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Review: labetalol for the treatment of hypertension in pregnancy __________________________________________________________________ Objectives: The objective of this evidence summary is to inform and advise a discussion on the inclusion of labetalol in the Essential Medicines List as an additional option for hypertension in pregnancy, and determine if atenolol is a suitable replacement for labetalol. Background: Pregnancy induced hypertension complicates about 10% of pregnancies; preeclampsia affects 2-8% of pregnancies; the incidence of eclampsia greatly varies between settings, being higher in developing countries where it affects between 1/100 and 1/1700 deliveries, whilst in industrialized countries it affects about 1/2000 deliveries. Pre-eclampsia and eclampsia increase maternal and perinatal morbidity and mortality. Perinatal mortality is also higher in women with severe essential hypertension (1). Antihypertensive drug groups represented in the WHO Model Formulary 2004 include beta-blocker (atenolol), ACE inhibitors (enalapril), vasodilators (hydralazine and nitroprusside), thiazide diuretics (hydrochlorothiazide), centrally acting antihypertensive drugs (methyldopa) and calcium channel blockers (nifedipine); some of these drugs are contraindicated in pregnancy. The WHO Model Formulary 2004 recommends magnesium sulfate for eclampsia and severe pre-eclampsia and highlights methyldopa as the safest antihypertensive in pregnancy (p 238). It discourages the use of ACE inhibitors and cautions against prescribing beta blockers in early pregnancy because of potential adverse effects to the baby, but stays short of making specific recommendations. WHO has issued guidelines recommending the use of hydralazine, nifedipine and labetalol (2) –the later not included in WHO Model Formulary 2004. Evidence summary: A regularly updated overview of the evidence on treatments for pre-eclampsia and hypertension in pregnancy (most recent update search December 2003) found a paucity of evidence on clinical effects of antihypertensive treatments in pregnancy; most studies focused on blood pressure reduction. Throughout, adverse effects of antihypertensive treatments in pregnancy remain poorly reported and studied in babies and women alike. (1) The overview assessed the effects of antihypertensive drugs in women with: severe pre-eclampsia and very high blood pressure; mild-moderate hypertension developed in pregnancy; high risk for pre-eclampsia and being offered prophylaxis with antihypertensives. (1) 1 In women with severe pre-eclampsia or very high blood pressure: the overview found one Cochrane review (search date 2002, 20 RCTs, 1637 women)(3) and one subsequent RCT (126 women). The overview found that all antihypertensives reduced blood pressure but studies were small and it was impossible to establish if a particular drug was overall better than others. Hydralazine was better than ketanserin at reducing persistent hypertension. Labetalol produced significantly less hypotension requiring treatment -a harmful effect that may compromise fetoplacental blood flow, than diazoxide (1 RCT, 0/45 with labetalol v 8/45 [18%] with diazoxide; RR 0.06, 95% CI 0 to 0.99).(3) Adverse effects were poorly reported and the indication to treat women with severe hypertension is based on experts’ consensus. (1) In women who develop mild-moderate hypertension during pregnancy: The overview found two Cochrane reviews(4; 5) and two small subsequent RCTs which didn’t assess the effects of beta blockers. (6; 7) The first systematic review found that overall, antihypertensive drugs halved the risk of developing severe hypertension, compared with no antihypertensive drugs (17 RCTs; 103/1113 v 196/1042; RR 0.52, 95% CI 0.41 to 0. 64).(4) The review included a subgroup analysis for beta blockers, which has been eclipsed by the second Cochrane Review that focuses on the effects of beta blockers and is more up-to-date.(5) The second Cochrane review found that beta blockers significantly reduced severe maternal hypertension and neonatal respiratory distress syndrome. Overall, it found no significant differences between beta blockers and placebo or no treatment in the incidence of preeclampsia, perinatal mortality, or the need to change drug treatment due to adverse maternal effects. Compared with placebo or no treatment, beta blockers increased the risk of newborns being small-for-gestational-age, but no significant differences were found in the incidence of caesarean sections, perinatal mortality, preterm delivery or admission of infants to special care (Table 1).(5) Table 1. Meta-analysis data comparing beta blockers versus placebo or no treatment in women who develop mild-moderate hypertension in pregnancy(5) Outcome RCTs AR [%] Beta blocker Severe hypertension 11 36/565 [6%] Proteinuria/Pre-eclampsia 11 102/666 [15%] Respiratory syndrome 4 6/283 [2%] Small for gestational age 12 99/676 [15%] Drugs stopped/changed due to maternal side effect 9 14/534 [3%] distress AR [%] Control 99/563 [18%] 123/674 [18%] 22/284 [8%] 68/670 [10%] 7/525 [1%] 10/710 [1%] 88/477 Preterm birth 8 91/485 [19%] [18%] Admission to special care 90/309 4 82/291 [28%] baby unit [29%] (NS) non significant statistical differences at 95% confidence interval Perinatal mortality 13 10/719 [1%] RR 95% CI 0.37 0.26 to 0.53 0.86 0.68 to 1.08 0.29 0.12 to 0.67 1.36 1.02 to 1.82 1.72 0.79 (NS) to 3.72 0.46 (NS) 0.76 (NS) 0.76 (NS) to 2.22 to 1.30 to 1.24 1.01 1.00 0.97 2 No significant differences were found between beta blockers and methyldopa in the incidence of perinatal mortality, small-for-gestational-age infants, admission to special newborn care units and few other clinically important outcomes (Table 2 presents outcomes with narrower confidence intervals). Table 2. Meta-analysis data comparing beta blockers versus methyldopa in women who develop mild-moderate hypertension in pregnancy(5) RCTs AR [%] AR [%] RR 95% CI Outcome Beta blocker Methyldopa Perinatal mortality 12 10/441 [2%] 15/397 [4%] 0.61 0.28 to 1.31 (NS) Severe hypertension 4 12/154 [8%] 14/143 [10%] 0.80 0.39 to 1.61 (NS) Proteinuria/Pre-eclampsia 9 71/392 [18%] 64/350 [18%] 0.99 0.74 to 1.32 (NS) Caesarean section 9 121/338 [36%] 118/316 [37%] 0.96 0.78 to 1.17 (NS) Preterm birth 4 28/136 [21%] 33/128 [26%] 0.81 0.52 to 1.24 (NS) Small for gestational age 5 30/193 [16%] 36/178 [20%] 0.76 0.50 to 1.16 (NS) baby Admission to special care 3 68/225 [30%] 64/203 [32%] 0.95 0.72 to 1.26 (NS) neonatal unit (NS) non significant statistical differences at 95% confidence interval The assessment and reporting of adverse effects was poor in most studies.(1) Beta blockers used in RCTs included labetalol, oxprenolol, pindolol, atenolol and metoprolol. Labetalol was the most frequently used beta-blocker (5 RCTs, 792 women, usually at doses of 200-300 mg/day administered by mouth). Atenolol was evaluated in 2 RCTs (153 women, usual doses of 50-100 mg/d by mouth). Prophylactic antihypertensives in women at high risk of pre-eclampsia: The overview found one small RCT (68 women without hypertension and with cardiac output >7.4 L/min) providing insufficient evidence to draw conclusions on the benefits of prophylactic antihypertensives. However it found a higher incidence of low-birth-weight in babies from primiparous women receiving atenolol (beta-blocker), compared with placebo (mean difference 440 g, P = 0.02).(1) Note: Atenolol and labetalol are distinctively different beta blockers. Their pharmacokinetics differ; atenolol has minimal hepatic metabolism, labetalol is metabolised predominantly in the liver. Atenolol is a cardioselective beta blocker reported to lack intrinsic sympathomimetic activity and membrane-stabilizing properties. Labetalol is a non cardio-selective beta blocker reported to have some sympathomimetic activity and membrane stabilizing activity, and alpha blocking properties.(8; 9) Given these differences, the effects of atenolol and labetalol are expected to be different. Recommendation: The Department of Reproductive Health and Research (WHO) is initiating a multicentre RCT to compare labetalol with placebo in the treatment of mild to moderate hypertension in pregnancy. However, the Department is still looking for alternatives to evaluate because of the relatively high cost of labetalol. We therefore think that while labetalol is different from other beta-blockers pharmacologically and is the most tested beta-blocker to date the evidence base is not robust enough to 3 add labetalol to the Essential Medicines List (EML) as a therapeutic option for pregnant women with high blood pressure in pregnancy. As new evidence on the safety and effectiveness of antihypertensive treatments in pregnancy emerges this recommendation and the status of antihypertensives for pregnancy may need to be revisited. References: (1) Duley L. Pre-eclampsia and hypertension. Clin Evid 2004; [search date December 2003](12):2013-2081. http://www.clinicalevidence.com/ceweb/ conditionpdf/1402.pdf (2) WHO Department of Reproductive Health and Research. Management of pregnancy-induced hypertension. WHO, UNFPA, UNICEF, World Bank, editors. Managing complications in pregnancy and childbirth: a guide for midwives and doctors. [WHO/RHR/00.7], S41-S50. 2000. World Health Organization. Integrated Management of Pregnancy and Childbirth. (3) Duley L, Henderson-Smart DJ. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev 2002;(4): CD001449.PM:12519557 (4) Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2001;(2):CD002252.PM:11406040 (5) Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2003;(3): CD002863. PM:12917933 (6) Elhassan EM, Mirghani OA, Habour AB, Adam I. Methyldopa versus no drug treatment in the management of mild pre-eclampsia. East Afr Med J 2002; 79(4):172-175.PM:12625668 (7) Rudnicki M, Frolich A, Pilsgaard K, Nyrnberg L, Moller M, Sanchez M et al. Comparison of magnesium and methyldopa for the control of blood pressure in pregnancies complicated with hypertension. Gynecol Obstet Invest 2000; 49(4):231-235.PM:10828704 (8) Cardiovascular drugs. In: Parfitt K, editor. Martindale: the complete drug reference. Taunton, MA: Pharmaceutical Press, 1999. (9) Lim PO, McDonald TM. Antianginal drugs and -adrenoreceptor antagonists. In: Dukes MNG, Aronson JK, editors. Meyler's Side Effects of Drugs. Elsevier, 2000: 575-628. _________________________ 15 December 2004 Department of Reproductive Health and Research World Health Organization 4