A comparison of the safety of oral labetalol versus nifedipine to manage hypertension in pregnancy in Australia: a target trial emulation

Background Hypertensive disorders of pregnancy are among the leading causes of maternal and neonatal morbidity and mortality worldwide. Labetalol and nifedipine are two of the most common oral antihypertensives used to manage these conditions; however, it is not clear whether one medication may offer greater benefit to mothers and babies than the other. The aim of this study was to compare the risks of adverse maternal and neonatal outcomes for oral labetalol versus nifedipine among women with hypertension in pregnancy. Methods This was a target trial emulation using linked data, including pregnancy episodes between January 1, 2009 and December 31, 2020 in Victoria, Australia. We included pregnant women with a hypertensive disorder (chronic hypertension, gestational hypertension, or preeclampsia) and prescribed oral labetalol or nifedipine between 11+0- and 36+6- weeks' gestation. Our co-primary outcomes were: 1) a composite of maternal mortality or serious morbidity; and 2) a composite of neonatal mortality or serious morbidity. All outcomes were assessed from first prescription until 28 days postpartum. Analyses used a doubly robust inverse probability-weighted regression adjustment (IPWRA) model and are reported as adjusted risk ratios (aRR) and risk differences (aRD) with 95% confidence intervals (95% CI). Analyses were based on intention-to-treat approach. Findings 7416 pregnancies were eligible for inclusion. Of these, 6745 (91.0%) pregnancies received labetalol as a first-line treatment and 671 (9.0%) received nifedipine. After adjusting for confounding factors, nifedipine was associated with a 33% increased risk of the composite maternal outcome (6.6% versus 9.4%; aRR 1.33, 95% CI 1.07, 1.64), and no difference in the risk of the composite neonatal outcome (43.0% versus 46.1%; aRR 0.97, 95% CI 0.89, 1.06). This was largely driven by increased rates of eclampsia (1.6% versus 3.0%), haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (3.0% versus 4.3%), and renal failure (1.0% versus 1.5%) in the nifedipine group. Among secondary outcomes, nifedipine use was associated with an increased risk of iatrogenic preterm birth and need for additional antihypertensives. Interpretation Among women with hypertension in pregnancy, nifedipine was associated with an increased risk of poor maternal outcomes and iatrogenic preterm birth when compared with labetalol. Labetalol may have a better safety profile as a first-line therapy for pregnant women with hypertension. Future clinical trials are required to validate these findings. Funding This work was supported by a Trevor B Kilvington Bequest, awarded by the University of Melbourne.