First-trimester Prediction of Preeclampsia
First-trimester Prediction of Preeclampsia
Preeclampsia is a complication of pregnancy related to adverse maternal and neonatal
 outcomes, including fetal growth restriction and perinatal death. Several measures are used
 or under investigation (low-dose aspirin, low-molecular weight heparin, calcium, folic acid,
 among others) for the prevention of preeclampsia. Unfortunately, most high-risk women who
 could benefit from those preventive measures are not identified until late in pregnancy.
 Recent evidences suggest that the investigators could identify women at risk of developing
 preeclampsia using a combination of serum and ultrasound biomarkers in the first-trimester of
 pregnancy. This screening test needs external validation. A first-trimester screening
 strategy will strengthen clinical research on preeclampsia and will contribute to the
 development of strategy combining the prediction and prevention of the disease and its
 related complications.
Background: Preeclampsia (PE) is a placenta-mediated pregnancy complication related to
 adverse maternal and neonatal outcomes, including intra-uterine growth restriction (IUGR) and
 perinatal death. A growing body of evidence suggests that the preterm and severe forms of PE
 are associated with deep placentation disorders that occur early in gestation. Over the last
 decade, maternal characteristic and first-trimester biomarkers, including some that are
 already used for aneuploidy screening (PAPP-A) have been strongly related to the preterm and
 early forms of PE, suggesting that early prediction is possible. Preventive measures are
 actually recommended (low-dose aspirin; calcium) or under investigation (folic acid;
 low-molecular weight heparin; anti-oxidant) in high-risk women. However, only women with
 chronic disease or prior adverse pregnancy outcomes are eligible for these measures while
 most cases of PE occur in nulliparous women. Moreover, there are actually no clear guidelines
 for clinicians in Canada whose pregnant patients have one or several risk factors for
 preeclampsia (obesity, chronic hypertension, low PAPP-A, etc.). On the other hand, it has
 been suggested that prediction of PE, and particularly the most severe cases, is possible
 with high sensitivity and specificity by using a combination of anamnestic, biophysical,
 biochemical and ultrasonographic biomarkers using the web-based Fetal-Medicine Foundation
 (FMF) screening test. This suggests that a strategy of prediction and prevention of PE and
 other placenta-mediated complications is becoming possible for nulliparous women as well.
 However, certain major concerns must be addressed: 1) The FMF screening test has not been
 validated prospectively; 2) a controversy exists about the need and feasibility of Doppler
 ultrasound in the general population.

 Objectives:

 1. To validate the 11-13 week FMF screening test for early-onset PE and a composite of
 placenta-mediated outcomes (preterm PE, IUGR <3rd percentile, stillbirth); and

 2. To compare the screening test with and without uterine artery (UtA) Doppler;

 3. To explore the efficiency of new potential biomarkers (ADAM-12; Placental protein (PP)
 -13; placental and subplacental volume; placental vascularization) for prediction of PE
 in our population.

 Methods: A multicenter prospective observational study of nulliparous women recruited between
 11 3/7 - 13 6/7 weeks (maternal characteristics; BMI; Mean arterial pressure (MAP); PAPP-A;
 placental growth factor (PIGF); UtA Doppler…) and followed until delivery. Delivery and
 neonatal data will be collected through chart reviews. Detection rates for early-onset PE
 (primary outcome) and other adverse pregnancy outcomes will be measured using the 11-13 weeks
 FMF screening test with and without UtA Doppler results. A case-cohort study will be
 performed using stored serum samples and three-dimensional ultrasound volume acquired at the
 11-13 weeks visit.

 Feasibility and power calculation: We estimate a minimum incidence of early-onset PE of 0.7%.
 A minimum of 7,600 women will be necessary to demonstrate that the FMF screening test is at
 least 80% sensitive and 90% specific where it is expected that it will be 95% sensitive and
 92% specific. We will have the power to detect an absolute difference of 15% in the detection
 rate between the different screening strategies (± Doppler). Recruitment will take 3.0 years.
 The overall study will take 5.0 years.

 Expectations: First, our research will potentially provide a validated, highly sensitive and
 specific, and cheap tool to help clinicians' decision in the care of nulliparous women with
 risk factors for PE. In case of negative results, the clinician will have good evidence to
 reassure the patients facing abnormal maternal serum screening values. The validation of a
 first-trimester screening strategy will strengthen clinical research on PE providing new
 information on the natural evolution of the disease. Finally, this study will contribute to
 develop the optimal design for randomized trials aiming at the prevention of early-onset PE
 and other placenta-mediated complications of pregnancy.
Inclusion Criteria:

 -  gestational age between 11 3/7 and 13 6/7 weeks;

 -  nulliparous women (no previous delivery ≥ 20 weeks).

 Exclusion Criteria:

 -  pregnant women <18 years old at recruitment;

 -  multiple pregnancies;

 -  fetal congenital malformation;

 -  positive for HIV or hepatitis C or hepatitis B;

 -  negative fetal heart at recruitment;

 -  women planning a delivery outside the participating hospitals;

 -  women not able to provide an informed consent to the study.