Cell-Free Fetal DNA for the Prediction of Pre-Eclampsia at the First and Second Trimesters: A Systematic Review and Meta-Analysis

Objective: A systematic review and pooled analysis was carried out to estimate whether the increase in the quantity of cell-free fetal DNA (cffDNA) before the onset of pre-eclampsia (PE) can predict the disease using real-time polymerase chain reaction (PCR). Method: A comprehensive literature search of the PubMed, Scopus, and Web of Knowledge databases was conducted to identify relevant studies that included evaluated cffDNA levels in pregnant women before the clinical onset of PE. A simulation model was generated to calculate the detection rate (DR) of cffDNA for PE, and a random variable was generated using the same number of cases and same statistical measurements of central tendency and dispersion as those reported in the papers considered for the analysis. Simulation of the receiver operating characteristic (ROC) curves was also carried out. Results: Four studies (82 cases and 1315 controls) evaluated cffDNA in early-onset PE, with DRs of 18 and 68.8% at 11–13 and 17–28 weeks, respectively, at a false positive rate of 10%. Nine studies (including two considered for early-onset PE) encompassing 376 cases and 1270 controls were available for the evaluation of ‘any PE’. At 11–14 weeks no significant DR was found, while at 15–28 weeks the DR was 37%. Conclusion: CffDNA quantification is a marker for predicting the development of both early-onset PE and ‘any PE’; however, it can probably only be used from the beginning of the second trimester, otherwise its predictive value is burdened with a DR that is too low or not significant. Due to the heterogeneity and difficulty in interpreting the published data, no conclusion regarding the statistical and clinical relevance, especially for screening ‘any PE’, can be made at present.