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ClinicalTrials.gov ID

NCT05521776

Lead Sponsor

Assistance Publique - Hôpitaux de ParisOTHER

Overall Status

Recruiting

Study Type

Interventional

Phase

Not Applicable

Enrollment

14,500Estimated

Last Update Posted

Mar 27, 2026Actual

Start Date

Mar 6, 2023Actual

Primary Completion Date

Aug 2026Estimated

Completion Date

Feb 2027Estimated

Official Title

Impact of First-trimester Preeclampsia Screening on Perinatal and Maternal Morbidity : a Multicenter Randomized Trial

Brief Summary

The purpose of this study is to determine whether first-trimester screening for preeclampsia based on the FMF algorithm (a combination of maternal clinical, sonographic and biochemical parameters), improves maternal or perinatal health.

Detailed Description

Preeclampsia (PE) complicates 2% of pregnancies and is a leading cause of severe maternal and perinatal complications. There is no curative treatment, and the only recognized beneficial primary prevention is low-dose aspirin. Meta-analyses of randomized trials show that the administration of aspirin, started before 16 weeks of gestation (WG) and at the dosage of 100-160 mg/d in pregnant women at high risk of PE, is associated with a 50% to 60% reduction in the rates of PE, prematurity and perinatal mortality. The group of patients benefiting most from aspirin is pregnant women with a history of PE. That is why all guidelines recommend early preventive administration of aspirin in pregnant women with PE in a previous pregnancy. However, patients with a history of PE represent a small fraction of pregnant women, and PE mostly occurs in women who do not have a history of PE, especially nulliparas. Recently, several national societies decided to broaden the indications for aspirin prevention on the basis of the number of known maternal risk factors. These recommendations lead to a wide use of low-dose aspirin in up to 30% of pregnant women. In order to better target patients at risk of PE among all pregnant women, screening tests have been developed integrating clinical characteristics, uterine Doppler (UD) parameters and biomarkers in a single score. The study by Poon et al. paved the way for early detection of PE. An algorithm based on maternal characteristics, UD parameters and serum levels of PlGF and PAPP-A between 11 and 14 WG yielded detection rates of 93% and 36% for the prediction of early- and late-onset PE, respectively, at 5% false-positive rate (FPR), which were superior to the detection rates of the traditional checklist-based approach, which relies on maternal factors only. This algorithm developed by the Fetal Medicine Foundation (FMF) has since evolved and is now integrated in the combined test for PE screening known as the FMF triple test (a combination of maternal characteristics with mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and serum PlGF). In a subsequent study using a risk cutoff of 1 in 100 for the predicted probability of preterm PE, a screen-positive rate of 10% has been reported, with detection rates for early-onset, preterm, and term PE of 88%, 69%, and 40%, respectively.

Very recently, the ASPRE study evaluated the impact of aspirin in patients identified at high risk of PE on the basis of this FMF test. Screening was offered to 26,941 women and identified 2,641 high-risk patients of whom 1,776 were randomized to aspirin or placebo. This trial showed a reduction in the incidence of PE <37 WG, occurring in 13/798 in the aspirin group versus 35/822 in the placebo group (p=0.004), but with no significant effect on the overall rate of PE and most importantly on perinatal morbidity. Screening had to be applied to almost 27,000 women for a benefit of 23 avoided cases of preterm PE, with no demonstrated effect on the health of the women and children. The ASPRE study is important but does not demonstrate the benefit of routinely implementing PE screening in the general population. Indeed, there is currently no randomized study comparing a group of women to which the screening procedure would be applied to a group of women without screening, the only design able to provide strong evidence of a benefit. In addition, implementing a national screening program in pregnant women may induce adverse events, especially iatrogenicity (more hospitalizations, more ultrasound examinations, more consultations) and anxiety. Such a screening program is also associated with an increase of direct and indirect health costs.

To consider implementing screening for PE in the general population, it is then essential to demonstrate its benefits on robust health outcomes and not only on the PE diagnosis, as well as to assess its potential adverse consequences and costs. This evaluation is all the more crucial since while this screening is not recommended by any national guideline, it is currently offered ton an increasing number of women.

The RANSPRE study will therefore be the first trial to test the impact on perinatal and maternal health outcomes of a screening procedure for preeclampsia in the first trimester of pregnancy associated with aspirin treatment of pregnant women screened at risk. A medical - economic evaluation allowing a cost-effectiveness analysis will also be carried out. The results of this study will constitute essential information relevant to the French health care system that will guide policymaking for the prevention of PE in the general population of pregnant women. If the results shows a benefit, they will provide further strong evidence for the dissemination in routine care of this screening with a demonstrated benefit for health. If they show no benefit or high adverse iatrogenic impact and costs, this will constitute important knowledge that will avoid the spread of a potentially deleterious practice. This project is part of the priority axis "health prevention in the general population" (Primary care).

The primary objective of the study is to evaluate the impact of first-trimester PE screening (FMF triple test) on the incidence of severe perinatal morbidity. The primary outcome is a composite criterion characterizing severe perinatal morbidity including one of the following criteria :

• perinatal mortality : stillbirth ≥ after 20 WG or with birth weight > 500g, or death of a newborn within the first 7 days of life.
• prematurity <34 WG: birth before 34 WG
• birth weight <3° percentile. Secondary objectives are: (i) to evaluate the impact of first-trimester PE screening on: the incidence of preeclampsia, the incidence of components of moderate and severe maternal morbidity, the incidence of components of moderate and severe perinatal morbidity; (ii) to evaluate the impact of first-trimester PE screening on potential adverse events: iatrogenicity, over-medicalization, women's satisfaction and anxiety status; (iii) to evaluate the impact of first-trimester PE screening and costs effectiveness.

Patients will be recruited in 22 maternity centers at university hospitals in France. The inclusion period during pregnancy is between 11 WG and 14. This period is the timeframe when pregnant women are systematically seen in routine care for the first trimester ultrasound and for Down Syndrome screnning. The intervention will be associated to first trimester routine management. Eligible women will be identified early in pregnancy at their first prenatal visit to the maternity hospital. Inclusion in the study will be performed at the time of the first-trimester ultrasound because the measurements of uterine Dopller indices are required for the screening. The FMF algorithm used in the study for PE screening is based on a combination of maternal clinical parameters (medical history, maternal characteristics, pregnancy characteristics, mean arterial pressure), sonographic parameters (uterine Doppler with measurement of mean pulsatility index) and biochemical parameters (PlGF concentration). Women agreeing to participate in the RANSPRE trial will be randomized either to the experimental group with first-trimester screening for PE or to the control group with usual care without screening for PE.

All patients will be asked to complete self-administered questionnaires at 20 (+/2) WG and during the postpartum period (within 30 days after delivery) assessing women's satisfaction and women's anxiety. These questionnaires will be collected for women included until 31/01/2025. A notebook will be given to patients of group A1 to monitor aspirin observance and to record potential side-effects related to aspirin.

An intention-to-treat analysis will be performed as the principal analysis.

• Preeclampsia (PE)

• First-trimester preeclampsia screening (FMF triple test)

Ages Eligible for Study

Adult (18-64)Older Adult (65+)

Sexes Eligible for Study

Female

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion Criteria :

• Pregnancy between 11 and 14 WG
• Age ≥18 years
• Affiliated to or beneficiary of a health insurance system (including AME)
• Signed informed consent

Exclusion Criteria :

• Gestational age <11 WG or >14 WG
• Known ectopic pregnancy
• Known non-ongoing pregnancy
• Known multiple pregnancy
• History of PE in a previous pregnancy
• Pregnancies complicated by major fetal abnormality identified at the first-trimester ultrasound if performed before randomization
• Absence of health insurance
• Contra-indication to aspirin (bleeding disorders such as von Willebrand's disease, active peptic ulceration, hypersensitivity to aspirin, active peptic ulceration, NSAID-exacerbated respiratory disease, severe liver or heart dysfunction)
• Women taking low-dose aspirin regularly and started before pregnancy (except ART indication)
• Age <18 years
• Poor understanding of the French language

Primary Purpose

Screening

Allocation

Randomized

Interventional Model

Parallel Assignment

Masking

None (Open Label)

Lead Sponsor

Assistance Publique - Hôpitaux de ParisOTHER

Collaborators

INSERM, Epopé teamUNKNOWN

URC-CIC Paris Descartes Necker CochinOTHER

louise.ghesquiere@chu-lille.fr

julievirginie.blanc@ap-hm.fr

o.morel@chru-nancy.fr

paul.berveiller@ght-yvelinesnord.fr