Aspirin Discontinuation at 24 to 28 Weeks' Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial

Abstract

Importance: Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy.

Objective: To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia.

Design, setting, and participants: Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants.

Interventions: Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group).

Main outcomes and measures: Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%.

Results: Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, -0.25% [95% CI, -1.86% to 1.36%]), indicating noninferiority.

Conclusions and relevance: Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio.

Trial registration: ClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26.

Figure 1.. Screening, Randomization, and Follow-up in the StopPRE Trial

sFlt-1:PlGF indicates ratio of soluble fms-like tyrosine kinase–1 to placental growth factor; and StopPRE, Detection of False-Positives From First-trimester Preeclampsia Screening at the Second-trimester of Pregnancy. ^aRisk of preterm preeclampsia was assessed by means of a gaussian algorithm that combined maternal factors, mean arterial blood pressure, mean uterine artery pulsatility index, maternal serum pregnancy-associated plasma protein A, and placental growth factor. Women with a risk ≥1/170 were considered at high risk.^,

Figure 2.. Pregnancy Outcomes

Data are number of events (%), relative risk (95% CI), or incidence difference (95% CI). NA indicates not applicable. ^aThe status of being small for gestational age was defined as a birth weight below the 10th percentile according to gestational age at birth by customized charts. ^bNose and/or gum bleeding. ^cHemoptysis and digestive and/or vaginal bleeding.

Figure 3.. Neonatal Outcomes

Data are number of events (%), relative risk (95% CI), or incidence difference (95% CI). ^aBirth weight percentiles were calculated according to gestational age at birth by customized charts.