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.
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 22 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 it is currently offered to 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 first-trimester screening for preeclampsia associated with
aspirin treatment of pregnant women screened at risk. A medical and economic evaluation
allowing a cost-effectiveness analysis will also be carried out. The results of this
study will constitute essential information relevant to the health care system that will
guide policymaking for the prevention of PE in the general population of pregnant women.
The primary objective of the study is to evaluate the impact of first-trimester PE
screening (FTPS) on the incidence of severe perinatal morbidity. The primary outcome will
be severe perinatal morbidity defined by a composite criterion including at least one of
the following: perinatal mortality (stillbirth at or after 20 WG or neonatal death within
7 days of life) or prematurity <34 WG or birth weight <3° percentile for gestational age.
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 economic impact of first-trimester PE screening on costs.
Patients will be recruited in 22 maternity centers at university hospitals in France. The
inclusion period during pregnancy is between 11 WG and 14 WG. Eligible women will be
identified in early pregnancy at their first prenatal visit in the maternity hospital,
before or at the time of the first-trimester ultrasound. 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 screened at risk and
with aspirin prescription 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.