Cell-Free Fetal DNA for the Prediction of Pre-Eclampsia at the First and Second Trimesters: A Systematic Review and Meta-Analysis
OBJECTIVE The purpose was to determine whether preeclampsia (PE) is caused by microfragments of syncytial trophoblast shed into the maternal circulation that stimulate an exaggerated inflammatory response. STUDY DESIGN A nested case control study was performed within the Calcium for Preeclampsia Prevention trial cohort of healthy nulliparous women. Each preeclampsia case was matched to 1 normotensive control. One hundred twenty pairs were randomly chosen for analysis of serum cell-free fetal DNA (cffDNA), a marker of placental debris, and C-reactive protein (CRP), a marker of inflammation, in all 658 specimens obtained before labor. RESULTS At 29 to 41 weeks of gestation, cffDNA concentrations were significantly higher after preeclampsia than before (219 vs 112 genome equivalents [GE]/mL, P<.001). Before preeclampsia, cffDNA in cases exceeded controls at 17 to 28 weeks (36 vs 16 GE/mL, P<.001), but at 29 to 41 weeks, only within 3 weeks before preeclampsia (176 vs 75 GE/mL, P<.001). CRP serum concentrations were neither associated with cffDNA nor elevated before preeclampsia. CONCLUSION Preeclampsia is accompanied by a 2-stage elevation of fetal DNA, but not by elevation of CRP. Elevated cffDNA at 17 to 28 weeks may be due to placental necrosis and apoptosis. Subsequent elevations may reflect impaired DNA elimination. The 2-stage elevation suggests the possibility of measurement of fetal DNA both to screen for preeclampsia and to indicate impending clinical disease.