Cell-free mitochondrial DNA and microRNA-137 for early diagnosis of preeclampsia

Background: Biomarkers for predicting preeclampsia are not routinely available. Currently, preeclampsia is diagnosed with the development of clinical manifestations and proteinuria when widespread endothelial dysfunction and end-organ dysfunction have occurred. Objectives: This study aimed to (1) compare the serial changes in circulating mitochondrial cell-free DNA (ccf-mtDNA) levels between pregnant women who developed preeclampsia and healthy pregnant controls and (2) to determine if circulating microRNAs (miRNAs) previously linked to placenta development and/or preeclampsia could be detected. Methods: This single-center, nested case-control study involved singleton pregnancies less than 16 weeks of gestation at increased risk for preeclampsia, with at least one high-risk factor or two moderate-risk factors, and healthy pregnant controls. Patients were followed throughout their pregnancy, with blood collected at three time points to quantify plasma levels of ccf-mtDNA and five microRNAs (miRNAs). All patients received 81 mg aspirin daily initiated before 16 weeks of gestation. Results: The mean and standard deviation (SD) of age in years was 31.1 ± 7.5 for the preeclampsia group and 31.9 ± 5.7 for the control group. Gestational age at delivery in weeks was 36.3 ± 3.2 for the preeclampsia group and 36.9 ± 4.3 for the healthy control group. The gestational age at diagnosis of preeclampsia was 34.8 ± 3.4 weeks. Participants who developed preeclampsia had a significantly reduced amount of ccf-mtDNA in the maternal circulation compared to that in healthy pregnant controls. The reduction in ccf-mtDNA reached significance at Visit 1 (1.688 ± 1.254 copies for the preeclampsia group versus 4.014 ± 2.381 copies for 1 µL of plasma for the healthy control group), corresponding to the second trimester. ccf-mtDNA levels in the exosomal fraction remained unchanged throughout pregnancy. The plasma levels of miRNA-137 were significantly decreased in patients with preeclampsia compared to healthy pregnant controls at all time points. Conclusions: Plasma levels of miRNA-137 and ccf-mtDNA are decreased as early as the first and second trimester, respectively before the clinical diagnosis of preeclampsia in the third trimester. Early detection of changes in plasma levels of miRNAs and ccf-mtDNA could be used for early prediction of preeclampsia.