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 remains a major cause of maternal and perinatal morbidity and mortality. The place of hypotensive therapy in the control of hypertensive disorders in pregnancy has in the past been difficult to assess. This was largely due to the reluctance of obstetricians to use antihypertensive drugs because of concern about their effects on the fetus. It is now accepted that the control of hypertension with antihypertensive agents is of unequivocal value in terms of fetal survival (Leather et al., 1968; Michael, 1975; Redman et al., 1976). Where hypertension arises in pregnancy and where the fetus is immature, it is possible with treatment to allow the pregnancy to continue by preventing hypertensive sequelae in the mother. Fetal maturity is increased and fetal loss from prematurity because of premature induction of labour for maternal reasons is therefore reduced. Caution should be exercised, however, in the use of antihypertensive drugs because of the risk of reduced placental perfusion. In the past many antihypertensive drugs have been used and side-effects from these drugs have been noted in both mother and fetus, making them undesirable for use in pregnancy. Reserpine may cause maternal depression and increase the susceptibility of patients with hyperten-
0306-5251/79/170211-05 $01.00
sion to convulsions. The fetus suffers nasal congestion, lethargy, increased secretions in the respiratory tract and an increased tendency to hypothermia. Methyldopa can cause excessive lethargy in the mother and may have an adverse effect on the developing neural mechanisms of the fetus. A positive Coomb's titre may occur in the mother and it causes a reduction in cardiac output and sodium retention, both undesirable in pregnancy. Bethanidine and guanethidine cause troublesome postural hypotension and diarrhoea in the mother. More recently, propranolol has been used. Fetal bradycardia and hypotension may occur and may aggravate fetal distress and mask the clinical diagnostic features of fetal hypoxia. It may increase neonatal hypoglycaemia. Myometrial irritability may be a problem and it may interfere with maternal bladder function in the puerperium. The purpose of this study was to evaluate the effectiveness of labetalol, a combined a- and fiadrenoceptor antagonist, in patients with severe hypertensive disease in pregnancy. The investigation includes those patients with severe pregnancy induced hypertension or essential hypertension with or without exacerbation in pregnancy. 00 Macmillan Journals Ltd 1979
212S
C.A. MICHAEL
Methods
Selection of patients was restricted to those who, during pregnancy, had a BP of 150/105 mm Hg or 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 labetalol was administered only where other hypotensive agents were unsuccessful or were discontinued because of side-effects or because of a poor effect on BP. The end point of treatment occurred when tests of feto-placental function demonstrated increasing fetal hypoxia, where the maternal hypertension was uncontrolled or associated with increasing proteinuria, or where fetal pulmonary maturity was attained. Twenty-five patients (three with twin pregnancy) were treated and delivered (Table 1). Six of these patients were known to be hypertensive before week 20 of pregnancy, the remainder developed hypertension for the first time after week 20. The longest duration of treatment was 12 weeks and the shortest 6 days. All patients were admitted to hospital for the commencement of therapy. The initial dose of labetalol was 100 mg orally three times daily and this was increased at half-weekly intervals until control of BP was achieved. Diuretics were not prescribed. An adequate reduction in BP was considered to be to levels of 90 mm Hg diastolic. It was thought undesirable to reduce BP below this level because of the risk of reduction in placental perfusion and exacerbation of any existing placental insufficiency. When adequate reduction in BP was obtained, where the proteinuria did not increase and if other adverse features were absent, the pregnancy was allowed to continue. Tests of renal and liver function were carried out weekly. In addition twice weekly tests of placental function (plasma urinary oestrogens Table 1 labetalol
Clinical data of patients treated with
Number of patients Primigravidae Age distribution Multiple pregnancy BP range (mm Hg) Proteinuria Underlying renal disease Diabetes
25 19 16-40 yr 3 150/105-210/130* 18 4t 1
*Only patients with severe hypertension arising during pregnancy were treated with labetalol. The first five patients were treated with other hypotensive agents and labetalol was administered when these agents failed to control the hypertension or where side-effects occurred. t Including patient with diabetes.
and human placental lactogen), fetal growth estimations (serial fetal cephalometry and fetal girth using ultrasound) and fetal cardiotocography were carried out.
Results
Satisfactory control was achieved in all but three patients (at 26, 28 and 29 weeks of gestation, respectively). In these patients BP reduction occurred only initially and was not maintained. In all but one patient the proteinuria either improved significantly (11 patients) or disappeared (6 patients). Eclampsia did not occur in any of the patients.
Side-effects Side-effects with the drug were not a significant problem. Postural hypotension occurred in two patients, lethargy in one and scalp tingling in another. It was not necessary to discontinue the drug in any patients. Lecithin: sphingomyelin ratio in amnioticfluid The results indicate fetal lung maturity in all patients except one. Increasing amounts of pulmonary surfactant were found from 31 weeks gestation and in higher concentration than normally expected for the gestational age of the fetus (Table 2). Renal and hepatic function In two patients an increase in the blood urea was noted and levels beyond the normal range were Table 2 Amniotic fluid lecithin/sphingomyelin ratio in patients treated with labetalol Gestation
+++
+++ +++
No No
+++
No
Foam test
3.0-6.4
+++
28(1) 29(1) 31 (5)
Respiratory Distress Yes (not H MD) No No 1 mild RDS, not HMD No No
L :S ratio
5.0 32(1) 3.4-7.0 33(4) (incl. twins, 1 set) 8.4-9.5 34(5) 6.0-8.6 35(6) (incl. twins, 2 sets) 7.4-9.5 36(4)
+++
*Number of patients in parenthesis. HMD, Hyaline membrane disease. R DS, Respiratory distress syndrome.
SEVERE HYPERTENSION DURING PREGNANCY
obtained. These returned to nonnal immediately following delivery. There was no alteration in hepatic function. Feto-placental function It was not necessary to deliver any patients for fetal reasons before the development of fetal pulmonary maturity. In two patients fetal cardiotocography indicated the possibility of fetal hypoxia, and labour was induced. In both cases fetal lung maturity had occurred. One patient showed a reduction of oestrogen estimation below the tenth percentile at 32 weeks gestation and labour was induced. Five patients showed evidence of reduced fetal growth on ultrasound. Ten of the 28 infants were small at birth for gestational age when assessed by the
paediatrician. The three patients who did not achieve a satisfactory reduction in BP were all delivered for maternal reasons, that is, exacerbation of BP. Two of the three infants did not survive. In one patient at 28 weeks' gestation, caesarean section was performed because of accelerating hypertension despite therapy. The infant died on day 6 of life from pulmonary consolidation. The other patient at 26 weeks' gestation was delivered of a stillborn infant following induction of labour again because of accelerating hypertension, "solid proteinuria" (on boiling) and gross peripheral oedema. Method of delivery Fourteen infants were delivered with forceps, and eight patients had caesarean section on the advice of Six patients delivered the paediatrician. spontaneously. Labetalol did not interfere with labour nor complicate caesarean section. There was no spontaneous onset of labour, indicating that myometrial irritability was not a problem.
Cord blood labetalol estimation 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 administered to the mother. With the exception of the one patient receiving 1200 mg daily the levels of labetalol reached were well below the therapeutic levels obtained in each mother when related to the total daily dose of labetalol. One of the infants was hypotensive at birth but none had bradycardia. Breast milk labetalol
The concentration of labetalol in breast milk is shown in Table 3 and was related to dose of the drug and mean maternal plasma levels. No adverse effects in the feeding infants were noted. One patient who received labetalol 400 mg daily for 5 weeks did not have any of the drug present in the breast milk. Another, a diabetic on 1200 mg daily, reached a peak level of 600 ng/ml in the breast milk but she did not breast feed. Perinatal outcome With the exception of the fetus delivered by caesarean section at 28 weeks gestation none of the infants was hypotensive. Respiratory distress due to hyaline membrane disease did not develop in any infant. Four of the infants were asphyxiated at birth and quickly recovered with resuscitation. Two infants developed necrotizing enterocolitis attributable to their prematurity. The fetal outcome in relation to birth weight is shown in Table 4. One still birth (720 g) and one neonatal death occurred giving a corrected perinatal mortality of 3.57%. In this study the first 15 infants were subjected to an extensive eye examination by an ophthalmologist. Their retinae were carefully examined and no abnormality was detected. The retinae of one of the
Table 3 Concentrations of labetalol in maternal and cord blood, and in milk Total maternal dose
(mg daily)*
330(4) 400(11) 600(6) 700(2)
800(1) 1200(1)
Mean maternal plasma concentration (ng/ml) 64 123 135 158 174 321
*Number of patients in parenthesis.
213S
Mean cord blood concentration
(ng/ml) 42 23 60 68 70 260
Mean breast milk concentration (ng/ml)
(samples obtained 3 d post partum) 29 27 39 46 43 600
214S
C.A. MICHAEL
Table 4 Fetal outcome in relation to birth weight in patients treated with labetalol Birth weight (g) 720 1000-1500 1500-2000 2000-2500 2500-3000 Total
Alive
Stillborn
Neonatal death Total
1 7
1
1
8
1
8 8 3 28
-_-
8 8
3 26
1
Total perinatal mortality = 7.1% Post-natal mortality excluding previable infant 3.57%
=
infants (720 g) who did not survive was found to be normal on histological examination. The pigmentary epithelium was not disrupted in any way. Discussion Labetalol effectively reduced BP in those women with severe hypertension complicating pregnancy. This response occurred in the supine position but there was some enhancement in the standing position, the latter probably because of the a-adrenoceptorblocking effect of the drug. Some antihypertensive drugs are largely dependent on posture for their effect, and because patients with hypertension in pregnancy are confined to bed in the early stages of treatment, their usefulness in this situation is reduced. Fetal bradycardia was not a problem and the drug was free from side-effects. The patient with diabetes and underlying renal disease required the largest dose in the series for adequate control of BP. Labetalol was administered for 4 weeks from week 27 of pregnancy, the maternal diabetes remained under control and the fetus (1250 g) survived. The finding of premature lung maturation in those infants whose mothers were treated with labetalol warrants further consideration. A major problem in the treatment of severe hypertension in pregnancy has in the past been the high neonatal loss from hyaline membrane disease complicating prematurity. No infants developed hyaline membrane disease in this 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. In another study of ten women with severe hypertension in pregnancy treated with other antihypertensive drugs showed that four infants before week 35 of pregnancy developed respiratory
distress due to hyaline membrane disease. One of these infants died in the neonatal period. The lecithin sphingomyelin ratios in the amniotic fluid of these infants were well below the values obtained in the labetalol group at the corresponding gestation. Studies in animals have also been carried out (Nicholas et al., 1978). Here labetalol was infused at 4 mg/kg for 1-2 h into rabbits at 27 d gestation. The doe was then anaesthetized and the fetuses removed by laparotomy. Pressure-volume curves were obtained for each fetal lung which was also lavaged with physiological saline for phospholipid analysis. In a control study, hydrallazine was also infused in similar 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 with labetalol showed a greater volume change per unit of pressure change in the fetal lung, indicating a more compliant lung. Biochemical analysis also indicated an increase in the phospholipid concentration in the fluid obtained from the fetal lung in this group. These results seem to suggest a direct effect from labetalol in stimulating fetal lung maturation. Two infants in the study developed necrotizing enterocolitis, from which they survived. In a similar group treated with other antihypertensive drugs one infant of similar gestational age (31 weeks) also developed the same problem. Necrotizing enterocolitis was also seen in two other infants during the period over which labetalol was being studied. These pregnancies were not complicated by hypertension and the only factor present was uncomplicated prematurity. Thus, the necrotizing enterocolitis seems to be a complication of prematurity rather than the hypertension or its treatment. The results of the use of labetalol in the treatment of severe hypertension arising in pregnancy are encouraging. The freedom from maternal and fetal side-effects, the efficient hypotensive action and consequent improved perinatal mortality in a condition usually accompanied by high fetal loss, indicate that labetalol is suitable for use during pregnancy. The added possibility that labetalol may precipitate early lung maturation in the fetus, an observation not recorded with other antihypertensive drugs, further supports its use in pregnancies complicated by hypertensive disease where the fetus is too immature to consider delivery.
am grateful to Dr Peter Forsell, Allen and Hanburys (Australia), for providing the labetalol for the trial and for his continued support. thank Dr David Richards of Glaxo Group Research Limited for his assistance in the early stages of the trial.
SEVERE HYPERTENSION DURING PREGNANCY
215S
References
LEATHER, H.M., HUMPHREYS, D.M., BAKER, P. & CHADD, M.A. (1968). A controlled trial of hypotensive agents in hypertension in pregnancy. Lancet, 2, 448-490. MARTIN, L.E., HOPKINS, R. & BLAND, R. (1976). Metabolism of labetalol by animals and man. Br. J. clin. Pharmac., 3, suppl., 695-710. MICHAEL, C. (1975). The use of bethanidine in severe hypertension in pregnancy. Aust. N. Z. J. Obstet. Gynaec., 15, 75. NICHOLAS, T.E., LUGG, M.A. & JOHNSON, R.G. (1978). Maternal administration of salbutamol and
labetalol increases the amount of alveolar surfactant in lung of the day 27 fetal rabbit. Proc. Aust. physiol. pharmac. Soc., 9 (2), 146P. POYNTER, D., MARTIN, L.E., HARRISON, C. & COOK, J. (1976). Affinity of labetalol for ocular melanin. Br. J. clin. Pharmac., 3, suppl., 711-720. REDMAN, C.W.G., BIELIN, L.J., BONNAR, J. & OUNSTED, M.K. (1976). Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet, 2, 753-756.
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 remains a major cause of maternal and perinatal morbidity and mortality. The place of hypotensive therapy in the control of hypertensive disorders in pregnancy has in the past been difficult to assess. This was largely due to the reluctance of obstetricians to use antihypertensive drugs because of concern about their effects on the fetus. It is now accepted that the control of hypertension with antihypertensive agents is of unequivocal value in terms of fetal survival (Leather et al., 1968; Michael, 1975; Redman et al., 1976). Where hypertension arises in pregnancy and where the fetus is immature, it is possible with treatment to allow the pregnancy to continue by preventing hypertensive sequelae in the mother. Fetal maturity is increased and fetal loss from prematurity because of premature induction of labour for maternal reasons is therefore reduced. Caution should be exercised, however, in the use of antihypertensive drugs because of the risk of reduced placental perfusion. In the past many antihypertensive drugs have been used and side-effects from these drugs have been noted in both mother and fetus, making them undesirable for use in pregnancy. Reserpine may cause maternal depression and increase the susceptibility of patients with hyperten-
0306-5251/79/170211-05 $01.00
sion to convulsions. The fetus suffers nasal congestion, lethargy, increased secretions in the respiratory tract and an increased tendency to hypothermia. Methyldopa can cause excessive lethargy in the mother and may have an adverse effect on the developing neural mechanisms of the fetus. A positive Coomb's titre may occur in the mother and it causes a reduction in cardiac output and sodium retention, both undesirable in pregnancy. Bethanidine and guanethidine cause troublesome postural hypotension and diarrhoea in the mother. More recently, propranolol has been used. Fetal bradycardia and hypotension may occur and may aggravate fetal distress and mask the clinical diagnostic features of fetal hypoxia. It may increase neonatal hypoglycaemia. Myometrial irritability may be a problem and it may interfere with maternal bladder function in the puerperium. The purpose of this study was to evaluate the effectiveness of labetalol, a combined a- and fiadrenoceptor antagonist, in patients with severe hypertensive disease in pregnancy. The investigation includes those patients with severe pregnancy induced hypertension or essential hypertension with or without exacerbation in pregnancy. 00 Macmillan Journals Ltd 1979
212S
C.A. MICHAEL
Methods
Selection of patients was restricted to those who, during pregnancy, had a BP of 150/105 mm Hg or 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 labetalol was administered only where other hypotensive agents were unsuccessful or were discontinued because of side-effects or because of a poor effect on BP. The end point of treatment occurred when tests of feto-placental function demonstrated increasing fetal hypoxia, where the maternal hypertension was uncontrolled or associated with increasing proteinuria, or where fetal pulmonary maturity was attained. Twenty-five patients (three with twin pregnancy) were treated and delivered (Table 1). Six of these patients were known to be hypertensive before week 20 of pregnancy, the remainder developed hypertension for the first time after week 20. The longest duration of treatment was 12 weeks and the shortest 6 days. All patients were admitted to hospital for the commencement of therapy. The initial dose of labetalol was 100 mg orally three times daily and this was increased at half-weekly intervals until control of BP was achieved. Diuretics were not prescribed. An adequate reduction in BP was considered to be to levels of 90 mm Hg diastolic. It was thought undesirable to reduce BP below this level because of the risk of reduction in placental perfusion and exacerbation of any existing placental insufficiency. When adequate reduction in BP was obtained, where the proteinuria did not increase and if other adverse features were absent, the pregnancy was allowed to continue. Tests of renal and liver function were carried out weekly. In addition twice weekly tests of placental function (plasma urinary oestrogens Table 1 labetalol
Clinical data of patients treated with
Number of patients Primigravidae Age distribution Multiple pregnancy BP range (mm Hg) Proteinuria Underlying renal disease Diabetes
25 19 16-40 yr 3 150/105-210/130* 18 4t 1
*Only patients with severe hypertension arising during pregnancy were treated with labetalol. The first five patients were treated with other hypotensive agents and labetalol was administered when these agents failed to control the hypertension or where side-effects occurred. t Including patient with diabetes.
and human placental lactogen), fetal growth estimations (serial fetal cephalometry and fetal girth using ultrasound) and fetal cardiotocography were carried out.
Results
Satisfactory control was achieved in all but three patients (at 26, 28 and 29 weeks of gestation, respectively). In these patients BP reduction occurred only initially and was not maintained. In all but one patient the proteinuria either improved significantly (11 patients) or disappeared (6 patients). Eclampsia did not occur in any of the patients.
Side-effects Side-effects with the drug were not a significant problem. Postural hypotension occurred in two patients, lethargy in one and scalp tingling in another. It was not necessary to discontinue the drug in any patients. Lecithin: sphingomyelin ratio in amnioticfluid The results indicate fetal lung maturity in all patients except one. Increasing amounts of pulmonary surfactant were found from 31 weeks gestation and in higher concentration than normally expected for the gestational age of the fetus (Table 2). Renal and hepatic function In two patients an increase in the blood urea was noted and levels beyond the normal range were Table 2 Amniotic fluid lecithin/sphingomyelin ratio in patients treated with labetalol Gestation
+++
+++ +++
No No
+++
No
Foam test
3.0-6.4
+++
28(1) 29(1) 31 (5)
Respiratory Distress Yes (not H MD) No No 1 mild RDS, not HMD No No
L :S ratio
5.0 32(1) 3.4-7.0 33(4) (incl. twins, 1 set) 8.4-9.5 34(5) 6.0-8.6 35(6) (incl. twins, 2 sets) 7.4-9.5 36(4)
+++
*Number of patients in parenthesis. HMD, Hyaline membrane disease. R DS, Respiratory distress syndrome.
SEVERE HYPERTENSION DURING PREGNANCY
obtained. These returned to nonnal immediately following delivery. There was no alteration in hepatic function. Feto-placental function It was not necessary to deliver any patients for fetal reasons before the development of fetal pulmonary maturity. In two patients fetal cardiotocography indicated the possibility of fetal hypoxia, and labour was induced. In both cases fetal lung maturity had occurred. One patient showed a reduction of oestrogen estimation below the tenth percentile at 32 weeks gestation and labour was induced. Five patients showed evidence of reduced fetal growth on ultrasound. Ten of the 28 infants were small at birth for gestational age when assessed by the
paediatrician. The three patients who did not achieve a satisfactory reduction in BP were all delivered for maternal reasons, that is, exacerbation of BP. Two of the three infants did not survive. In one patient at 28 weeks' gestation, caesarean section was performed because of accelerating hypertension despite therapy. The infant died on day 6 of life from pulmonary consolidation. The other patient at 26 weeks' gestation was delivered of a stillborn infant following induction of labour again because of accelerating hypertension, "solid proteinuria" (on boiling) and gross peripheral oedema. Method of delivery Fourteen infants were delivered with forceps, and eight patients had caesarean section on the advice of Six patients delivered the paediatrician. spontaneously. Labetalol did not interfere with labour nor complicate caesarean section. There was no spontaneous onset of labour, indicating that myometrial irritability was not a problem.
Cord blood labetalol estimation 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 administered to the mother. With the exception of the one patient receiving 1200 mg daily the levels of labetalol reached were well below the therapeutic levels obtained in each mother when related to the total daily dose of labetalol. One of the infants was hypotensive at birth but none had bradycardia. Breast milk labetalol
The concentration of labetalol in breast milk is shown in Table 3 and was related to dose of the drug and mean maternal plasma levels. No adverse effects in the feeding infants were noted. One patient who received labetalol 400 mg daily for 5 weeks did not have any of the drug present in the breast milk. Another, a diabetic on 1200 mg daily, reached a peak level of 600 ng/ml in the breast milk but she did not breast feed. Perinatal outcome With the exception of the fetus delivered by caesarean section at 28 weeks gestation none of the infants was hypotensive. Respiratory distress due to hyaline membrane disease did not develop in any infant. Four of the infants were asphyxiated at birth and quickly recovered with resuscitation. Two infants developed necrotizing enterocolitis attributable to their prematurity. The fetal outcome in relation to birth weight is shown in Table 4. One still birth (720 g) and one neonatal death occurred giving a corrected perinatal mortality of 3.57%. In this study the first 15 infants were subjected to an extensive eye examination by an ophthalmologist. Their retinae were carefully examined and no abnormality was detected. The retinae of one of the
Table 3 Concentrations of labetalol in maternal and cord blood, and in milk Total maternal dose
(mg daily)*
330(4) 400(11) 600(6) 700(2)
800(1) 1200(1)
Mean maternal plasma concentration (ng/ml) 64 123 135 158 174 321
*Number of patients in parenthesis.
213S
Mean cord blood concentration
(ng/ml) 42 23 60 68 70 260
Mean breast milk concentration (ng/ml)
(samples obtained 3 d post partum) 29 27 39 46 43 600
214S
C.A. MICHAEL
Table 4 Fetal outcome in relation to birth weight in patients treated with labetalol Birth weight (g) 720 1000-1500 1500-2000 2000-2500 2500-3000 Total
Alive
Stillborn
Neonatal death Total
1 7
1
1
8
1
8 8 3 28
-_-
8 8
3 26
1
Total perinatal mortality = 7.1% Post-natal mortality excluding previable infant 3.57%
=
infants (720 g) who did not survive was found to be normal on histological examination. The pigmentary epithelium was not disrupted in any way. Discussion Labetalol effectively reduced BP in those women with severe hypertension complicating pregnancy. This response occurred in the supine position but there was some enhancement in the standing position, the latter probably because of the a-adrenoceptorblocking effect of the drug. Some antihypertensive drugs are largely dependent on posture for their effect, and because patients with hypertension in pregnancy are confined to bed in the early stages of treatment, their usefulness in this situation is reduced. Fetal bradycardia was not a problem and the drug was free from side-effects. The patient with diabetes and underlying renal disease required the largest dose in the series for adequate control of BP. Labetalol was administered for 4 weeks from week 27 of pregnancy, the maternal diabetes remained under control and the fetus (1250 g) survived. The finding of premature lung maturation in those infants whose mothers were treated with labetalol warrants further consideration. A major problem in the treatment of severe hypertension in pregnancy has in the past been the high neonatal loss from hyaline membrane disease complicating prematurity. No infants developed hyaline membrane disease in this 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. In another study of ten women with severe hypertension in pregnancy treated with other antihypertensive drugs showed that four infants before week 35 of pregnancy developed respiratory
distress due to hyaline membrane disease. One of these infants died in the neonatal period. The lecithin sphingomyelin ratios in the amniotic fluid of these infants were well below the values obtained in the labetalol group at the corresponding gestation. Studies in animals have also been carried out (Nicholas et al., 1978). Here labetalol was infused at 4 mg/kg for 1-2 h into rabbits at 27 d gestation. The doe was then anaesthetized and the fetuses removed by laparotomy. Pressure-volume curves were obtained for each fetal lung which was also lavaged with physiological saline for phospholipid analysis. In a control study, hydrallazine was also infused in similar 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 with labetalol showed a greater volume change per unit of pressure change in the fetal lung, indicating a more compliant lung. Biochemical analysis also indicated an increase in the phospholipid concentration in the fluid obtained from the fetal lung in this group. These results seem to suggest a direct effect from labetalol in stimulating fetal lung maturation. Two infants in the study developed necrotizing enterocolitis, from which they survived. In a similar group treated with other antihypertensive drugs one infant of similar gestational age (31 weeks) also developed the same problem. Necrotizing enterocolitis was also seen in two other infants during the period over which labetalol was being studied. These pregnancies were not complicated by hypertension and the only factor present was uncomplicated prematurity. Thus, the necrotizing enterocolitis seems to be a complication of prematurity rather than the hypertension or its treatment. The results of the use of labetalol in the treatment of severe hypertension arising in pregnancy are encouraging. The freedom from maternal and fetal side-effects, the efficient hypotensive action and consequent improved perinatal mortality in a condition usually accompanied by high fetal loss, indicate that labetalol is suitable for use during pregnancy. The added possibility that labetalol may precipitate early lung maturation in the fetus, an observation not recorded with other antihypertensive drugs, further supports its use in pregnancies complicated by hypertensive disease where the fetus is too immature to consider delivery.
am grateful to Dr Peter Forsell, Allen and Hanburys (Australia), for providing the labetalol for the trial and for his continued support. thank Dr David Richards of Glaxo Group Research Limited for his assistance in the early stages of the trial.
SEVERE HYPERTENSION DURING PREGNANCY
215S
References
LEATHER, H.M., HUMPHREYS, D.M., BAKER, P. & CHADD, M.A. (1968). A controlled trial of hypotensive agents in hypertension in pregnancy. Lancet, 2, 448-490. MARTIN, L.E., HOPKINS, R. & BLAND, R. (1976). Metabolism of labetalol by animals and man. Br. J. clin. Pharmac., 3, suppl., 695-710. MICHAEL, C. (1975). The use of bethanidine in severe hypertension in pregnancy. Aust. N. Z. J. Obstet. Gynaec., 15, 75. NICHOLAS, T.E., LUGG, M.A. & JOHNSON, R.G. (1978). Maternal administration of salbutamol and
labetalol increases the amount of alveolar surfactant in lung of the day 27 fetal rabbit. Proc. Aust. physiol. pharmac. Soc., 9 (2), 146P. POYNTER, D., MARTIN, L.E., HARRISON, C. & COOK, J. (1976). Affinity of labetalol for ocular melanin. Br. J. clin. Pharmac., 3, suppl., 711-720. REDMAN, C.W.G., BIELIN, L.J., BONNAR, J. & OUNSTED, M.K. (1976). Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet, 2, 753-756.
