Oral Antihypertensives for Nonsevere Pregnancy Hypertension: Systematic Review, Network Meta- and Trial Sequential Analyses

Abstract

Background: We aimed to address which antihypertensives are superior to placebo/no therapy or another antihypertensive for controlling nonsevere pregnancy hypertension and provide future sample size estimates for definitive evidence.

Methods: Randomized trials of antihypertensives for nonsevere pregnancy hypertension were identified from online electronic databases, to February 28, 2021 (registration URL: https://www.crd.york.ac.uk/PROSPERO/; unique identifier: CRD42020188725). Our outcomes were severe hypertension, proteinuria/preeclampsia, fetal/newborn death, small-for-gestational age infants, preterm birth, and admission to neonatal care. A Bayesian random-effects model generated estimates of direct and indirect treatment comparisons. Trial sequential analysis informed future trials needed.

Results: Of 1246 publications identified, 72 trials were included; 61 (6923 women) were informative. All commonly prescribed antihypertensives (labetalol, other β-blockers, methyldopa, calcium channel blockers, and mixed/multi-drug therapy) versus placebo/no therapy reduced the risk of severe hypertension by 30% to 70%. Labetalol decreased proteinuria/preeclampsia (odds ratio, 0.73 [95% credible interval, 0.54-0.99]) and fetal/newborn death (odds ratio, 0.54 [0.30-0.98]) compared with placebo/no therapy, and proteinuria/preeclampsia compared with methyldopa (odds ratio, 0.66 [0.44-0.99]) and calcium channel blockers (odds ratio, 0.63 [0.41-0.96]). No other differences were identified, but credible intervals were wide. Trial sequential analysis indicated that 2500 to 10 000 women/arm (severe hypertension or safety outcomes) to >15 000/arm (fetal/newborn death) would be required to provide definitive evidence.

Conclusions: In summary, all commonly prescribed antihypertensives in pregnancy reduce the risk of severe hypertension, but labetalol may also decrease proteinuria/preeclampsia and fetal/newborn death. Evidence is lacking for many other safety outcomes. Prohibitive sample sizes are required for definitive evidence. Real-world data are needed to individualize care.

Keywords: blood pressure; morbidity; network meta-analysis; proteinuria; sample size.

Figure 1.

League table comparing primary drugs of interest with placebo/no therapy and with each other. All estimates are odds ratios (OR) and 95% credible intervals. Outcomes are (from top left to bottom right): severe hypertension (A), proteinuria (B), perinatal death (C), small-for-gestational age infants (D), preterm birth (E), and neonatal care unit admission (F). Blue represents an OR >1.0 and orange an OR <1.0, stronger effects are illustrated by darker colors, drugs with more favourable effects are located in columns to the left, and statistically significant results (at P<0.05) are marked by double asterisks.

Figure 2.

Estimated sample size per arm from trial sequential analysis, for future drug-vs-drug to reach 5% statistical significance with 90% power for various risk reductions in severe hypertension. The comparisons are β-blocker vs calcium channel blocker (red), methyldopa vs β-blocker (green), methyldopa vs calcium channel blocker (blue) and methyldopa vs labetalol (purple). The vertical dotted line represents a median severe hypertension rate of 13%.