Maternal cell-free DNA in early pregnancy for preeclampsia screening: a systematic review

To quantify the separation between maternal blood cell-free (cf)DNA markers in preeclampsia and unaffected pregnancies and compare with existing markers. This approach has not been used in previous studies.

Comprehensive systematic literature search of PubMed to identify studies measuring total cfDNA, fetal cf(f)DNA or the fetal fraction (FF) in pregnant women. Included-studies of asymptomatic pregnancies with subsequent preeclampsia (cases) and unaffected pregnancies (controls) tested in the first or second trimester and before the clinical onset of preeclampsia. Excluded-studies not reporting the median or mean, standard deviation, inter-quartile range or range in cases and controls. Information from 26 eligible studies was entered into a meta-analysis to estimate, for each marker, the Mahalanobis distance, a measure of separation between the overlapping distributions in preeclampsia and unaffected pregnancies. This was compared with estimates for mean arterial pressure (MAP), uterine artery Doppler pulsatility index (UtA-PI), pregnancy associated plasma protein (PAPP)-A and placental growth factor (PlGF).

The mean Mahalanobis distance for total cfDNA was 0.44 (95% CI 0.12-0.76), which fell between UtA-PI (0.53) and the absolute value of PAPP-A (- 0.36). For cffDNA the distance was 1.03 (0.37-1.69), which is superior to MAP (0.74), UtA-PI, PlGF (- 0.57) and PAPP-A. The distance for FF was - 0.34 (- 0.56 to - 0.12), similar to PAPP-A.

All three markers have a potential preeclampsia screening role, particularly cffDNA. However, to estimate the screening performance in combination with existing markers further large studies are needed. The current analysis will help in the power calculation for such studies.