Periconceptual Progesterone Use and Hypertensive Disorders of Pregnancy: A Population‐Based Cohort Study

ABSTRACT Objective To investigate whether periconceptual use of progesterone is associated with an altered risk of new‐onset hypertensive disorders of pregnancy (gestational hypertension, preeclampsia, or superimposed preeclampsia). Design Population‐based cohort study using statewide pregnancy and birth data from Victoria, Australia, linked with hospital and medication prescribing data. Setting Victoria, Australia (2009–2020). Population Nulliparous women who gave birth between 2009 and 2020 in Victoria, Australia. Women with missing delivery dates, medicine dispensation dates, or who were exposed to progesterone in the second or third trimester were excluded. Methods We compared nulliparous women exposed to progesterone in the periconceptual period (6 weeks preconception until the end of the first trimester) with those not exposed to progesterone. Inverse probability‐weighted regression adjustment was used to control for confounding factors and investigate the effect of progesterone on the risk of preeclampsia (including superimposed preeclampsia) and gestational hypertension. Main Outcome Measures Development of preeclampsia or gestational hypertension. Results Among 386 475 pregnancies, 5657 (1.5%) women used progesterone in the periconceptual period. Progesterone use was associated with a statistically significant reduction in the risk of any new onset hypertensive disorders of pregnancy (adjusted risk ratio [aRR] 0.81 [95% confidence interval [CI] 0.67, 0.98]; adjusted risk difference [aRD] −1.72% [95% CI −3.21%, −0.24%]). Investigating type of hypertension, we found progesterone use was associated with a 1.69% absolute reduced risk of gestational hypertension (aRR 0.60 [95% CI 0.43, 0.83]; aRD −1.69% [95% CI −2.52%, −0.86%]) but no significant change was observed for preeclampsia (aRR 0.97 [95% CI 0.75, 1.25]; aRD −0.13% [95% CI −1.49%, 1.23%]). Restricting our analyses to pregnancies conceived via assisted reproductive technology only, we found similar results, with a statistically significant reduction in the risk of gestational hypertension (aRR 0.80 [95% CI 0.67, 0.95]; aRD −1.02% [95% CI −1.73%, −0.30%]) but not preeclampsia (aRR 0.96 [95% CI 0.83, 1.11]; aRD −0.25% [95% CI −1.23%, 0.72%]). Conclusions Among 386 475 nulliparous women, we found periconceptual progesterone use to be associated with a statistically significant reduction in the risk of gestational hypertension, but not preeclampsia. However, these findings are unlikely to be clinically meaningful.