Comparative Effectiveness and Safety of Three Oral Antihypertensive Therapies on Maternal and Infant Outcomes in a California Medicaid Population, 2016–2020

PURPOSE: To extend the Chronic Hypertension and Pregnancy (CHAP) trial findings, this study compared labetalol, nifedipine, and methyldopa initiation at or before 23 weeks' gestation in pregnant patients with chronic hypertension, examining effects on a composite effectiveness outcome and on small for gestational age birth (SGA). METHODS: We used California Medicaid claims from deliveries between 2016 and 2020, linked to the California Study of Outcomes in Mothers and Infants (SOMI). The exposure was defined as ≥ 1 paid Medicaid fill for labetalol, extended-release nifedipine, or methyldopa in the first 23 weeks of pregnancy among women who did not use oral antihypertensive therapy in the period starting 90 days prior to last menstrual period (LMP) through LMP. Like CHAP, the composite outcome was preeclampsia with severe features, preterm birth < 35 weeks (PTB), placental abruption, and/or fetal or neonatal death. SGA was modeled as a safety outcome. RESULTS: The analysis included 2281 singleton births: 1496 labetalol initiators, 653 methyldopa initiators, and 132 nifedipine initiators. Composite outcome incidence varied by medication (labetalol: 23%; methyldopa: 19%; nifedipine: 24%). The adjusted risk ratio (aRR) comparing methyldopa versus labetalol was 0.82 (95% CI: 0.68, 1.00); nifedipine versus labetalol was 1.01 (95% CI: 0.72, 1.41); and nifedipine versus methyldopa was 1.22 (95% CI: 0.85, 1.76). For SGA, results were similar (aRR (95% CI): methyldopa vs. labetalol: 0.81 (0.62, 1.05); nifedipine vs. labetalol: 1.07 (0.65, 1.75); nifedipine vs. methyldopa: 1.32 (0.78, 2.24)). CONCLUSIONS: Nifedipine and labetalol were equivalent in effectiveness and safety. Methyldopa was associated with lower risks of adverse outcomes. Potential residual confounding and limited overlap between treatment groups warrant caution in interpretation of our findings. Future research is needed to clarify whether the apparent advantages of methyldopa reflect true therapeutic benefit or underlying biases. There is currently no international consensus on which drug is preferable in treating chronic hypertension in pregnancy. Thus, we aimed to compare labetalol, nifedipine, and methyldopa initiation prior to 23 weeks of pregnancy to treat chronic hypertension in pregnancy. Using California Medicaid data linked with birth and hospital records from women who delivered between 2016 and 2020, we examined risks of preterm birth before 35 weeks, preeclampsia with severe features, placental abruption, fetal or newborn death, and small‐for‐gestational‐age (SGA) birth. We found that all outcomes were similar between nifedipine and labetalol users. Contrastingly, we found that people who started methyldopa had lower risks of these complications than those who started nifedipine or labetalol, largely because of lower risk of preterm birth occurring before 35 weeks. Methyldopa users also had a lower risk of SGA infants. Although these results show methyldopa may offer advantages in preventing these outcomes, differences in patient characteristics, lack of baseline blood pressure data, and potential increased side effects mean the findings should be interpreted cautiously. Further studies with detailed clinical data, such as blood pressure readings, are needed to confirm whether methyldopa truly provides better outcomes during pregnancy.