European Journal of Obstetrics & Gynecology and Reproductive Biology, 45 (1992) 47-51 0 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00
47
EUROBS 01347
Does labetalol influence the development of proteinuria in pregnancy hypertension? A randomised controlled study D.J. Cruickshank a, A.A. Robertson b, D.M. Campbell a and I. MacGillivray ’ a Department of Obstetrics and Gynaecology, Maternity Hospital, Foresterhill, Aberdeen, b Cameron Hospital, Hartlepool and ’ Department of Obstetrics & Gynaecology, University of Bristol, UK
Accepted for publication 2 January 1992
Summary It is the development of proteinuria in pregnancy-induced hypertension which is associated with an increased perinatal mortality. There is some evidence to suggest that labetalol may diminish the amount of proteinuria in.patients who have already developed proteinuric pre-eclampsia. A randomised controlled study design was used to investigate whether labetalol treatment, started when a persistent diastolic blood pressure greater than 90 mmHg was observed, influenced the subsequent development of proteinuria. One hundred and fourteen women with singleton pregnancies and hypertension in the absence of proteinuria were randomised to receive either labetalol or no antihypertensive therapy. At recruitment maternal age, blood pressure and gestation were similar in both the labetalol and control groups. There was no difference in the frequency, quantity or timing of subsequent proteinuria between treatment and control groups. Overall 34% of primigravidae and 10% of parous women developed proteinuria. Labetalol did, however, control the blood pressure in 45 of the 51 treated women (88%) within 24 h. This effect was often shortlived requiring dose escalation after 3 to 5 days in the majority of cases. Labetalol was well tolerated and no significant maternal toxicity was noted. Labetalol; Proteinuria; Pregnancy hypertension
Introduction The most significant perinatal prognostic factor in pregnancy hypertension is the presence or absence of associated proteinuria. Maternal hypertension alone is associated with a perinatal mortality similar or lower than that of normoten-
Correspondence:
Dr. D.J. Cruickshank, Department of Obstetrics & Gynaecology, Maternity Hospital, Foresterhill, Aberdeen, AB9 2ZA, UK.
sive women [l]. With hypertension and proteinuria particularly in primigravidae the perinatal death rate is almost trebled [2]. The aetiology and pathogenesis of preeclampsia remain unknown. Altered vascular reactivity with an imbalance of vasoactive agents has however figured prominently in the aetiological theories of this complex syndrome. Such vasoactive agents include angiotensin II, from the renin-angiotensin-aldosterone system, the vasodilator prostaglandin E series and the vasoconstrictors thromboxane and F prostaglandins [3,4].
48
It therefore seems logical that therapy aimed primarily at altering peripheral vascular tone may be useful in the management of pregnancy hypertension and perhaps the prevention of its sequelae. Labetalol is a unique antihypertensive agent which acts as a competitive inhibitor of (Y- and P-adrenoceptors. It lowers the blood pressure by blocking peripheral arteriolar cY,-adrenoceptors thus reducing peripheral resistance. Concurrent P-blockade protects the heart from the reflex sympathetic drive normally produced by peripheral vasodilators so the reduction in blood pressure is achieved without cardiac stimulation. Conversely this increased reflex activity modulates the p-blocking effect of the drug on the heart so that the heart rate and cardiac output are not significantly reduced [5,6]. Labetalol has now been widely used in the treatment of pregnancy hypertension for more than 10 years and is generally regarded as a safe and efficient drug [7,8]. Several possible advantages over other antihypertensive agents used in the management of hypertension in pregnancy have been suggested. Firstly, labeta101 may exert a direct beneficial action on the maturation of the fetal lung [9]. Secondly, it appears to have no deleterious effect on uteroplacental blood flow [lO,ll]. Additional work from Michael suggests that labetalol may diminish the amount of proteinuria in women who have already developed proteinuric pre-eclampsia before commencement of therapy [12]. The aim of this study was to determine whether labetalol treatment, commenced as soon as a persistent diastolic blood pressure over 90 mmHg was observed, influenced the subsequent development of proteinuria. This question has not been previously addressed in a randomised controlled study. The additional outcome analysis from this trial, including maternal obstetric end points and fetal outcome, is presented elsewhere [13]. Patients
and Methods
Over a 2-year period 123 women between 24 and 39 weeks gestation with a diastolic blood pressure greater than 90 mmHg persisting over 24 hours were recruited from the antenatal clinics
TABLE I Labetalol dose escalation required for effective blood pressure control Dose Level
Labetalol
Effective BP Control (n = 51)
1 2 3 4 5
lOOmgX2perday 200 mg x 2 per day 300 mg x 2 per day 4OOmgX2perday 400 mg x 3 per day
6 13 20 5 5
Ref. 13.
within Aberdeen City. Only patients without proteinuria in a clean morning mid-stream urine sample tested by the salicylsulphonic acid method, for a further 48 h were included in the study. For analysis nine sets of twins were excluded leaving 114 women with singleton pregnancies. Additional exclusion criteria were asthma, diabetes mellitus, psychosis, several psychoneuroses or any cardiac abnormality precluding the use of pblockers. After stratification according to whether they were primigravid (76) or parous (38) the study women were randomly allocated using numbered sealed envelopes to receive either oral labetalol or no specific antihypertensive therapy. The aim in the labetalol treatment group was to reduce and maintain the diastolic blood pressure to below 90 mmHg. The starting dose of labetalol was 100 mg twice per day with a facility for dose escalation at 48-h intervals to a maximum of 400 mg X 3 per day until the desired effect on diastolic blood pressure was maintained (Table I). Labetalol treatment when effective was continued into the puerperium. None of the controls received antihypertensive agents antenatally. Study women remained in-patients until a diastolic blood pressure below 90 mmHg was achieved. Antenatally they were all seen at least weekly as out-patients. A diastolic blood pressure above 1OO’mmHg or the development of proteinuria by the salicylsulphonic acid test were indications for admission and in-patient management. Otherwise subsequent obstetric management decisions for both groups were based on current consultant practice and were independent of
49
group allocation. Delivery was expedited when the clinician felt the risk to the fetus or mother was greater if the pregnancy continued. Blood pressure recording was standardised by using the systolic and Phase IV (Korotkoff sounds) diastolic pressures measured in the semirecumbent left lateral position from the left arm with a cuff not less than 3;” wide placed at the level of the heart. Proteinuria was quantified daily from a 24-h urine collection using an Esbach albuminometer, only if proteinuria was detected by the salicylsulphonic acid test in a clean morning mid-stream sample of urine. Protein was considered to be present in abnormal or significant amounts if it was 0.25 g/l or more in a 24 hour specimen of urine [14]. Ethical approval for the study was obtained from the hospital Ethical Committee and all patients gave informed consent prior to participation. Originally it was intended to randomise 140 singleton primigravidae but this was not achieved with the resources available. This would have correctly detected a reduction in the development of proteinuria from 30% to 10% at the 5% significance level with a power of 80%. All data were prospectively recorded and statistical analysis was by Student t-test and the chi square test with Yate’s correction. Results Of the 114 evaluable women, 76 were primigravidae, of whom 51 were randomised to receive
labetalol with 45 controls. There were 38 parous women, with 20 in the labetalol treatment group and 18 in the control group. After randomisation there were no exclusions from the analysis. The treatment and control groups for primigravid and parous women were similar with regard to mater: nal age (means of 24.5, 24.8, 28.0 and 28.1 years); average recruitment blood pressure (140/94, 142/94, 144/94 and 144/96 mmHg) and average gestation at entry (34.2,35.3,32.1 and 32.5 weeks). There was no significant difference in subsequent maternal obstetric outcome measures, including gestation at delivery, mode of onset of labour, mode of delivery and mean birthweight, between treatment and control groups. These end points are elaborated upon elsewhere [13]. A satisfactory reduction in diastolic blood pressure to less than 90 mmHg was achieved within 24 h in 45 of the 51 labetalol-treated women (88%). The antihypertensive effect of labeta101 was similar in both primigravidae and multigravidae with 27 of 31 (87%) and 18 of 20 (90%‘0),respectively, achieving the desired reduction in diastolic blood pressure. Similarly the labetalol antihypertensive effect was independent of gestation. The duration of response at dose levels 1 and 2 was frequently shortlived requiring dose escalation after 3 to 5 days in 80% of instances (77/96 dose escalation opportunities). Twenty of the 51 (39%) labetalol-treated women were maintained at dose level 3 (300 mg x 2 per day) with five women escalating to dose level 5 (1.2 g per day) (Table I). There were only two
TABLE II Development of proteinuria Proteinuria incidence (%)
Maximal proteinuria (g/24 h) mean (range)
Time to onset of Proteinuria (days) Mean (SE)
1.5(33) 11 (35)
1.5 (0.5-4) 1.3 (0.5-3.5)
10.9 (1.6) 11.3 (2.5)
1.0, 2.5 1.0, 2.0
16,25 20,21
Primigravidae
Control group (n = 45) Labetalol group (n = 31) Multigravidae
Control group (n = 18)
2(11)
Labetalol group (n = 20)
2 (10)
x2 and I-test: no statistical differences.
50
women in the labetalol treatment group in whom effective control of blood pressure was not achieved. With regard to possible toxicities there were three women who reported dizziness and two women complained of lethargy. It was not necessary to discontinue treatment because of side effects in any of the labetalol-treated women. There was no difference in the frequency of subsequent proteinuria between labetalol-treated and control women for both primigravidae and multigravidae (Table II>. Overall 34% (26/76) of primigravidae developed proteinuria whereas only 10% (4/38) of parous women became proteinuric. The amount of proteinuria was the same in both labetalol and control groups, as was the interval between recruitment and development of proteinuria. Discussion Despite the intensive study of pre-eclampsia this century, there remains no consensus view regarding its aetiology. Until the intricacies of the pathogenesis of this disease(s) become more clearly understood, it is unlikely there will be any major advances in the treatment of this complex syndrome. The only effective treatment for preeclampsia remains delivery. No medical treatment has yet been conclusively shown to prevent or retard the development of pre-eclampsia [15]. An earlier uncontrolled study by Michael suggested that labetalol may alter the natural history of pre-eclampsia by reducing the amount of proteinuria in patients who had already developed proteinuric pre-eclampsia before commencement of labetalol [12]. Unfortunately, our randomised controlled study was unable to confirm any beneficial effect of labetalol on the natural history of pre-eclampsia. There was no difference in the incidence, quantity or timing of subsequent proteinuria between control and labetalol treated women who presented with hypertension in the absence of proteinuria. Sibai made a similar observation in one of the few other randomised controlled studies of labetalol in pregnancy hypertension [16]. Comparing labetalol plus hospitalisation versus hospitalisation alone for established proteinuric pre-eclampsia there was no
significant difference in the serial changes in proteinuria in the two groups. Michael’s observation may represent a transient beneficial effect of labetalol on renal function in hypertensive women rather than a direct effect on the pre-eclamptic process. An improvement in renal function has been reported by Lamming and colleagues [17]. Thus the place for antihypertensive therapy in pre-eclampsia remains merely to control one of the dangerous manifestations of this disorder, namely maternal hypertension. Blood pressure control does not influence the other changes of pre-eclampsia. The efficacy and acceptability of labetalol in the treatment of hypertension in pregnancy has been confirmed in this randomised controlled study. The rapid control of blood pressure with oral labetalol achieving a satisfactory response in 88% (54/51) of cases within 24 h is an obvious advantage. It is interesting that several other workers have found similar response rates - Lardoux’s group .82%, Michael 92%, and 88% [8,12,18]. Lardoux’s group found that the average daily dose of labetalol required for satisfactory blood pressure control was 600 mg [8]. This is equivalent to the dose level in our study which was required to achieve a satisfactory response in 39% (20/51) of labetalol-treated women. The incidence of side effects and acceptability of labeta101 in this study compares favourably with reports from other series [12,18,19]. It has been suggested that the side effects attributable to the P-blocking component are less obtrusive than those seen with pure P-blocking drugs without a-activity, because the alpha blockade modifies the consequences of P-blocking [20]. Although the design of this trial allowed a reliable comparison between the effect of labeta101 therapy and conventional non-drug management on the development of proteinuria in pregnancy hypertension, bias would have been minimised by a double-blind placebo controlled study. Despite the lack of effect of labetalol on the development of proteinuria, its efficacy in terms of blood pressure control with minimal toxicity will ensure its continued use in pregnancy hypertension.
51
Acknowledgements This study was funded by a grant from Glaxo. We would also like to acknowledge the help of the nursing staff in the antenatal and research wards and the laboratory staff at Aberdeen Maternity Hospital. The manuscript was typed by Miss Rebecca Moir. References Chamberlain G, Philip E, Howlett B, Masters K. British births 1970, 2. In: Obstetric Care. London: Heinemann, 1978;80. MacGillivray I. In: Pre-eclampsia, the Hypertensive Disease of Pregnancy. London: WB Saunders Co Ltd, 1983;174-190. Symonds EM, Broughton-Pipkin F, Craven DJ. Changes in the renin angiotensin system in primigravidae with hypertensive disease of pregnancy. Br J Obstet Gynaecol 1975;82:643. Remuzzi G, Zoja C, Marchesi D, et al. Plasmatic regulation of vascular prostacyclin in pregnancy. Br Med J 1981;282:512. Edwards RC, Raftery EP. Haemodynamic effects of long term oral labetalol. Br J Clin Pharmacol 1976;3(Suppl):733. 6 MacCarthy EP, Bloomfield SS. Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects. Pharmacotherapy 1983;3:193. 7 Michael CA, Potter JM. A comparison of labetalol with antihypertensive drugs in the treatment of hypertensive disease of pregnancy. In: Riley A, Symonds EM, eds. Investigation of labetalol in the management of hypertension in pregnancy. International Congress Series 591. Amsterdam: Excerpta Medica 1982;111-112. 8 Lardoux H, Gerard J, Blazquez G, Chouty F, Flouvat B. Hypertension in pregnancy: evaluation of the two P-blockers atenalol and labetalol. Eur Heart J 1983;4(Suppl G):35-40.
9 Michael CA. Early fetal lung maturation associated with labetalol therapy. Singapore J Obstet Gynaecol 1980; 11143-47. 10 Lunell NO, Fredholm B, Hjemdahl P, et al. Labetalol, a combined (Y-and P-blocker in hypertension of pregnancy. Acta Med Stand 1982$Suppl)665:143-147. 11 Nylund L, Lunnell NO, Lewander R, Sarby B, Thornstron? S. Labetalol for the treatment of hypertension in pregnancy. Pharmacokinetics and effects on the uteroplacental blood flow. Acta Obstet Gynecol Stand 1984; (Suppl)ll8;71-73. 12 Michael CA. Use of labetalol in the treatment of severe hypertension during pregnancy. Br J Clin Pharmacol 1979;8(Suppl3):2llS-215s. 13 Cruickshank DJ, Robertson AA, Campbell DM, MacGillivray I. Maternal obstetric outcome measures in a randomised controlled study of labetalol in the treatment of hypertension in pregnancy. Clin Exp Hypertens 199l;BlO(3)333-344. 14 Nelson TR. A clinical study of pre-eclampsia. J. Obstet. Gynaecol. Br. Emp. 1955;62:48. 15 Redman CWG. Hypertension in pregnancy. In: DeSwiet M, ed. Medical Disorders in Obstetric Practice. Oxford: Blackwell Scientific Publications, 1989;283. 16 Sibai BN, Gonzalez AR, Mabie WC, Moretti M. A comparison of labetalol plus hospitalisation versus hospitalisation alone in the management of pre-eclampsia remote from term. Obstet Gynecol 1987;70:323. 17 Lamming GD, Pipkin FB, Symonds EM. Comparison of the (Y-and P-blocking drug, labetalol and methyl dopa in the treatment of moderate and severe pregnancy induced hypertension. Clin Exp Hypertens 1980;2:865-895. 18 Michael CA. The evaluation of labetalol in the treatment of hypertension complicating pregnancy. Br J Clin Pharmacol 1982;3(Supp0:127S-131s. 19 Walker JJ, Greer I, Calder AA. Treatment of acute pregnancy related hypertension: labetalol and hydrallazine compared. Postgrad Med J 1983;59(Suppl3):168-170. 20 Prichard BN. Combined (Y- and P-receptor inhibition in the treatment of hypertension. Drugs 1984;28(Suppl2):5768.
47
EUROBS 01347
Does labetalol influence the development of proteinuria in pregnancy hypertension? A randomised controlled study D.J. Cruickshank a, A.A. Robertson b, D.M. Campbell a and I. MacGillivray ’ a Department of Obstetrics and Gynaecology, Maternity Hospital, Foresterhill, Aberdeen, b Cameron Hospital, Hartlepool and ’ Department of Obstetrics & Gynaecology, University of Bristol, UK
Accepted for publication 2 January 1992
Summary It is the development of proteinuria in pregnancy-induced hypertension which is associated with an increased perinatal mortality. There is some evidence to suggest that labetalol may diminish the amount of proteinuria in.patients who have already developed proteinuric pre-eclampsia. A randomised controlled study design was used to investigate whether labetalol treatment, started when a persistent diastolic blood pressure greater than 90 mmHg was observed, influenced the subsequent development of proteinuria. One hundred and fourteen women with singleton pregnancies and hypertension in the absence of proteinuria were randomised to receive either labetalol or no antihypertensive therapy. At recruitment maternal age, blood pressure and gestation were similar in both the labetalol and control groups. There was no difference in the frequency, quantity or timing of subsequent proteinuria between treatment and control groups. Overall 34% of primigravidae and 10% of parous women developed proteinuria. Labetalol did, however, control the blood pressure in 45 of the 51 treated women (88%) within 24 h. This effect was often shortlived requiring dose escalation after 3 to 5 days in the majority of cases. Labetalol was well tolerated and no significant maternal toxicity was noted. Labetalol; Proteinuria; Pregnancy hypertension
Introduction The most significant perinatal prognostic factor in pregnancy hypertension is the presence or absence of associated proteinuria. Maternal hypertension alone is associated with a perinatal mortality similar or lower than that of normoten-
Correspondence:
Dr. D.J. Cruickshank, Department of Obstetrics & Gynaecology, Maternity Hospital, Foresterhill, Aberdeen, AB9 2ZA, UK.
sive women [l]. With hypertension and proteinuria particularly in primigravidae the perinatal death rate is almost trebled [2]. The aetiology and pathogenesis of preeclampsia remain unknown. Altered vascular reactivity with an imbalance of vasoactive agents has however figured prominently in the aetiological theories of this complex syndrome. Such vasoactive agents include angiotensin II, from the renin-angiotensin-aldosterone system, the vasodilator prostaglandin E series and the vasoconstrictors thromboxane and F prostaglandins [3,4].
48
It therefore seems logical that therapy aimed primarily at altering peripheral vascular tone may be useful in the management of pregnancy hypertension and perhaps the prevention of its sequelae. Labetalol is a unique antihypertensive agent which acts as a competitive inhibitor of (Y- and P-adrenoceptors. It lowers the blood pressure by blocking peripheral arteriolar cY,-adrenoceptors thus reducing peripheral resistance. Concurrent P-blockade protects the heart from the reflex sympathetic drive normally produced by peripheral vasodilators so the reduction in blood pressure is achieved without cardiac stimulation. Conversely this increased reflex activity modulates the p-blocking effect of the drug on the heart so that the heart rate and cardiac output are not significantly reduced [5,6]. Labetalol has now been widely used in the treatment of pregnancy hypertension for more than 10 years and is generally regarded as a safe and efficient drug [7,8]. Several possible advantages over other antihypertensive agents used in the management of hypertension in pregnancy have been suggested. Firstly, labeta101 may exert a direct beneficial action on the maturation of the fetal lung [9]. Secondly, it appears to have no deleterious effect on uteroplacental blood flow [lO,ll]. Additional work from Michael suggests that labetalol may diminish the amount of proteinuria in women who have already developed proteinuric pre-eclampsia before commencement of therapy [12]. The aim of this study was to determine whether labetalol treatment, commenced as soon as a persistent diastolic blood pressure over 90 mmHg was observed, influenced the subsequent development of proteinuria. This question has not been previously addressed in a randomised controlled study. The additional outcome analysis from this trial, including maternal obstetric end points and fetal outcome, is presented elsewhere [13]. Patients
and Methods
Over a 2-year period 123 women between 24 and 39 weeks gestation with a diastolic blood pressure greater than 90 mmHg persisting over 24 hours were recruited from the antenatal clinics
TABLE I Labetalol dose escalation required for effective blood pressure control Dose Level
Labetalol
Effective BP Control (n = 51)
1 2 3 4 5
lOOmgX2perday 200 mg x 2 per day 300 mg x 2 per day 4OOmgX2perday 400 mg x 3 per day
6 13 20 5 5
Ref. 13.
within Aberdeen City. Only patients without proteinuria in a clean morning mid-stream urine sample tested by the salicylsulphonic acid method, for a further 48 h were included in the study. For analysis nine sets of twins were excluded leaving 114 women with singleton pregnancies. Additional exclusion criteria were asthma, diabetes mellitus, psychosis, several psychoneuroses or any cardiac abnormality precluding the use of pblockers. After stratification according to whether they were primigravid (76) or parous (38) the study women were randomly allocated using numbered sealed envelopes to receive either oral labetalol or no specific antihypertensive therapy. The aim in the labetalol treatment group was to reduce and maintain the diastolic blood pressure to below 90 mmHg. The starting dose of labetalol was 100 mg twice per day with a facility for dose escalation at 48-h intervals to a maximum of 400 mg X 3 per day until the desired effect on diastolic blood pressure was maintained (Table I). Labetalol treatment when effective was continued into the puerperium. None of the controls received antihypertensive agents antenatally. Study women remained in-patients until a diastolic blood pressure below 90 mmHg was achieved. Antenatally they were all seen at least weekly as out-patients. A diastolic blood pressure above 1OO’mmHg or the development of proteinuria by the salicylsulphonic acid test were indications for admission and in-patient management. Otherwise subsequent obstetric management decisions for both groups were based on current consultant practice and were independent of
49
group allocation. Delivery was expedited when the clinician felt the risk to the fetus or mother was greater if the pregnancy continued. Blood pressure recording was standardised by using the systolic and Phase IV (Korotkoff sounds) diastolic pressures measured in the semirecumbent left lateral position from the left arm with a cuff not less than 3;” wide placed at the level of the heart. Proteinuria was quantified daily from a 24-h urine collection using an Esbach albuminometer, only if proteinuria was detected by the salicylsulphonic acid test in a clean morning mid-stream sample of urine. Protein was considered to be present in abnormal or significant amounts if it was 0.25 g/l or more in a 24 hour specimen of urine [14]. Ethical approval for the study was obtained from the hospital Ethical Committee and all patients gave informed consent prior to participation. Originally it was intended to randomise 140 singleton primigravidae but this was not achieved with the resources available. This would have correctly detected a reduction in the development of proteinuria from 30% to 10% at the 5% significance level with a power of 80%. All data were prospectively recorded and statistical analysis was by Student t-test and the chi square test with Yate’s correction. Results Of the 114 evaluable women, 76 were primigravidae, of whom 51 were randomised to receive
labetalol with 45 controls. There were 38 parous women, with 20 in the labetalol treatment group and 18 in the control group. After randomisation there were no exclusions from the analysis. The treatment and control groups for primigravid and parous women were similar with regard to mater: nal age (means of 24.5, 24.8, 28.0 and 28.1 years); average recruitment blood pressure (140/94, 142/94, 144/94 and 144/96 mmHg) and average gestation at entry (34.2,35.3,32.1 and 32.5 weeks). There was no significant difference in subsequent maternal obstetric outcome measures, including gestation at delivery, mode of onset of labour, mode of delivery and mean birthweight, between treatment and control groups. These end points are elaborated upon elsewhere [13]. A satisfactory reduction in diastolic blood pressure to less than 90 mmHg was achieved within 24 h in 45 of the 51 labetalol-treated women (88%). The antihypertensive effect of labeta101 was similar in both primigravidae and multigravidae with 27 of 31 (87%) and 18 of 20 (90%‘0),respectively, achieving the desired reduction in diastolic blood pressure. Similarly the labetalol antihypertensive effect was independent of gestation. The duration of response at dose levels 1 and 2 was frequently shortlived requiring dose escalation after 3 to 5 days in 80% of instances (77/96 dose escalation opportunities). Twenty of the 51 (39%) labetalol-treated women were maintained at dose level 3 (300 mg x 2 per day) with five women escalating to dose level 5 (1.2 g per day) (Table I). There were only two
TABLE II Development of proteinuria Proteinuria incidence (%)
Maximal proteinuria (g/24 h) mean (range)
Time to onset of Proteinuria (days) Mean (SE)
1.5(33) 11 (35)
1.5 (0.5-4) 1.3 (0.5-3.5)
10.9 (1.6) 11.3 (2.5)
1.0, 2.5 1.0, 2.0
16,25 20,21
Primigravidae
Control group (n = 45) Labetalol group (n = 31) Multigravidae
Control group (n = 18)
2(11)
Labetalol group (n = 20)
2 (10)
x2 and I-test: no statistical differences.
50
women in the labetalol treatment group in whom effective control of blood pressure was not achieved. With regard to possible toxicities there were three women who reported dizziness and two women complained of lethargy. It was not necessary to discontinue treatment because of side effects in any of the labetalol-treated women. There was no difference in the frequency of subsequent proteinuria between labetalol-treated and control women for both primigravidae and multigravidae (Table II>. Overall 34% (26/76) of primigravidae developed proteinuria whereas only 10% (4/38) of parous women became proteinuric. The amount of proteinuria was the same in both labetalol and control groups, as was the interval between recruitment and development of proteinuria. Discussion Despite the intensive study of pre-eclampsia this century, there remains no consensus view regarding its aetiology. Until the intricacies of the pathogenesis of this disease(s) become more clearly understood, it is unlikely there will be any major advances in the treatment of this complex syndrome. The only effective treatment for preeclampsia remains delivery. No medical treatment has yet been conclusively shown to prevent or retard the development of pre-eclampsia [15]. An earlier uncontrolled study by Michael suggested that labetalol may alter the natural history of pre-eclampsia by reducing the amount of proteinuria in patients who had already developed proteinuric pre-eclampsia before commencement of labetalol [12]. Unfortunately, our randomised controlled study was unable to confirm any beneficial effect of labetalol on the natural history of pre-eclampsia. There was no difference in the incidence, quantity or timing of subsequent proteinuria between control and labetalol treated women who presented with hypertension in the absence of proteinuria. Sibai made a similar observation in one of the few other randomised controlled studies of labetalol in pregnancy hypertension [16]. Comparing labetalol plus hospitalisation versus hospitalisation alone for established proteinuric pre-eclampsia there was no
significant difference in the serial changes in proteinuria in the two groups. Michael’s observation may represent a transient beneficial effect of labetalol on renal function in hypertensive women rather than a direct effect on the pre-eclamptic process. An improvement in renal function has been reported by Lamming and colleagues [17]. Thus the place for antihypertensive therapy in pre-eclampsia remains merely to control one of the dangerous manifestations of this disorder, namely maternal hypertension. Blood pressure control does not influence the other changes of pre-eclampsia. The efficacy and acceptability of labetalol in the treatment of hypertension in pregnancy has been confirmed in this randomised controlled study. The rapid control of blood pressure with oral labetalol achieving a satisfactory response in 88% (54/51) of cases within 24 h is an obvious advantage. It is interesting that several other workers have found similar response rates - Lardoux’s group .82%, Michael 92%, and 88% [8,12,18]. Lardoux’s group found that the average daily dose of labetalol required for satisfactory blood pressure control was 600 mg [8]. This is equivalent to the dose level in our study which was required to achieve a satisfactory response in 39% (20/51) of labetalol-treated women. The incidence of side effects and acceptability of labeta101 in this study compares favourably with reports from other series [12,18,19]. It has been suggested that the side effects attributable to the P-blocking component are less obtrusive than those seen with pure P-blocking drugs without a-activity, because the alpha blockade modifies the consequences of P-blocking [20]. Although the design of this trial allowed a reliable comparison between the effect of labeta101 therapy and conventional non-drug management on the development of proteinuria in pregnancy hypertension, bias would have been minimised by a double-blind placebo controlled study. Despite the lack of effect of labetalol on the development of proteinuria, its efficacy in terms of blood pressure control with minimal toxicity will ensure its continued use in pregnancy hypertension.
51
Acknowledgements This study was funded by a grant from Glaxo. We would also like to acknowledge the help of the nursing staff in the antenatal and research wards and the laboratory staff at Aberdeen Maternity Hospital. The manuscript was typed by Miss Rebecca Moir. References Chamberlain G, Philip E, Howlett B, Masters K. British births 1970, 2. In: Obstetric Care. London: Heinemann, 1978;80. MacGillivray I. In: Pre-eclampsia, the Hypertensive Disease of Pregnancy. London: WB Saunders Co Ltd, 1983;174-190. Symonds EM, Broughton-Pipkin F, Craven DJ. Changes in the renin angiotensin system in primigravidae with hypertensive disease of pregnancy. Br J Obstet Gynaecol 1975;82:643. Remuzzi G, Zoja C, Marchesi D, et al. Plasmatic regulation of vascular prostacyclin in pregnancy. Br Med J 1981;282:512. Edwards RC, Raftery EP. Haemodynamic effects of long term oral labetalol. Br J Clin Pharmacol 1976;3(Suppl):733. 6 MacCarthy EP, Bloomfield SS. Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects. Pharmacotherapy 1983;3:193. 7 Michael CA, Potter JM. A comparison of labetalol with antihypertensive drugs in the treatment of hypertensive disease of pregnancy. In: Riley A, Symonds EM, eds. Investigation of labetalol in the management of hypertension in pregnancy. International Congress Series 591. Amsterdam: Excerpta Medica 1982;111-112. 8 Lardoux H, Gerard J, Blazquez G, Chouty F, Flouvat B. Hypertension in pregnancy: evaluation of the two P-blockers atenalol and labetalol. Eur Heart J 1983;4(Suppl G):35-40.
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