Early identification of high-risk pregnancies to develop preeclampsia through non-invasive cell-free DNA methylation profiling

Abstract

Background Aberrant embryo implantation and suboptimal placentation can lead to (severe) complications such as preeclampsia and fetal growth restriction later in pregnancy. Current identification of high-risk pregnancies relies on a combination of risk factors, biomarkers, and ultrasound examinations, a relatively inaccurate approach. Previously, aberrant DNA methylation due to placental hypoxia has been identified as a potential marker of placental insufficiency and, hence, potential (future) pregnancy complications. The goal of the Early Prediction of prEgnancy Complications Testing, or the ExPECT study, is to validate a genome-wide, cell-free DNA (cfDNA) methylation strategy for the accurate diagnosis of preeclampsia. More importantly, the predictive potential of this strategy is also explored to reliably identify high-risk pregnancies early in gestation. Furthermore, a longitudinal study was conducted, including sequential blood samples from women experiencing both uneventful and complicated gestations, to assess the methylation dynamics of cfDNA throughout these pregnancies. A significant strength of this study lies in its genome-wide approach, overcoming the limitations of studies with predefined target genomic regions. Results Investigation of methylation patterns throughout pregnancy showed different methylation trends between unaffected and affected pregnancies. We detected differentially methylated regions (DMRs) in pregnancies complicated with preeclampsia as early as 12 weeks of gestation, with distinct differences in the methylation profile between early and late pregnancy. Two classification models were developed to diagnose and predict preeclampsia, demonstrating promising results on a small set of validation samples. Conclusions This study offers valuable insights into methylation changes at specific genomic regions throughout pregnancy, revealing critical differences between normal and complicated pregnancies. The power of non-invasive cfDNA methylation profiling was successfully proven, suggesting the potential to integrate this non-invasive approach into routine prenatal care.