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What is the evidence for using labetalol as a first-line treatment option for hypertension in pregnancy?
  1. Louise M Webster,
  2. Andrew J Webb,
  3. Lucy C Chappell
  1. Department of Women and Children’s Health, King’s College London, 10th Floor North Wing, St Thomas’ Hospital, London, UK
  1. Correspondence to Louise M Webster; louise.m.webster{at}kcl.ac.uk

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Key learning points

  • Hypertensive disorders complicate around 8% of pregnancies and are associated with adverse maternal and perinatal outcome

  • The National Institute for Health and Care Excellence (NICE) guidelines do not specify a first-line antihypertensive agent for the treatment of chronic hypertension due to limited evidence in this area

  • Labetalol is recommended by NICE guidelines as first-line antihypertensive treatment for gestational hypertension and pre-eclampsia as it has been proven to be as effective as other antihypertensive agents and is licensed for use in pregnancy

  • Methyldopa and nifedipine are suitable alternative antihypertensive agents for the treatment of hypertension in pregnancy

  • Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists should be stopped within two days of pregnancy notification as they are associated with congenital malformations

  • Selection of antihypertensive treatment in pregnancy should include consideration of pre-existing medication, adverse effect profile and potential teratogenicity

Introduction

Labetalol is a racemate with alpha and non-selective beta adrenoceptor antagonist activity.1 The National Institute for Health and Care Excellence (NICE) recommends labetalol as first-line antihypertensive treatment for non-severe (<160/110 mm Hg) gestational hypertension and pre-eclampsia once blood pressure exceeds 150/100 mm Hg.2 Importantly, the NICE guidelines do not specify a single antihypertensive agent as first line for the treatment of chronic hypertension in pregnancy, but instead suggest women should be offered treatment based on their current antihypertensive prescription, adverse effect profiles and with consideration of potential teratogenicity. Beta blockers (including labetalol) are not recommended as first-line agents by NICE for the treatment of hypertension outside pregnancy and are regarded as fourth-line add-on antihypertensive treatments.3 The recommendation for use of labetalol as first-line treatment in pregnancy is based on limited evidence from randomised controlled trials and influenced by labetalol being the only antihypertensive drug that is licensed for use in pregnancy. Robust safety data for each class of drug, as well as individual agents, are limited. Other antihypertensive agents commonly used in pregnancy include nifedipine (calcium-channel blocker) and methyldopa (centrally acting agent). This review summarises the evidence available to guide clinicians in the selection of antihypertensive agents for the management of hypertension in pregnancy with reference to why labetalol is recommended by NICE and highlighting important considerations to ensure a patient-centred approach to treatment.

Why is the management of hypertension in pregnancy important?

Hypertension is estimated to complicate around 8% of pregnancies and encompasses pre-existing (chronic) hypertension, gestational hypertension (de novo hypertension >140/90 mm Hg after 20 weeks’ gestation) and pre-eclampsia (worsening pre-existing or de novo hypertension with proteinuria).4 Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality and are increasing in incidence with the rise in maternal age and the global obesity epidemic. Maternal morbidity is most notable in women who develop de novo or superimposed pre-eclampsia, with cohort studies reporting an increase in acute kidney injury, pulmonary oedema, eclampsia and stroke (compared with those without pre-eclampsia),5 but women with chronic and gestational hypertension are also at increased risk of such complications compared with normotensive pregnant women. Adverse perinatal outcomes associated with hypertensive disorders include stillbirth, fetal growth restriction and prematurity.6

Pregnancy poses a physiological challenge to the maternal vasculature, and hypertensive disorders are often associated with maladaptation to this challenge. Although there has previously been debate about the optimal blood pressure treatment threshold and the ideal blood pressure treatment target in pregnancy (primarily due to concerns that low blood pressure might be associated with fetal growth restriction),4,7 there is growing evidence that severe hypertension (≥160/110 mm Hg) is associated with a further increase in adverse maternal and perinatal outcomes (compared with those with hypertension who do not develop severe hypertension).8 More recently, the Control of Hypertension In Pregnancy Study (CHIPS) has highlighted the maternal benefit of ‘tight’ (diastolic target 85 mm Hg) compared with ‘less tight’ control (diastolic target 100 mm Hg) on reducing the maternal risk of severe hypertension without an increase in perinatal adverse outcomes.9 The optimal antihypertensive agent(s) to achieve tighter blood pressure control requires further investigation. The potential teratogenicity of antihypertensive agents is an additional challenge when selecting treatment for chronic hypertension in the first 12 weeks of pregnancy, with NICE recommending that ACE inhibitors and angiotensin II receptor antagonists (AIIRAa) be stopped within 2 days of pregnancy notification.2 ACE inhibitors and AIIRAs are associated with an increased risk of congenital abnormalities, oligohydramnios, fetal growth restriction, fetal hypocalvaria, renal dysplasia and stillbirth.10,11 Avoidance of chlorothiazide is also recommended in pregnancy as it is associated with congenital malformations, neonatal thrombocytopenia, hypoglycaemia and hypovolaemia; this agent is only available as hydrochlorothiazide in the UK and is infrequently prescribed as an antihypertensive. Assessing the risk of teratogenicity of antihypertensive agents is compounded by the impact of the disease process itself on the risk of congenital malformations. A matched case–control study used a Medicaid cohort (878,126 women) to compare women with treated and untreated chronic hypertension in pregnancy with normotensive pregnant controls to investigate the risk of congenital malformations.12 Pregnancies complicated by treated chronic hypertension compared with normotensive controls were at increased risk of congenital malformations (OR 1.3, 95% CI 1.2 to 1.5); however, pregnancies with untreated chronic hypertension compared with normotensive controls were also at increased risk (OR 1.2, 95% CI 1.1 to 1.3). Similar findings were reported in a retrospective cohort study of 465,754 mother–infant pairs assessing the risk of congenital malformations following maternal exposure to ACE inhibitors in the first trimester.13 Given these complexities, it is important that selection of an antihypertensive agent for the treatment of hypertension in the first trimester of pregnancy involves careful discussion around the limitations of the information available to clinicians to guide prescription.

Evidence for labetalol for gestational hypertension and pre-eclampsia

Labetalol is recommended as first-line antihypertensive agent by NICE for gestational hypertension and pre-eclampsia because it has been shown to be ‘as effective and safe as other antihypertensive agents’ for managing these conditions and it has a licence for use in pregnancy. Labetalol is between three and seven times more potent for beta blockade than alpha blockade. Blood pressure is lowered through beta adrenoceptor blockade preventing reflex sympathetic stimulation of heart rate and cardiac output, and reducing renal renin secretion, and alpha blockade causing decreased peripheral vascular resistance and therefore vasodilation. Labetalol has extensive first-pass hepatic metabolism and demonstrates increased bioavailability when taken with food. Peak plasma concentrations usually occur 2 hours after oral ingestion and maximal blood pressure lowering effect is noted 1 to 4 hours post ingestion. It has a short half-life (4 to 6 hours), requiring dosing to be split to two to three times per day, which can contribute to difficulties with adherence. A study that examined the impact of gestation on the pharmacokinetics of labetalol found a significant increase in the oral clearance rate across gestation and when compared with the oral clearance rate outside pregnancy, which might explain the findings of a recent mechanistic study that showed that pregnant women prescribed labetalol, compared with nifedipine, had greater variation in blood pressure over 24 hours.14,15 Possible adverse effects include lethargy, weakness and somnolence, and it is relatively contraindicated in women with asthma as it can cause bronchospasm.Labetalol is the only antihypertensive agent that holds a Medicines and Healthcare Regulatory Agency licence for use in pregnancy, but this is primarily a reflection of the difficulties and apathy surrounding licensing drugs for use in pregnancy. In spite of this, the manufacturers of labetalol advise avoidance in the first trimester, which is not relevant for prescription in women with gestational hypertension or pre-eclampsia and may not be feasible for women with chronic hypertension in whom other agents may be preferred anyway; however, the fetal risks of labetalol appear to be low.2

Information for patients

High blood pressure in pregnancy can cause complications for mother and baby. Labetalol is a blood pressure medication that is recommended for use in pregnancy as it has been shown to work well to lower blood pressure and it has a licence for use in pregnancy. Other blood pressure treatments that are commonly used in pregnancy include methyldopa and nifedipine. It is important to discuss the benefits and risks of these different blood pressure treatments with your doctors.

A Cochrane review of oral beta blockers for mild to moderate hypertension in pregnancy found an increased risk of small-for-gestational age infants (RR 1.36, 95% CI 1.02 to 1.82; 12 trials, 1346 women), but raised concerns that this finding related to one small (29 women) outlying trial that compared atenolol (including doses above those currently recommended; 150 to 200 mg) with placebo.16 The Cochrane review authors stated that ‘beta blockers appear to be no more effective (than methyldopa) and probably equally as safe’.17 There are no convincing data from adequately powered randomised controlled trials to suggest that labetalol use is associated with fetal growth restriction, given the independent association of hypertension with this risk. Two trials (including 158 women) have investigated the effectiveness of labetalol versus placebo for the treatment of gestational hypertension alone in pregnancy.18,19 One of the studies demonstrated a reduction in the risk of severe hypertension with labetalol compared with placebo (RR 0.35, 95% CI 0.14 to 0.92)19 and the other found a reduction in the mean antenatal stay in women randomised to labetalol rather than placebo.18 There is only one trial (200 women) that has compared labetalol with no antihypertensive treatment for non-severe hypertension in pre-eclampsia20 and this demonstrated a 0.36 risk reduction (95% CI 0.14 to 0.97) in severe hypertension with the use of labetalol.

Evidence for labetalol for chronic hypertension in pregnancy

Treatment of chronic hypertension, particularly in the first trimester, has an even more sparse evidence base. A recent meta-analysis highlighted the paucity of data from randomised controlled trials to guide the prescription of antihypertensive agents for the treatment of chronic hypertension in pregnancy, identifying only 15 studies including 1166 women for the analysis. This meta-analysis did, however, demonstrate a reduction in the incidence of severe hypertension with antihypertensive treatment compared with non-active treatment (RR 0.33, 95% CI 0.19 to 0.56; five studies, 446 women) with no difference in adverse perinatal outcomes found between active and non-active treatment.21 None of these trials addressed the impact severe hypertension might have on long-term maternal cardiovascular morbidity. It is important to note that the randomised controlled trials informing the NICE guidance are over 20 years old and clinical and research practices have seen substantial change during this time.

What are the alternative antihypertensive treatment options for hypertension in pregnancy?

The NICE 2010 guideline lists methyldopa and nifedipine as alternative antihypertensive agents for the treatment of hypertensive disorders of pregnancy.2 A Cochrane review included a meta-analysis of data from randomised controlled trials to assess the effects of antihypertensive treatments for women with mild to moderate hypertension (up to 169/109 mm Hg) during pregnancy. They compared classes of antihypertensive agents with each other and found that alternative drugs (including beta blockers and calcium channel blockers) were better than methyldopa for reducing the risk of severe hypertension (11 trials, 638 women; RR 0.54, 95% CI 0.30 to 0.95), but these effects were not evident when individual agents were compared. A systematic review and meta-analysis of antihypertensive agents for the treatment of chronic hypertension in pregnancy identified only one randomised controlled trial (263 women) that compared labetalol with methyldopa and placebo, and no trials that compared labetalol (or methyldopa) with nifedipine; no significant differences in maternal or perinatal outcome with the use of one antihypertensive agent versus another were demonstrated.21 More recently, a secondary analysis of the CHIPS trial found a reduction in adverse perinatal and maternal outcomes with prescription of methyldopa compared with labetalol, but participants were not randomised to antihypertensive medication and the authors conceded that these findings might be subject to residual confounding.22 These analyses highlight the need for further randomised controlled trials comparing the most common antihypertensive agents for the treatment of hypertension in pregnancy.

Methyldopa

The antihypertensive effect of methyldopa is mediated by an accumulation of methylated catecholamine analogues in vasoactive centres of the central nervous system, which interferes with the effect and synthesis of noradrenaline and other active catecholamines. The medium and long-term safety of methyldopa has been assessed in randomised controlled trials, with 7-year follow-up of offspring in a small trial showing no apparent adverse effects.23,24However, in the postnatal period, NICE recommends cessation immediately following delivery due to the risk of depression.2 Depression and somnolence are potential issues for use during pregnancy which could limit the utility of this agent, particularly for longer-term use in chronic hypertension, as opposed to treatment for a few weeks in the late third trimester. It is important to note that a Cochrane review of the treatment of mild to moderate hypertension in pregnancy reports the potential for reporting/detection bias, when comparing whether beta blockers or methyldopa are better tolerated (RR 0.69, 95% CI 0.52 to 0.91), as the five trials (352 women) reporting adverse effects are all open label, and trials which report drug stoppage due to adverse effects do not show a difference.25

Nifedipine

Nifedipine is a dihydropyridine subtype of calcium-channel blocker (calcium antagonist). It primarily acts to prevent calcium ions entering at the L-type calcium channels in cardiac muscle and blood vessels; a decrease in cellular calcium results in less contraction of the vascular smooth muscle and therefore vasodilation. Adverse effects commonly experienced include headache, oedema, flushing and fatigue. Animal data have suggested teratogenic risk in normotensive models using supratherapeutic doses, but this increased risk has not been observed in human pregnancy. Nifedipine is widely prescribed by obstetricians throughout pregnancy for hypertensive women, particularly in women with chronic hypertension managed on a calcium-channel blocker prior to pregnancy or those who have asthma. The European Network of Teratology Information Services has been used to compare the incidence of major birth defects between a cohort of pregnant women exposed to calcium channel blockers during the first trimester (n=299) and a control group not exposed to potential teratogens (n=806); it demonstrated that major birth defects were no more common in the study group than the control group.26 It has been suggested that since nifedipine is off-patent, it is not in the financial interest of pharmaceutical companies to pursue an additional licence for this indication (which also applies to methyldopa).

Other considerations in the management of hypertension in pregnancy

The importance of prepregnancy counselling and postnatal hypertensive management should not be underestimated. Routine prepregnancy counselling for all women with pre-existing hypertension is recommended by serial reports from MBRRACE-UK (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK).27 Discussion regarding potential change in antihypertensive treatment to agents that are safe in pregnancy and optimisation of blood pressure control are recommended. General health advice including discussion of potential lifestyle and dietary changes that may benefit pregnancy outcome are also advised; these preventative measures should also be discussed at the 6-week postnatal review in women who have experienced hypertensive disorders in pregnancy given their association with long-term cardiovascular morbidity and mortality.28The NICE Hypertension in Pregnancy guideline discusses alternatives to labetalol given the possibility of reduced effectiveness of labetalol in women of African or Caribbean family origin who demonstrate limited therapeutic response to beta blockers in and outside pregnancy.29,30 In non-pregnant women of African/Caribbean family origin, calcium-channel blockers are recommended as first-line antihypertensive treatment3; the impact of ethnicity on the efficacy of antihypertensive treatment in pregnancy warrants further investigation.

Summary

Labetalol is recommended as first-line antihypertensive agent by NICE for gestational hypertension and pre-eclampsia. However, this recommendation is based on limited evidence from randomised controlled trials demonstrating that it is as effective and safe as other antihypertensive agents for managing these conditions and it has a licence for use in pregnancy. NICE does not specify a single agent as first-line treatment for women with chronic hypertension in pregnancy but lists labetalol, methyldopa and nifedipine as options and suggests treatment selection should be based on current antihypertensive prescription, adverse effect profiles and with consideration of potential teratogenicity.

References

Footnotes

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.