Effect of aspirin on small for gestational age neonates in pregnancies at high-risk for preeclampsia: a secondary analysis of a cluster randomised clinical trial.

Background: Data on the effect of 100-160 mg/day aspirin prophylaxis on small for gestational age neonates (SGA) in pregnancies at high-risk for preeclampsia (PE) is limited. We aimed to determine the impact of aspirin administration on the incidence of SGA. Methods: This is a secondary analysis of a multicenter stepped wedge cluster-randomized trial included 18 maternity/diagnostic units across ten Asian regions between 1st August 2019 and 28th February 2022. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At six-week intervals, one cluster was randomized to transition from non-intervention phase to intervention phase. In the intervention phase, women identified as high-risk for preterm-PE received aspirin from <16 weeks until 36 weeks. Primary outcomes of the study were the delivery of an SGA neonate with birthweight <10th, <5th, or <3rd percentile for gestational age, adjusted for maternal weight and height, gravida, parity, ethnicity and newborn sex. The trial was registered with https://www.clinicaltrials.gov (Unique identifier: NCT03941886). Findings: 42,897/48,647 women accepted screening for preterm-PE. 10,294 (26.91%) and 27,965 (73.09%) women were included in the non-intervention and intervention phases, respectively. 2909/4688 (62.05%) high-risk women received aspirin in the trial. Pooling data from the whole trial demonstrated that aspirin was associated with increased rates of early-SGA <10th percentile (Relative risk, RR, 1.37, 95% confidence interval, CI 1.02 to 1.90). In the intervention phase, aspirin was associated with lower rates of SGA neonates with birthweight <3rd, <5th, and <10th percentile, delivered before 32 weeks (early-SGA; RR, 0.39, 95% CI: 0.20 to 0.75, 0.38, 95%CI 0.20 to 0.70, 0.41, 95%CI 0.23 to 0.74 respectively) alongside a concurrent trend indicating an increased rate of late-SGA. Interpretation: Aspirin prophylaxis appears to be associated with a reduction in the rate of early-SGA and a simultaneous increase in the rate of late-SGA neonates born at or after 32 weeks. These findings underscore the importance of implementing the screen-and-prevent program for preterm-PE to reduce early-SGA, and emphasizing the heightened alert in follow-up to optimize the outcomes for late-SGA. Funding: This work was supported by the National Key Research and Development Program of China from the Ministry of Science and Technology of China (MOST 2021YFC2701604) and a start up grant from the Faculty of Medicine, the Chinese University of Hong Kong.