Aspirin Discontinuation at 24 to 28 Weeks’ Gestation in Pregnancies at High Risk of Preterm Preeclampsia

Abstract

ImportanceAspirin 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.ObjectiveTo 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 ParticipantsMulticenter, 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.InterventionsEnrolled 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 MeasuresNoninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%.ResultsAmong 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 RelevanceAspirin 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 RegistrationClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26

Biomarkers and the Risk of Preeclampsia

“…These guidelines arose from systematic reviews and meta-analyses demonstrating a reduction in preeclampsia, preterm birth at less than 37 weeks, and fetal and neonatal deaths for patients in whom low-dose aspirin, 75-100 mg, was initiated between 12 and 16 weeks' gestation. [3][4][5] In this issue of JAMA, Mendoza et al 6 investigated the discontinuation of low-dose aspirin for preeclampsia prophylaxis at 24 to 28 weeks of gestation and the risks of preterm preeclampsia and hemorrhage in a noninferiority trial conducted at 9 hospitals across Spain. The authors identified patients at increased risk of preeclampsia based on first trimester screening for maternal factors, uterine artery pulsatility index (UTPI), mean arterial pressure (MAP), and serum pregnancy-associated plasma protein A (PAPP-A), who were treated with 150 mg/d of low-dose aspirin prior to 16 weeks and had ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) measurements performed between 24 and 28 weeks' gestation.…”

“…Mendoza et al 6 found that early discontinuation of 150-mg aspirin was noninferior to continuation until 36 weeks with regard to their primary outcome: incidence of preterm preeclampsia (1.48% in the aspirin discontinuation group vs 1.73% in the aspirin continuation group). Consistent with their rationale for conducting this trial, they found a higher incidence of minor antepartum hemorrhage in the continuation group (7.61% in the low-dose aspirin discontinuation group vs 12.31% in the low-dose aspirin continuation group; absolute difference, −4.70 [95% CI, −8.53 to −0.87]).…”

“…In the trial by Mendoza et al, 6 the rationale for focusing on preterm preeclampsia requires careful consideration. Although preterm preeclampsia overwhelmingly contributes to adverse fetal, neonatal, and maternal outcomes related to hypertensive disorders of pregnancy, limiting outcomes to preterm preeclampsia minimizes the absolute contributions of all subtypes of preeclampsia to perinatal and maternal outcomes.…”

“…By implementing an individualized approach to low-dose aspirin prophylaxis, Mendoza et al 6 highlight the potential to apply multimodal approaches for risk assessment and management to reduce the burden of major complications of pregnancy. This paradigm is poised to capitalize on ongoing efforts, including several in the US, to identify molecular biomarkers with high sensitivity and predictive value for all types of preeclampsia (not just preterm preeclampsia), as well as for other important complications of pregnancy, such as stillbirth, preterm birth, and fetal growth restriction.…”

“…Given the current reliance on maternal factors in the US for selection of pregnancies for low-dose aspirin prophylaxis, the adoption of the risk assessment paradigm applied in the Mendoza et al study (ie, maternal factors, UTPI, MAP, and PAPP-A for universal first-trimester screening followed by second-trimester reassessment using sFlt-1:PlGF) would represent a marked change in practice accompanied by a substantial increase in cost. Moreover, low-dose aspirin–related bleeding complications may not be relevant to the US population, where accepted guidelines recommend an aspirin dose of 81 mg daily, which some meta-analyses have found to have similar efficacy to the 150-mg dose in prevention of preeclampsia .…”