Aspirin and Preterm Birth Among Pregnant People With Increased Heat Exposure: Secondary Analysis of a Randomized Clinical Trial.

Importance: Scalable interventions are urgently needed to mitigate the adverse effects of heat on pregnancy and newborn health. Objective: To evaluate whether low-dose aspirin modifies the association between heat exposure and preterm birth. Design, Setting, and Participants: This secondary analysis of the Global Network for Women's and Children's Health Research Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) randomized, double-blinded, placebo-controlled clinical trial was conducted from March 2016 to June 2018. Statistical analyses were performed from June 2024 to June 2025. The study settings included the Democratic Republic of Congo, Zambia, Kenya, Guatemala, Pakistan, and Belagavi and Nagpur, India. Participants included nulliparous individuals between 6 and 13 weeks' gestation recruited through local clinics and communities, with delivery at 20 or more weeks' gestation. Exposures: Prenatal care site-specific daily maximum humid heat averaged across gestation and by gestational week, and randomization to aspirin or placebo. Main Outcome and Measure: The main outcome was preterm birth (delivery between 20 and <37 weeks' gestation) with gestational age confirmed by enrollment ultrasonography. Results: Of 11 558 participants (mean [SD] age, 20.9 [3.3] years), 5787 were randomized to receive aspirin and 5771 to receive placebo. Preterm birth occurred among 754 placebo recipients (13.1%) and 668 aspirin recipients (11.6%). In mixed-effects pooled logistic regression, each 1 °C increase in mean daily maximum shaded wet-bulb globe temperature across gestation was associated with a 5% increased odds of preterm birth (adjusted odds ratio, 1.05; 95% CI, 1.01-1.10). In stratified analyses, this increased risk was observed only among placebo recipients (adjusted odds ratio [AOR], 1.07; 95% CI, 1.02-1.13), not among aspirin recipients (AOR, 1.03; 95% CI, 0.97-1.10). In pooled mixed-effects logistic distributed lag models, increased odds of preterm birth were observed 17 to 19 weeks before delivery among individuals whose daily maximum shaded wet-bulb globe temperature exceeded the site-specific 75th percentile compared with the lowest 3 quartiles. This vulnerability was not observed among aspirin recipients. In contrast, the association of heat with perinatal mortality was observed only among those receiving aspirin (AOR, 1.15; 95% CI, 1.05-1.26) and not among those receiving placebo (AOR, 1.03; 95% CI, 0.96-1.11). Conclusions and Relevance: The findings of this secondary analysis of the Global Network ASPIRIN trial suggest that low-dose aspirin initiated early in pregnancy among nulliparous individuals may mitigate the effects of heat exposure on preterm birth. The increasing global prevalence of heat stress warrants testing its efficacy more broadly among pregnant people as well as its safety with respect to perinatal mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02409680.