SYSTEMATIC REVIEW Year : 2022  |  Volume : 8  |  Issue : 3  |  Page : 144-151

Effect of labetalol for treating patients with pregnancy-induced hypertension: A systematic review

Punyatoya Bej1, Sambhunath Das2
1 Associate Professor, Department of Community Medicine, Rama Medical College and Research Centre, Hapur, Uttar Pradesh, India
2 Professor, Department of Cardiac Anaesthesia, All India Institute of Medical Sciences, New Delhi, India

Date of Submission28-Oct-2022Date of Decision24-Nov-2022Date of Acceptance27-Nov-2022Date of Web Publication20-Dec-2022

Correspondence Address:
Punyatoya Bej
Associate Professor, Department of Community Medicine, Rama Medical College and Research Centre, Hapur, Uttar Pradesh
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/jpcs.jpcs_69_22

Pregnancy-induced hypertension (PIH) is one of the main causes of maternal mortality. Many first- and second-line drugs are available to treat the condition. Labetalol lowers blood pressure by blocking both α and β adrenergic receptors. It preserves uteroplacental blood flow efficiently. A systemic review was carried out to find the efficacy and safety of labetalol in the treatment of PIH. Three thousand twenty-six studies were retrieved in 20 years. Finally, 28 studies were selected after applying the review criteria. Twenty-three studies detected that labetalol had superior or similar action compared to other drugs in controlling hypertension in patients with preeclampsia and eclampsia. The systematic review concluded that labetalol is a safe, effective, first-choice of drug with few side effects in treating PIH.

Keywords: Eclampsia, fetal outcome, labetalol, maternal outcome, nifedipine, preeclampsia, pregnancy-induced hypertension

How to cite this article:
Bej P, Das S. Effect of labetalol for treating patients with pregnancy-induced hypertension: A systematic review. J Pract Cardiovasc Sci 2022;8:144-51
How to cite this URL:
Bej P, Das S. Effect of labetalol for treating patients with pregnancy-induced hypertension: A systematic review. J Pract Cardiovasc Sci [serial online] 2022 [cited 2022 Dec 22];8:144-51. Available from: https://www.j-pcs.org/text.asp?2022/8/3/144/364550   Introduction 

Pregnancy-induced hypertension (PIH) is one of the main reasons for maternal morbidity and mortality in pregnancy. Many patients are admitted in an emergency. Treatment of PIH disorders such as preeclampsia and eclampsia is a challenging task.[1],[2] Proper treatment is essential to choose the best antihypertensive agent.

Many first and second-line drugs are available. Labetalol is one of them. Labetalol reduces blood pressure (BP) by blocking α and β adrenergic receptors. It can better preserve uteroplacental circulation as compared to other β blockers.[1] The onset of action is faster in labetalol compared to methyldopa.[1] PIH drug treatment should be titrated to prevent sudden drop in BP and the drug should not have any adverse effect on the fetus.[3],[4]

A literature search in peer-reviewed journals found a small number of systematic reviews and meta-analysis related to the use of labetalol in PIH. The present systematic review was planned to detect the effect of labetalol compared to all other antihypertensive drugs used in clinical practice to treat PIH in patients with preeclampsia and eclampsia for more than 20 years; and which antihypertensive drug is safer with ease of administration.

  Methodology 

Research question

The systematic review was planned to detect the effect of labetalol in comparison to other antihypertensive drugs in reducing PIH in preeclampsia and eclampsia patients which antihypertensive medication is safer with ease of administering.

Research protocol

We searched for original articles detecting the efficacy of labetalol in PIH patients. Studies of comparison between labetalol and hydralazine, methyldopa, nifedipine, and any other antihypertensive drugs were included in the review. Original full-text articles were retrieved. Articles of review, systemic review, meta-analysis, case reports, and editorial and qualitative studies were excluded.

Literature search

The literature search on the effect of labetalol on preeclampsia and eclampsia was conducted from PubMed and Google Scholar databases over the last 20 years. The literature search was conducted by two independent reviewers. The keywords used for the literature search were labetalol, PIH, original studies, and clinical trials. Articles with other antihypertensive drugs that were compared with labetalol for PIH were considered. The maternal, fetal, and renal outcomes and other side effects were studied. The effects on BP control with these drugs also were compared. The systematic review methodology according to the recommendations for systematic review and meta-analyses (PRISMA) guideline is mentioned in [Figure 1].

Data interpretation

The efficacy and safety of labetalol were assessed and represented in tabular form. The number of articles showing labetalol as the first choice or superior among studies was noted. Studies showing similar or inferior results or results between labetalol and others were also highlighted. The final clinical utility of labetalol for controlling PIH was derived.

  Results 

A total of 28 full-text articles were finalized for systemic review. The articles were mentioned in tabular form with the respective findings [Table 1].

From 28 studies, 11 (39.2%) studies reported that labetalol was the best and first-line drug for the treatment of preeclampsia and eclampsia as compared to nifedipine, hydralazine, methyldopa, and magnesium sulfate. In 3 (10.7%) studies, it is depicted that the efficacy of hydralazine and labetalol was similar to control the acute rise in BP.[6],[27] In 7 (25%) studies, nifedipine and labetalol were proven to be similarly effective in reducing BP in preeclampsia and eclampsia patients. Labetalol and methyldopa were comparable in lowering BP among preeclampsia and eclampsia patients in two studies. Hence, in 12 studies, labetalol had a similar effect compared to others. In total labetalol was an effective drug to treat PIH in 23 (82.1%) studies out of 28. Labetalol was proved inferior in 5 (17.8%) articles (3 studies to oral nifedipine, 1 study to methyldopa, and 1 study to nicardipine) [Figure 2].

Figure 2: Efficacy of labetalol in treating hypertension during PIH. PIH: Pregnancy-induced hypertension.

Click here to view

Labetalol was beneficial in patients with reflex tachycardia, myocardial infarction, and renal diseases associated with PIH. Side effect such as fetal bradycardia was observed with labetalol in one study.[33] Labetalol was contraindicated in severe asthma patients.

  Discussion 

Some women develop high BP during pregnancy only, which returns to normal after the birth of the baby.[2] This is called PIH or gestational hypertension (HTN). PIH may be associated with preeclampsia and eclampsia. Eclampsia manifests with HTN, proteinuria, visual disturbance, convulsion, preterm delivery, high incidence of intrauterine death, and maternal multi-organ failure.[2]

A group of medications is available for the treatment of PIH during preeclampsia and eclampsia.[1] The effectiveness and safety profile of the drugs need to be evaluated for proper clinical use in PIH. Rapid control of PIH is the prime importance for the survival of the mother and fetus.[34] The first-line antihypertensive drug must be chosen for the rapid control of high BP in preeclampsia and eclampsia cases. The oral dose of labetalol is 100 mg two times a day.[35] The intravenous dose of labetalol is 20 mg starting over 2 min. Additional 40 or 80 mg may be supplemented every 10 min as per the need up to a maximum of 300 mg.[35] Labetalol also can be started at 1–2 mg/min intravenously.[2]

This systematic review noticed that 23 (82.1%) out of 28 studies were in favor of labetalol as the first choice of drug to control PIH. Labetalol was better compared to all other drugs. Eleven studies had detected superior and 12 articles proved similar efficacy and safety between labetalol and other drugs like hydralazine, nifedipine, and methyldopa. Labetalol use was safe for the baby and mother.[36] Labetalol did not cause miscarriage. It can also better preserve uteroplacental circulation in comparison to the rest of the beta blockers. It acts faster compared to methyldopa. In a randomized control clinical trial, Molvi et al. compared labetalol with either methyldopa or nifedipine; have proved labetalol to be safe during pregnancy.[36] Few studies depicted that aspirin can be used in preeclampsia and eclampsia patients to prevent thrombosis.[37]

Labetalol has some side effects and limitations which were observed during the studies and have to be in consideration. Labetalol is contraindicated in asthmatic patients, atrioventricular block (2nd and 3rd degree), and in uncontrolled heart failure with bradycardia.[33] A few side effects are blurred vision, sweating, difficulty in breathing, dizziness, lightheadedness when rising from lying down or sitting posture, dyspnea, swelling of limbs, chest rigidity, and wheezing. Labetalol can mask the early warning symptoms of hypoglycemia, like tremors and tachycardia. Therefore, patients taking insulin and oral hypoglycemic drugs may need to increase the dose to prevent accidental hypoglycemia. Labetalol may produce liver toxicity. It is imperative to recognize this side effect of hemolysis, elevated liver enzymes, and low platelet count syndrome.[38] The liver function derangement due to labetalol gradually subsides after discontinuation of treatment.[39]

The prompt and effective control of PIH will reduce the development of congestive heart failure, acute myocardial ischemia, intracranial hemorrhage, stroke, and renal injury. A recent guideline by the American College of Obstetrics and Gynecology has published recommendations for preeclampsia and eclampsia patients with PIH.[40] A systolic BP of ≥160 mmHg and diastolic BP of ≥110 mmHg should be diagnosed with PIH. It recommends aspirin in a dose of 81 mg/day from 16 weeks of gestation to the delivery of newborn. The recommended drugs for the control of HTN are labetalol, hydralazine, and oral nifedipine. Magnesium sulfate should be started with the development of convulsions in eclampsia and preeclampsia. Nonsteroidal anti-inflammatory drugs should be advised as analgesics rather than opioids to avoid respiratory depression. Anti-hypertensive drug treatment should be started as soon as possible once PIH, preeclampsia, eclampsia, and convulsion are observed in a patient. Delivery is recommended when gestational HTN, preeclampsia, and maternal adverse events are diagnosed at or after 34 weeks.

An Internet search found 5 systematic reviews and meta-analyses on the antihypertensive treatment for PIH.[41],[42],[43],[44],[45] The outcome is in favor of nifedipine, labetalol, and hydralazine for effective control of BP. Two meta-analyses showed, nifedipine as the first line of antihypertensive agent.[43],[44] One meta-analysis detected, labetalol reduced proteinuria and fetal as well as neonatal death.[41] One meta-analysis found hydralazine treatment had more tachycardia, and higher maternal and fetal morbidity.[42] Ketanserin, diazoxide, and dihydralazine had more adverse effects and were unsafe for use.[43],[46] A Cochrane review by Duley et al. observed that the antihypertensive therapy for PIH was based on the clinician's experience with the drug and the availability at the hospital.[46] Labetalol, hydralazine, and nifedipine were commonly used drugs for the control of HTN. Nimodipine and magnesium were used in patients of PIH with associated convulsions.[46]

Despite these side effects, labetalol proved to be more effective for the successful control of HTN due to PIH. The benefits outweigh the minor risks. Labetalol is safe to be used for the mother, fetus, and newborn with negligible adverse outcomes. The systemic review recommends that labetalol may be the preferred and first-line drug of choice compared with nifedipine, methyldopa, hydralazine, nicardipine, and magnesium in the management of PIH.

Limitations

Data from all types of prospective studies were included with a heterogeneous design of studies in the present systemic review. All the patients had not adopted the intention to treat principle. The randomized controlled trial were both open and double-blinded studies. Despite the limitations, the study included a large number of studies over 20 years to derive an evidence based practice.

  Conclusion 

Labetalol is a more effective and safe drug in controlling HTN among preeclampsia and eclampsia patients. It has a faster onset of action both in oral and intravenous routes as compared to other available drugs. The prevalence of side effects with labetalol is less. Hence, labetalol may be chosen as the first choice drug in managing PIH in clinical practice.

Ethics clearance

Not applicable.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

  References 
1.Odigboegwu O, Pan LJ, Chatterjee P. Use of antihypertensive drugs during preeclampsia. Front Cardiovasc Med 2018;5:50.  
    2.Lain KY, Roberts JM. Contemporary concepts of the pathogenesis and management of preeclampsia. JAMA 2002;287:3183-6.  
    3.Orbach H, Matok I, Gorodischer R, Sheiner E, Daniel S, Wiznitzer A, et al. Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes. Am J Obstet Gynecol 2013;208:6.e1-6.  
    4.Shekhar S, Gupta N, Kirubakaran R, Pareek P. Oral nifedipine versus intravenous labetalol for severe hypertension during pregnancy: A systematic review and meta-analysis. BJOG 2016;123:40-7.  
    5.Elatrous S, Nouira S, Ouanes Besbes L, Marghli S, Boussarssar M, Sakkouhi M, et al. Short-term treatment of severe hypertension of pregnancy: Prospective comparison of nicardipine and labetalol. Intensive Care Med 2002;28:1281-6.  
    6.Vigil-De Gracia P, Lasso M, Ruiz E, Vega-Malek JC, de Mena FT, López JC, et al. Severe hypertension in pregnancy: Hydralazine or labetalol. A randomized clinical trial. Eur J Obstet Gynecol Reprod Biol 2006;128:157-62.  
    7.Dhali B, Bhattacharya S, Ganguly RP, Bandyopadhyay S, Mondal M, Dutta M. A randomized trial of intravenous labetalol & oral nifedipine in severe pregnancy induced hypertension. Int J Reprod Contracept Obstet Gynecol 2012;1:42-7.  
    8.Raheem IA, Saaid R, Omar SZ, Tan PC. Oral nifedipine versus intravenous labetalol for acute blood pressure control in hypertensive emergencies of pregnancy: A randomised trial. BJOG 2012;119:78-85.  
    9.Subhedar V, Inamdar S, Hariharan C, Subhedar S. Comparison of efficacy of labetalol and methyldopa in patients with pregnancy-induced hypertension. Int J Reprod Contracept Obstet Gynecol 2013;2:27-34.  
    10.Shekhar S, Sharma C, Thakur S, Verma S. Oral nifedipine or intravenous labetalol for hypertensive emergency in pregnancy: A randomized controlled trial. Obstet Gynecol 2013;122:1057-63.  
    11.Kavitha C. Comparison of Efficacy of tablet labetalol and tablet Nifedipine and its Fetomaternal outcome in mild preeclampsia. Med Biol Diss 2014. p. 1-107. Available from: http://repository-tnmgrmu.ac.in/4050/1/220600514christinamarykavitha.pdf.  
    12.Qasim A, Siddiqui MH, Salam JU, Nusrat U. Labetalol versus methyldopa: Efficacy in pregnancy induced hypertension. Gomal J Med Sci 2014;12:233-6.  
    13.Stott D, Bolten M, Paraschiv D, Papastefanou I, Chambers JB, Kametas NA. Maternal ethnicity and its impact on the haemodynamic and blood pressure response to labetalol for the treatment of antenatal hypertension. Open Heart 2016;3:e000351.  
    14.Magee LA, CHIPS Study Group, von Dadelszen P, Singer J, Lee T, Rey E, et al. Do labetalol and methyldopa have different effects on pregnancy outcome? Analysis of data from the Control of Hypertension In Pregnancy Study (CHIPS) trial. BJOG 2016;123:1143-51.  
    15.Babbar K, Armo M, Bhanja RL. A comparative study of efficacy of antihypertensive drugs and feto-maternal outcome in the treatment of pregnancy induced hypertension. Int J Reprod Contracept Obstet Gynecol 2015;4:1846-53.  
    16.Shi DD, Yang FZ, Zhou L, Wang N. Oral nifedipine versus. Intravenous labetalol for treatment of pregnancy-induced severe pre-eclampsia. J Clin Pharm Ther 2016;41:657-61.  
    17.Thakur V, Thakur A, Saroshe S. Comparison of effect of nifedipine, labetalol and methyldopa in treatment of hypertension in pregnancy in a tertiary care government hospital. Int J Reprod Contracept Obstet Gynecol 2016;5:1-7.  
    18.Webster LM, Myers JE, Nelson-Piercy C, Harding K, Cruickshank JK, Watt-Coote I, et al. Labetalol versus nifedipine as antihypertensive treatment for chronic hypertension in pregnancy: A randomized controlled trial. Hypertension 2017;70:915-22.  
    19.Duro-Gómez J, Rodríguez-Marín AB, Giménez de Azcárete M, Duro-Gómez L, Hernández-Angeles C, Arjona-Berral JE, et al. A trial of oral nifedipine and oral labetalol in preeclampsia hypertensive emergency treatment. J Obstet Gynaecol 2017;37:864-6.  
    20.Pentareddy MR, Shailendra D, Prasuna G, Subbaratnam Y, Naresh D, Katta R. Safety and efficacy of methyldopa and labetalol in controlling blood pressure in hypertensive disorders of pregnancy. Int J Basic Clinic Pharmacol 2017;6:942-7.  
    21.Tariq S, Shahid A, Yousof TA. Comparison of maternal hypotension after administration of labetalol versus hydralazine in treating patients having severe pregnancy induced hypertension. Pak J Med Health Sci 2017;11:541-3.  
    22.Khan A, Hafeez S, Nasrullah FD. Comparison of hydralazine and labetalol to lower severe hypertension in pregnancy. Pak J Med Sci 2017;33:466-70.  
    23.Akhtar N, Hayat Z, Nazim F. Comparison between labetalol and methyldopa in the treatment of pre-eclampsia. J Postgrad Med Inst 2018;32:35-9.  
    24.Zulfeen M, Tatapudi R, Sowjanya R. IV labetalol and oral nifedipine in acute control of severe hypertension in pregnancy-A randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2019;236:46-52.  
    25.Gurjar BG, Malewar SS. Study of labetalol versus. Methyldopa in treatment of pregnancy induced hypertension. Int J Reprod Contracept Obstet Gynecol 2019;8:2378-83.  
    26.Easterling T, Mundle S, Bracken H, Parvekar S, Mool S, Magee LA, et al. Oral antihypertensive regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in pregnancy: An open-label, randomised controlled trial. Lancet 2019;394:1011-21.  
    27.Gaur N, Kathuria P. Hydralazine versus labetalol for acute control of blood pressure in patients with severe pre-eclampsia: A randomized controlled trial. Int J Reprod Contracept Obstet Gynecol 2019;8:1626-9.  
    28.Wang Y, Bao J, Peng M. Effect of magnesium sulfate combined with labetalol on serum sFlt-1/PlGF ratio in patients with early-onset severe pre-eclampsia. Exp Ther Med 2020;20:276.  
    29.Nivethana KB, Priya S, Karunanithi K. A comparative study of IV labetalol with oral nifedipine in severe preeclampsia. Int J Clin Obstet Gynaecol 2020;4:388-92.  
    30.Patel AR, Arora SR, Bhatt JK. Comparison of oral nifedipine and oral labetalol as a single drug therapy for control of blood pressure in preeclampsia. Int J Reprod Contracept Obstet Gynecol 2020;9:2328-32.  
    31.Muhammad S, Usman H, Dawha YM, Yahya A, Yekeen A, Bako B. Comparison of intravenous labetalol and hydralazine for severe hypertension in pregnancy in Northeastern Nigeria: A randomized controlled trial. Pregnancy Hypertens 2022;29:1-6.  
    32.Thakur M, Gainder S, Saha SC, Prakash M. To study the changes in maternal hemodynamics with intravenous labetalol or nifedipine in acute severe hypertension. Pregnancy Hypertens 2020;21:180-3.  
    33.Magee LA, Abalos E, von Dadelszen P, Sibai B, Easterling T, Walkinshaw S, et al. How to manage hypertension in pregnancy effectively. Br J Clin Pharmacol 2011;72:394-401.  
    34.American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American college of obstetricians and gynecologists' task force on hypertension in pregnancy. Obstet Gynecol 2013;122:1122-31.  
    35.Zell-Kanter M, Leikin JB. Oral labetalol in hypertensive urgencies. Am J Emerg Med 1991;9:136-8.  
    36.Molvi SN, Mir S, Rana VS, Jabeen F, Malik AR. Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: A prospective randomized study comparing labetalol with alpha methyldopa. Arch Gynecol Obstet 2012;285:1553-62.  
    37.Henderson JT, Vesco KK, Senger CA, Thomas RG, Redmond N. Aspirin use to prevent preeclampsia and related morbidity and mortality: Updated evidence report and systematic review for the US preventive services Task Force. JAMA 2021;326:1192-206.  
    38.Bennett M. Do not forget about HELLP! BMJ Case Rep 2011;2011:bcr082011.4693. page 1-2.  
    39.Clark JA, Zimmerman HJ, Tanner LA. Labetalol hepatotoxicity. Ann Intern Med 1990;113:210-3.  
    40.Gestational Hypertension and Preeclampsia. ACOG Practice Bulletin, Number 222. Obstet Gynecol 2020;135:e237-60.  
    41.Bone JN, Sandhu A, Abalos ED, Khalil A, Singer J, Prasad S, et al. Oral antihypertensives for nonsevere pregnancy hypertension: Systematic review, network meta and trial sequential analyses. Hypertension 2022;79:614-28.  
    42.Antza C, Dimou C, Doundoulakis I, Akrivos E, Stabouli S, Haidich AB, et al. The flipside of hydralazine in pregnancy: A systematic review and meta-analysis. Pregnancy Hypertens 2020;19:177-86.  
    43.Awaludin A, Rahayu C, Daud NA, Zakiyah N. Antihypertensive medications for severe hypertension in pregnancy: A systematic review and meta-analysis. Healthcare (Basel) 2022;10:325.  
    44.Alavifard S, Chase R, Janoudi G, Chaumont A, Lanes A, Walker M, et al. First-line antihypertensive treatment for severe hypertension in pregnancy: A systematic review and network meta-analysis. Pregnancy Hypertens 2019;18:179-87.  
    45.Sridharan K, Sequeira RP. Drugs for treating severe hypertension in pregnancy: A network meta-analysis and trial sequential analysis of randomized clinical trials. Br J Clin Pharmacol 2018;84:1906-16.  
    46.Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev 2013;2013:CD001449.  
    
  [Figure 1], [Figure 2]
 
 
  [Table 1]