Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

Preeclampsia and associated hypertensive disorders of pregnancy represent a leading cause of global maternal and neonatal morbidity and mortality. Identification of women at high risk for developing preterm-preeclampsia and prophylaxis with low-dose aspirin has the potential to significantly reduce the rate of preterm-preeclampsia. In addition, risk assessment and monitoring of women in the second and third trimester of pregnancy, to aid in early detection of evolving disease, timely referral to specialist care, and active monitoring of women with confirmed or suspected preeclampsia is essential for improving maternal and neonatal outcomes. The angiogenesis-related biomarkers sFlt-1 and PlGF have been shown to have clinical value to aid in the prediction, diagnosis, and risk stratification of preeclampsia when used either alone or in combination with other risk factors. However, currently there is no consensus on the optimum strategy to link first trimester screening for preterm-preeclampsia with appropriate second and third trimester risk assessment strategies. This opinion paper will outline the current evidence for first trimester preeclampsia screening and prevention, as well as the evidence for various risk stratification approaches for detection of evolving preeclampsia through the second and third trimesters of pregnancy, and proposes a potential model integrating these tools. This article is protected by copyright. All rights reserved.

Introduction: The role of aspirin in the primary or secondary prevention of preeclampsia has beenthe subject of numerous studies and great controversy. Our aim reports on LDA usage rates bywomen with an increased PE risk, as well as on determinants and reasons given for use and non‐use. Material and Method: In this multicenter, double-blind, placebo-controlled trial, the currentstudy randomly assigned 2100 women with singleton pregnancies who were at high risk for pretermpreeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks ofgestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before37 weeks of gestation. The analysis was performed according to the intention-to-treat principle.Results: Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as comparedwith 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval,0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took intoaccount participants who had withdrawn or were lost to follow-up. Conclusion: This randomizedtrial showed that among women with singleton pregnancies who were identified using first-trimesterscreening as being at high risk for preterm preeclampsia, the administration of aspirin at a dose of150 mg per day from 11 to 14 weeks of gestation until 36 weeks of gestation resulted in asignificantly lower incidence of preterm preeclampsia than that with placebo.

Aim To compare the magnitude of fetuses with congenital anomalies, pregnant women identified at high risk for preterm pre-eclampsia (PE) or with preterm PE, and with early fetal growth restriction (FGR) or high risk for FGR at the second trimester assessment at 20 to 24 weeks of gestation. Methods A standardized trimester-specific protocol that included clinical and demographic details, fetal biometry, estimated fetal weight (EFW), fetal abdominal circumference (FAC), mean arterial blood pressure and fetal Doppler studies was used to identify high risk for preterm PE and FGR. The Targeted Imaging for Fetal Anomalies (TIFFA) scan was used to identify congenital anomalies. In addition, 95% confidence intervals of the point estimates were derived, and the p -value was estimated to assess the statistical significance of the difference in proportions. Results Analysis of the data of 4,572 pregnant women screened between 20 and 24 gestation weeks showed a significantly lower prevalence ( p < 0.001) of congenital abnormalities (3.81%) compared to women diagnosed with early PE (2.71%) or with a high risk for PE (4.00%) and women (6.80%) with early FGR or at higher risk for fetal growth restriction with both EFW and FAC < 10th percentile. Conclusion The data on prevalence from Samrakshan show that the second-trimester assessment of pregnant women in India must expand its scope from the TIFFA scan to also focus on screening to identify women at high risk for preterm PE and FGR.

To investigate the impact of aspirin administration on the incidence of preterm birth, according to the type of delivery and gestational age at preterm birth, and to examine the hypothesis that aspirin delays preterm delivery. This was a secondary analysis of a multicenter stepped-wedge cluster randomized trial of a first-trimester screen-and-prevent strategy for preterm pre-eclampsia (PE), which included 18 maternity/diagnostic units in 10 regions across Asia between 1 August 2019 and 28 February 2022. Women deemed to be at high risk for preterm PE according to a Bayes' theorem-based triple test, i.e. those with an adjusted risk for preterm PE of ≥ 1 in 100, received low-dose aspirin from < 16 weeks until 36 weeks' gestation. Outcome measures were the incidence of early preterm birth (24 + 0 to 31 + 6 weeks' gestation) and late preterm birth (32 + 0 to 36 + 6 weeks). The treatment effect of aspirin on the rate of preterm birth, stratified by gestational age at birth, type of delivery and presence of pregnancy complications, was estimated by computing the relative risks (RR) between the aspirin and non-aspirin groups with their 95% CIs. A shift model was designed to evaluate the effect of aspirin on preterm birth, based on the hypothesis that aspirin delays a preterm birth to a more advanced gestational age. In the randomized trial, 42 897/48 647 women accepted screening for preterm PE. Following exclusions, 10 294 and 27 965 women were included in the non-intervention and intervention phases, respectively. Of the 4688 women at high risk for preterm PE, 2909 (62.05%) received aspirin in the trial. Aspirin was associated with a 42% reduction in the risk of early preterm birth (adjusted relative risk (aRR), 0.577 (95% CI, 0.380-0.852)), and there was a significant upward trend in the rate of late preterm birth accordingly (test for trend, P < 0.01). Similar findings were observed for iatrogenic preterm birth and pregnancies with a small-for-gestational-age neonate. Additionally, aspirin was associated with a 60% reduction in the risk of iatrogenic early preterm birth in pregnancies with PE (aRR, 0.398 (95% CI, 0.192-0.788)). However, aspirin did not have a significant effect on iatrogenic late preterm birth in pregnancies with PE. Aspirin significantly delayed early preterm birth, with the effect decreasing by 0.26 (95% credibility interval, -0.40 to -0.05) weeks for each week of advancing gestation. At 24 weeks, aspirin delayed delivery by 3.63 weeks, while at 37 weeks, the delay was only 0.25 weeks. This secondary explanatory analysis found that early administration of aspirin could effectively reduce the risk of early preterm birth in women at high risk for preterm PE. While the reasons for preterm birth are often multifactorial, this study provides greater insight into the relationship between aspirin and different types of preterm birth at different gestational ages. Our findings support the hypothesis that aspirin helps to prevent preterm birth by delaying the timing of delivery, with a greater impact observed for deliveries that would have occurred at an earlier gestational age had aspirin not been administered. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

To investigate the use of low dose aspirin in the reduction of perinatal morbidity and mortality in women with unexplained raised maternal serum alpha-fetoprotein and abnormal uteroplacental Doppler waveform patterns. Prospective randomised controlled trial. A tertiary referral obstetric service. One hundred and sixty-four women referred to our unit with raised maternal serum alpha-fetoprotein and a structurally normal fetus had abnormal uteroplacental Doppler waveform patterns at 24 weeks of gestation. Women were randomly allocated to two groups, receiving either low dose aspirin 75 mg (n = 76) or placebo (n = 88) daily until delivery. Preterm labour, low birthweight, the occurrence of placental abruptions and perinatal mortality. The frequency of severely small for gestational age infants (birthweight < 5th centile) was reduced in the aspirin treated group to 16% compared with 25% in the placebo group (95% CI-21% to 13%). The frequency of delivery before 34 weeks of gestation was 26% in the aspirin group and 42% in the placebo group (95% CI--30% to 1%). The perinatal mortality was 240/1000 in the aspirin group and 320/1000 in the placebo group (95% CI--22% to 6%). None of these reductions was statistically significant. Although the frequency of placental abruptions was similar in the two groups, significantly more babies died from abruption in the aspirin treated group (91% versus 30%, 95% CI 28% to 94%). Low dose aspirin did cause a significant reduction (P = 0.008) in deaths from causes other than placental abruption. This trial revealed a benefit of low dose aspirin therapy in women with raised maternal serum alpha-fetoprotein and abnormal uteroplacental Doppler waveform patterns, but the effect was smaller than expected. Although a reduction in deaths from small preterm babies was observed, there was an increase in the number of deaths following placental abruption without a significant increase in the number of abruptions. We recommend that this should be considered before giving aspirin to these high risk women and that other investigators should specifically look for this effect.

The effect of aspirin on the risk of preeclampsia based on the Fetal Medicine Foundation first-trimester risk.

Aim To determine the impact of a community‐oriented model integrating first‐trimester risk stratification, fetal Doppler and routine antenatal ultrasound on preeclampsia (PE) and perinatal mortality rates in a rural population of central India. Methods The program covered 168 public sector centres providing pregnancy care services to nearly 1500 pregnancies annually. First‐trimester assessments included measurement of mean arterial blood pressure, mean uterine artery pulsatility index, risk stratification for preterm PE, recommending low‐dose aspirin 150 mg for women at high risk for preterm PE, and health education for public sector community health workers, pregnant women and their families. Second and third trimester assessments included fetal biometry, growth, fetal Doppler studies of uterine, umbilical, middle cerebral arteries and estimation of the cerebroplacental ratio, staging and protocol‐based management of fetal growth restriction and individualised clinical management of PE. Results The analysis included 4808 pregnant women screened from September 2019 to May 2025. Childbirth outcomes were available for 4016 (83.5%) women. The first trimester screening protocol ( n = 2933) identified 4.2% ( n = 124) women only at high risk for preterm PE and 10.7% ( n = 313) women at high risk for both preterm PE and fetal growth restriction. PE was reported in 28 (0.7%) of the 4016 women with childbirth outcomes. The perinatal mortality rate was 16.4/1000 childbirths in 2025 compared to 37.0/1000 childbirths in 2016. Health education was provided to all screened pregnant women and healthcare staff of the healthcare centres. Conclusion The community‐oriented model reduced the magnitude of PE and perinatal mortality in this rural community.

Aim To determine the effectiveness of the first trimester Samrakshan protocol for the identification of pregnant women at high risk for preterm pre-eclampsia (PE). Methods Samrakshan uses a protocol that integrates routine first-trimester ultrasound assessment at 11 to 14 gestation weeks with the measurement of mean arterial blood pressure and mean uterine artery pulsatility index assessment to determine a customized risk for preterm PE and fetal growth restriction. Based on the risk assessment, pregnant women are classified as high or low risk. Results The protocol had a high specificity (90.4%, 95% CI: 89.4%, 91.2%) and negative predictive value (98.1%, 95% CI: 97.6%, 99%) for preterm PE. The odds ratio and positive likelihood ratio for preterm PE were 16.7 (95% CI: 12.3, 22.6) and 6.64 (95% CI: 5.77, 7.63), respectively. Conclusions The positive likelihood ratio and odds ratios indicate that pregnant women identified as high risk for preterm PE using the first-trimester protocol of Samrakshan are significantly more likely to develop preterm PE than low-risk women.

To compare maternal haemodynamics in women at low and high risk for preterm pre-eclampsia (PE), and between those at high risk who are randomised to aspirin or placebo. Prospective, longitudinal observational study. Maternity units in six UK hospitals. Women participating in the Aspirin for Prevention of Preterm Pre-eclampsia (ASPRE) trial. The population comprised three groups of women: low risk for preterm PE (n=1362), high risk for preterm PE treated with aspirin (n=208) and high risk for preterm PE on placebo (n=220). Women had four visits during pregnancy: 11-14, 19-24, 30-34, and 35-37weeks' gestation. Blood pressure was measured with a device validated for pregnancy, and PE and maternal haemodynamics were assessed with a bioreactance monitor at each visit. A multilevel linear mixed-effects analysis was performed to examine longitudinal changes of maternal haemodynamic variables, controlling for demographic characteristics, past medical history and medication use. Longitudinal changes of cardiac output (CO), mean arterial pressure (MAP), and peripheral vascular resistance (PVR). The low-risk group demonstrated the expected changes with an increase in CO and reduction in MAP and PVR, with a quadratic change across gestation. In contrast, the high-risk groups had a declining CO, and higher MAP and PVR during pregnancy. The administration of aspirin did not appear to affect maternal haemodynamics. Women screened as high risk for preterm PE have a pathological cardiac adaptation to pregnancy and the prophylactic use of aspirin (150mg oral daily from the first trimester) in this group may not alter this haemodynamic profile. In women at high risk of pre-eclampsia, prophylactic use of aspirin may not alter the impaired maternal cardiac adaptation.

International professional organizations recommend aspirin prophylaxis to women screened high risk for preterm preeclampsia (PE) in the first trimester. The UK Fetal Medicine Foundation (FMF) screening test for preterm PE using mean arterial pressure (MAP), uterine artery pulsatility index (UTPI) and placental growth factor (PlGF) was demonstrated to have lower detection rate (DR) in Asian population studies. Additional biomarkers are therefore needed in Asian women to improve screening DRs as a significant proportion of women with preterm and term PE are currently not identified. To evaluate maternal serum inhibin-A at 11-13 weeks as an alternative to PlGF or as an additional biomarker within the FMF screening test for preterm PE. This is a nested case-control study using pregnancies initially screened at 11-13 weeks for preterm PE using the FMF triple test in a non-intervention study conducted between December 2016 and June 2018. Inhibin-A levels were retrospectively measured in 1,792 singleton pregnancies, 112 (1.7%) with PE matched for time of initial screening with 1,680 unaffected pregnancies. Inhibin-A levels were transformed to multiple of the expected median (MoM). The distribution of log10 inhibin-A MoM in PE and unaffected pregnancies and the association between log10 inhibin-A MoM and gestational age (GA) at delivery in PE were assessed. The screening performance determined by area under receiver operating characteristic curves (AUC) and detection rates (DRs) at a 10% fixed false positive rate (FPR), for preterm and term PE was determined. All risks for preterm and term PE were based on the FMF competing risk model and Bayes theorem. Differences in AUC (ΔAUC) between different biomarker combinations were compared using the Delong test. McNemar's test was used to assess the off-diagonal change in screening performance at a fixed 10% FPR after adding inhibin-A or replacing PlGF in the preterm PE adjusted risk estimation model. Inhibin-A levels in unaffected pregnancies were significantly dependent on GA, maternal age and weight and were lower in parous women with no previous history of PE. Mean log10 inhibin-A MoM in any-onset PE (p<0.001), preterm (p<0.001) and term PE (p = 0.015) pregnancies were all significantly higher than that of unaffected pregnancies. Log10 inhibin-A MoM was inversely but not significantly correlated (p = 0.165) with GA at delivery in PE pregnancies. Replacing PlGF with inhibin-A in the FMF triple test reduced AUC and DR from 0.859 and 64.86% to 0.837 and 54.05%, the ΔAUC was not statistically significant. AUC and DR when adding inhibin-A to the FMF triple test were 0.814, 54.05% and the -0.045 reduction in AUC was statistically significant (p = 0.001). At a fixed 10% FPR, replacing PlGF with inhibin-A identified 1 (2.7%) additional pregnancy but missed 5 (13.5%) pregnancies which subsequently developed preterm PE identified by the FMF triple test. Adding inhibin-A missed 4 (10.8%) pregnancies and did not identify any additional pregnancies with preterm PE. Replacing PlGF by inhibin-A or adding inhibin-A as an additional biomarker in and to the FMF triple screening test for preterm PE does not improve screening performance and will fail to identify pregnancies that are currently identified by the FMF triple test.

Risk assessment for preterm preeclampsia in first trimester: Comparison of three calculation algorithms

Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history

The aim of the present meta-analysis study was to evaluate the efficacy of low-dose aspirin, commenced at ≤16 weeks of gestation, in preventing preterm and term preeclampsia, as well as associated maternal and neonatal adverse events in women at risk of preeclampsia. The Embase, PubMed, Cochrane Central Register of Controlled Trials and the Web of Science databases were searched for relevant random controlled trials (RCTs) published between January 1979 and October 2017. After quality assessment and data extraction, a meta-analysis was performed using RevMan 5.3 software. Outcomes of interest were preeclampsia with subgroups of preterm preeclampsia (delivery at <37 weeks) and term preeclampsia, as well as maternal adverse outcomes, including gestational hypertension, postpartum hemorrhage and preterm birth, and neonatal adverse outcomes, including intrauterine growth retardation (IUGR) or small for gestation age infant (SGA), stillbirth or death, and newborn weight. A total of 10 RCTs involving 3,168 participants were included. The meta-analysis demonstrated that, compared with placebo or no treatment, low-dose aspirin was associated with a significant reduction in the overall risk ratio (RR) of preeclampsia regardless of the time to delivery [RR=0.67; 95% confidence interval (CI)=0.57–0.80]. This was apparent for preterm preeclampsia (RR=0.35; 95% CI=0.13–0.94) but not for term preeclampsia (RR=1.01; 95% CI=0.60–1.70). Except for postpartum hemorrhage, low-dose aspirin also significantly reduced the risk of maternal and neonatal adverse outcomes. In conclusion, low-dose aspirin in women at risk of preeclampsia, commenced at ≤16 weeks of gestation, was associated with a reduced risk of preterm preeclampsia, and of adverse maternal and neonatal outcomes.

Aspirin and the prevention of colorectal neoplasia

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