First Trimester Screening for Late-onset Preeclampsia: Evaluation of Novel Predictive Biomarker MMP-7 in Combination With MAP and Uterine Artery Pulsatility Index in a Danish Population

The aim of this study is to improve the current first-trimester screening regimes for early detection of late-onset preeclampsia (PE) using maternal serum biomarkers in combination with maternal history, uterine artery flow, and mean arterial blood pressure.

Hypothesis: Matrix metalloproteinase 7 (MMP-7) in combination with maternal history, uterine artery flow and mean arterial blood pressure can improve the detection rate of late onset PE.

The Fetal Medicine Foundation (FMF) algorithm is developed with the objective of identifying women at high risk of PE in the first trimester of pregnancy, allowing for effective prophylactic use of low-dose acetylsalicylic acid (ASA) started before 16 weeks of pregnancy. The algorithm utilizes Bayes' theorem by combining maternal characteristics and medical history with uterine artery pulsatility index (PI), mean arterial pressure (MAP), maternal serum pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF) and has been validated in several populations. It has been shown to identify up to 90% of early-onset PE (EO-PE) cases, however, the detection rate of late-onset PE (LO-PE) remains low and the biomarkers PAPP-A and PlGF do not appear to significantly improve performance of screening for these cases compared to screening by maternal characteristics and medical history alone.

An abundance of biomarkers have been suggested and researched for the prediction of LO-PE and of these, matrix metalloproteinase 7 (MMP-7) has shown to be a potentially useful predictor with a sensitivity of 69% at a false positive rate (FPR) 20% at 8-16 weeks of pregnancy. Additionally, MAP appears to be a relatively good predictor for LO-PE at the same gestational age (GA). Ultimately, the search for more accurate biomarkers and prediction models for PE and especially for LO-PE remains relevant and necessary, both with regards to improving antenatal care and taking the necessary precautions for PE mothers, researching potential treatments, and gaining a better understanding of PE pathophysiology altogether.

This study will be a nested case-control study carried out as a sub-study of the larger multicenter study "Preeclampsia Screening in Denmark" (PRESIDE) comprising six major hospitals in Denmark, including Odense University Hospital (OUH). Throughout the time period September 2019 to March 2020, 1400 participants are expected to enroll in PRESIDE through OUH with the goal of validating the FMF screening algorithm in a Danish population. These women will be giving birth from March to June 2020. In our sub-study, the case group will consist of women diagnosed with PE after 34 weeks of gestation. With an expected late-onset PE incidence of 2,5%, the sample size of the case group will be n=35. The control group will include 165 participants who were not diagnosed with PE in their pregnancies.