Oral regimen management of acute hypertension in pregnancy
Authors: Elizabeth R Lemoine, S Ananth Karumanchi
Journal: The Lancet (2019)

Hypertensive disorders of pregnancy are among the leading causes of maternal morbidity and mortality worldwide, and they are directly responsible for approximately 14% of maternal deaths.1Say L Chou D Gemmill A et al.Global causes of maternal death: a WHO systematic analysis.Lancet Glob Health. 2014; 2: e323-e333Summary Full Text Full Text PDF PubMed Scopus (2807) Google Scholar Often, women present in hypertensive urgency, requiring rapid pharmacological intervention to prevent severe complications.2Bernstein PS Martin Jr, JN Barton JR et al.National partnership for maternal safety: consensus bundle on severe hypertension during pregnancy and the postpartum period.Obstet Gynecol. 2017; 130: 347-357Crossref PubMed Scopus (53) Google Scholar The largest burden of disease is found in low-income and middle-income countries (LMICs),1Say L Chou D Gemmill A et al.Global causes of maternal death: a WHO systematic analysis.Lancet Glob Health. 2014; 2: e323-e333Summary Full Text Full Text PDF PubMed Scopus (2807) Google Scholar where poor access to refrigeration, trained health-care professionals, fetal monitoring, and drug options create substantial challenges to the administration of rapid-acting intravenous medications. Oral medications, which are more stable in extreme environments, facilitate treatment of severe hypertension in rural areas, with the added benefit of fewer reactive, labile changes in blood pressure. Although effective oral antihypertensives exist, data from direct comparisons of these medications in the maternal population are scarce, leaving a dearth of evidence on which to build caregiver guidelines.3Duley L Meher S Jones L Drugs for treatment of very high blood pressure during pregnancy.Cochrane Database Syst Rev. 2013; 7CD001449PubMed Google Scholar, 4Sridharan 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: 1906-1916Crossref PubMed Scopus (47) Google Scholar The gold standard for practice and guidelines—the randomised controlled trial (RCT)—is an expensive undertaking that has received little interest by the pharmaceutical industry in the pregnant population because of the risk of teratogenicity and other lifelong, unknown risks to the fetus.5Fisk NM Atun R Market failure and the poverty of new drugs in maternal health.PLoS Med. 2008; 5: e22Crossref PubMed Scopus (87) Google Scholar The financial and risk-assessment hurdles of the RCT are compounded in LMICs by the lack of infrastructure to execute standardised protocols. Therefore, the choice of lifesaving antihypertensives in treatment of maternal severe hypertension is often determined by clinician preference, cost, and local availability.6WHOWHO recommendations: drug treatment for severe hypertension in pregnancy.https://apps.who.int/iris/handle/10665/277234Date: 2018Date accessed: June 4, 2019Google Scholar In The Lancet, Thomas Easterling and colleagues7Easterling T Mundle S Bracken H 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; (published online Aug 1.)http://dx.doi.org/10.1016/S0140-6736(19)31282-6Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar report the first, to our knowledge, RCT directly comparing the three most common oral antihypertensives for the treatment of severe acute hypertension in two public hospitals in Nagpur, India. In an open-label, parallel-group study design, they randomly assigned 894 pregnant women presenting with severe hypertension at a mean gestational age of 36·5–36·7 weeks to receive one of three drugs: nifedipine retard (n=298), labetalol (n=295), or methyldopa (n=301). All three drugs were effective first-line treatments in controlling severe hypertension in the short-term without adverse maternal outcomes, the primary outcome of the study: 249 (84%) women in the nifedipine group, 228 (77%) women in the labetalol group, and 230 (76%) women in the methyldopa group had a systolic blood pressure of 120–150 mm Hg and a diastolic blood pressure of 70–100 mm Hg within 6 h of study drug administration. Although the three oral regimens are all viable first-line options, only nifedipine and labetalol were shown to be effective as single drugs; 56 (19%) women who received methyldopa required an additional antihypertensive drug to reach the target blood pressure. These results are reassuring to maternal caregivers; acutely ill patients can be managed successfully with readily available oral regimens and might not require several drugs if nifedipine and labetalol are used, an elegant and efficient solution in the most resource-scarce settings. The three oral medications also had good safety profiles, with few adverse maternal outcomes across all groups. Only one eclamptic seizure was observed (labetalol group), an incidence that was lower than the hospital's reported incidence of eclampsia (1·7%), and lower than was observed in the treatment group of the Magpie trial,8Altman D Carroli G Duley L et al.Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie trial: a randomised placebo-controlled trial.Lancet. 2002; 359: 1877-1890Summary Full Text Full Text PDF PubMed Scopus (1083) Google Scholar despite the low use of magnesium sulphate (in 105 [12%] women). Notably, although gestational age at delivery was equivalent across all groups, there was a significant increase in the number of neonatal intensive care unit admissions for low or very low birthweight in the nifedipine group, leading to greater resource use. Given that neonates were delivered within an average of 1 day of randomisation, it is unlikely that the short-term use of nifedipine had a significant effect on the low birthweights observed. The difference is more likely attributable to the baseline disease state of the nifedipine group. Unfortunately, limitations of the study by Easterling and colleagues7Easterling T Mundle S Bracken H 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; (published online Aug 1.)http://dx.doi.org/10.1016/S0140-6736(19)31282-6Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar are that the authors did not subclassify the cause of the severe hypertension at randomisation or at delivery, and they did not capture more specific diagnoses in neonates when they were admitted to the intensive care unit. Furthermore, the primary outcome was only assessed for up to 6 h; therefore, the findings might not be broadly generalisable to the real-world need to manage severe hypertension until delivery (on average, about 24 h after randomisation in this population). However, given the difficulty of rigorous protocol assessment without standard research infrastructure, the 6-h study period provides a practical understanding of the short-term oral management of acute hypertension on a relatively aggressive dosing schedule. Despite these limitations, the study is reassuring to providers in LMIC settings that oral regimens are safe and viable options for acute hypertension in this population, and that nifedipine and labetalol might be used successfully as single drugs. The low incidence of eclampsia in this study suggests that a standardised treatment regimen as simple as regular blood pressure monitoring and oral antihypertensives could have a substantial effect on adverse maternal events when escalation of care is not possible in rural settings. Novel interventions for the treatment of hypertensive disorders of pregnancy, particularly pre-eclampsia, are on the horizon.9Lemoine E Thadhani R Affordable preeclampsia therapeutics.Trends Pharmacol Sci. 2019; 40: 85-87Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar Rigorous, multicentre RCTs must be done to demonstrate the efficacy and safety of therapies in LMICs with the greatest burden of disease. SAK reports consulting fees from Roche and Thermo Fisher Scientific, grants from Siemens, and equity interest in Aggamin Pharmaceuticals, outside the area of work commented on here. SAK is also a listed co-inventor on patents related to pre-eclampsia biomarkers that are held by Beth Israel Deaconess Medical Center. ERL declares no competing interests. Oral antihypertensive regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in pregnancy: an open-label, randomised controlled trialAll oral antihypertensives reduced blood pressure to the reference range in most women. As single drugs, nifedipine retard use resulted in a greater frequency of primary outcome attainment than labetalol or methyldopa use. All three oral drugs—methyldopa, nifedipine, and labetalol—are viable initial options for treating severe hypertension in low-resource settings. Full-Text PDF Open Access