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

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ObjectiveTo assess whether aspirin treatment can be discontinued in pregnancies with normal uterine artery pulsatility index (≤90th percentile) at 24–28 weeks.DesignPost‐hoc analysis of a clinical trial.SettingNine maternity hospitals in Spain.Population or SamplePregnant individuals at high risk of pre‐eclampsia at 11–13 weeks and normal uterine artery Doppler at 24–28 weeks.MethodsAll participants received treatment with daily aspirin at a dose of 150 mg. Participants were randomly assigned, in a 1:1 ratio, either to continue aspirin treatment until 36 weeks (control group) or to discontinue aspirin treatment (intervention group), between September 2019 and September 2021. In this secondary analysis, women with a UtAPI >90th percentile at 24–28 weeks were excluded. The non‐inferiority margin was set at a difference of 1.9% for the incidence of preterm pre‐eclampsia.Main outcome measuresIncidence of preterm pre‐eclampsia.ResultsOf the 1611 eligible women, 139 were excluded for UtAPI >90th percentile or if UtAPI was not available. Finally, 804 were included in this post‐hoc analysis. Preterm pre‐eclampsia occurred in three of 409 (0.7%) women in the aspirin discontinuation group and five of 395 (1.3%) women in the continuation group (−0.53; 95% CI −1.91 to 0.85), indicating non‐inferiority of aspirin discontinuation.ConclusionsDiscontinuing aspirin treatment at 24–28 weeks in women with a UtAPI ≤90th percentile was non‐inferior to continuing aspirin treatment until 36 weeks for preventing preterm pre‐eclampsia.

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Background Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term. Objective The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes. Methods This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs. Results Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023. Conclusions The angiogenic factor–based protocol may reduce the number of pregnancies classified as having fetal growth restriction without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities. Trial Registration ClinicalTrials.gov NCT04502823; https://clinicaltrials.gov/ct2/show/NCT04502823 International Registered Report Identifier (IRRID) DERR1-10.2196/37452