ten of the 28 infants were small at birth mean maternal plasma levels. No adverse effects in for gestational age when assessed by the the feeding infants were noted. One patient who paediatrician. received labetalol 400 mg daily for 5 weeks did not The three patients who did not achieve a have any of the drug present in the breast milk. satisfactory reduction in BP were all delivered for Another, a diabetic on 1200 mg daily, reached a peak maternal reasons, that is, exacerbation of BP. Two of level of 600 ng/ml in the breast milk but she did not the three infants did not survive. In one patient at 28 breast feed. weeks' gestation, caesarean section was performed because of accelerating hypertension despite therapy. The infant died on day 6 of life from pulmonary Perinatal outcome consolidation. The other patient at 26 weeks' gestation was delivered of a stillborn infant following With the exception ofthe fetus delivered by caesarean induction of labour again because of accelerating section at 28 weeks gestation none of the infants was hypertension, "solid proteinuria" (on boiling) and hypotensive. Respiratory distress due to hyaline gross peripheral oedema. membrane disease did not develop in any infant. Four of the infants were asphyxiated at birth and quickly recovered with resuscitation. Method of delivery Two infants developed necrotizing enterocolitis attributable to their prematurity. Fourteen infants were delivered with forceps, and The fetal outcome in relation to birth weight is eight patients had caesarean section on the advice of shown in Table 4. One still birth (720 g) and one the paediatrician. Six patients delivered neonatal death occurred giving a corrected perinatal spontaneously. mortality of 3.57%. Labetalol did not interfere with labour nor In this study the first 15 infants were subjected to complicate caesarean section. There was no spon- an extensive eye examination by an ophthalmologist. taneous onset of labour, indicating that myometrial Their retinae were carefully examined and no irritability was not a problem. abnormality was detected. The retinae of one of the

Table 3 Concentrations of labetalol in maternal and cord blood, and in milk Mean breast milk Total maternal Mean maternal plasma Mean cord blood concentration (ng/ml) dose concentration concentration (samples obtained (mg daily)* (ng/ml) (ng/ml) 3 d post partum) 330(4) 64 42 29 400(11) 123 23 27 600(6) 135 60 39 700(2) 158 68 46 800(1) 174 70 43 1200(1) 321 260 600 *Number of patients in parenthesis. 214S C.A. MICHAEL

Table 4 Fetal outcome in relation to birth weight in distress due to hyaline membrane disease. One of patients treated with labetalol these infants died in the neonatal period. The lecithin sphingomyelin ratios in the amniotic fluid of these Birth Neonatal infants were well below the values obtained in the weight (g) Alive Stillborn death Total labetalol group at the corresponding gestation. 720 1 1 Studies in animals have also been carried out 1000-1500 7 1 8 (Nicholas et al., 1978). Here labetalol was infused at 1500-2000 8 -_- 8 4 mg/kg for 1-2 h into rabbits at 27 d gestation. The 2000-2500 8 8 2500-3000 3 3 doe was then anaesthetized and the fetuses removed Total 26 1 1 28 by laparotomy. Pressure-volume curves were ob- tained for each fetal lung which was also lavaged with Total perinatal mortality = 7.1% physiological saline for phospholipid analysis. In a Post-natal mortality excluding previable infant = control study, hydrallazine was also infused in similar 3.57% pregnant does at a dose titrated to induce a similar fall in mean arterial BP (10 mm Hg). Pressure-volume curves of the fetal lungs of the does infused with hydrallazine did not differ significantly from the saline-infused controls. The does treated infants (720 g) who did not survive was found to be with labetalol showed a greater volume change per normal on histological examination. The pigmentary unit of pressure change in the fetal lung, indicating a epithelium was not disrupted in any way. more compliant lung. Biochemical analysis also indicated an increase in the phospholipid concen- tration in the fluid obtained from the fetal lung in this Discussion group. These results seem to suggest a direct effect from labetalol in stimulating fetal lung maturation. Labetalol effectively reduced BP in those women with Two infants in the study developed necrotizing severe hypertension complicating pregnancy. This enterocolitis, from which they survived. In a similar response occurred in the supine position but there group treated with other antihypertensive drugs one was some enhancement in the standing position, the infant of similar gestational age (31 weeks) also latter probably because of the a-adrenoceptor- developed the same problem. Necrotizing en- blocking effect of the drug. Some antihypertensive terocolitis was also seen in two other infants during drugs are largely dependent on posture for their the period over which labetalol was being studied. effect, and because patients with hypertension in These pregnancies were not complicated by hyperten- pregnancy are confined to bed in the early stages of sion and the only factor present was uncomplicated treatment, their usefulness in this situation is reduced. prematurity. Thus, the necrotizing enterocolitis seems Fetal bradycardia was not a problem and the drug to be a complication of prematurity rather than the was free from side-effects. hypertension or its treatment. The patient with diabetes and underlying renal The results of the use of labetalol in the treatment disease required the largest dose in the series for of severe hypertension arising in pregnancy are adequate control of BP. Labetalol was administered encouraging. The freedom from maternal and fetal for 4 weeks from week 27 of pregnancy, the maternal side-effects, the efficient hypotensive action and diabetes remained under control and the fetus (1250 g) consequent improved perinatal mortality in a survived. condition usually accompanied by high fetal loss, The finding of premature lung maturation in those indicate that labetalol is suitable for use during infants whose mothers were treated with labetalol pregnancy. The added possibility that labetalol may warrants further consideration. A major problem in precipitate early lung maturation in the fetus, an the treatment of severe hypertension in pregnancy has observation not recorded with other antihypertensive in the past been the high neonatal loss from hyaline drugs, further supports its use in pregnancies membrane disease complicating prematurity. No complicated by hypertensive disease where the fetus is infants developed hyaline membrane disease in this too immature to consider delivery. study. It may be that the premature lung maturation was due to a stress phenomenon of the hypertension on the fetus or the result of fetal hypoxia. However, it is possibly attributable to the labetalol. am grateful to Dr Peter Forsell, Allen and Hanburys In another study of ten women with severe (Australia), for providing the labetalol for the trial and for hypertension in pregnancy treated with other his continued support. thank Dr David Richards of Glaxo antihypertensive drugs showed that four infants Group Research Limited for his assistance in the early before week 35 of pregnancy developed respiratory stages of the trial. SEVERE HYPERTENSION DURING PREGNANCY 215S

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