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

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SYSTEMATIC REVIEW

Cell-Free Fetal DNA for the Prediction of Pre-Eclampsia at the First and Second Trimesters: A Systematic Review and Meta-Analysis Elena Contro1 • Dalila Bernabini1 • Antonio Farina1

Published online: 12 November 2016 Ó Springer International Publishing Switzerland 2016

Abstract 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 preeclampsia (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

& Antonio Farina [email protected] 1

Division of Obstetrics and Gynecology, Department of Medicine and Surgery (DIMEC), University of Bologna, Bologna, Italy

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.

Key Points This paper reports a pooled analysis of the detection rates (DRs) of all available papers that evaluated cell-free fetal DNA as an early marker of preeclampsia (PE). A comparison among the DRs quoted for both ‘early-onset’ and ‘any’ PE at the first and the second trimesters of pregnancy was carried out. No conclusion regarding statistical and clinical relevance, especially for screening ‘any PE’, could be reached at present.

1 Introduction Pre-eclampsia (PE) is a multisystem pregnancy-associated disorder that complicates 3–8% of pregnancies worldwide and is associated with significant maternal and perinatal morbidity and mortality [1]. PE is classified as early- or late-onset, depending on gestational age (before or after 34 weeks) of clinical onset [2]. The etiopathogenesis of PE is still incompletely understood and is probably