Maternal total cell-free DNA in preeclampsia with and without intrauterine growth restriction

Dong Wook Kwak,Shin Young Kim,Young-Han Kim,Hyun Jin Kim,Ji Hyae Lim,Hyun Mee Ryu,Hyun Mee Ryu

doi:10.1038/s41598-020-68842-1

Abstract

Elevation of total cell-free DNA (cfDNA) in patients with preeclampsia is well-known; however, whether this change precedes the onset of symptoms remains inconclusive. Here, we conducted a nested case–control study to determine the elevation of cfDNA levels in women who subsequently developed preeclampsia. Methylated HYP2 (m-HYP2) levels were determined in 68 blood samples collected from women with hypertensive disorders of pregnancy, along with 136 control samples, using real-time quantitative PCR. The measured m-HYP2 levels were converted to multiples of the median (MoM) values for correction of maternal characteristics. The m-HYP2 levels and MoM values in patients with preeclampsia were significantly higher than in controls during the third trimester (P < 0.001, both), whereas those for women who subsequently developed preeclampsia did not differ during the second trimester. However, when patients with preeclampsia were divided based on the onset-time of preeclampsia or 10th percentile birth weight, both values were significantly higher in women who subsequently developed early-onset preeclampsia (P < 0.05, both) and preeclampsia with small-for-gestational-age (SGA) neonate (P < 0.01, both) than controls. These results suggested that total cfDNA levels could be used to predict early-onset preeclampsia or preeclampsia with SGA neonate.

Highlights

Hypertensive disorders of pregnancy (HDP) are classified into four categories: chronic hypertension, preeclampsia (PE), PE superimposed on chronic hypertension, and gestational hypertension (GH)
A few previous studies had shown total Cell-free DNA (cfDNA) to be increased in patients with PE during the first or second trimester[22,23,24], whereas a recent case–control study of a relatively large sample size demonstrated the total cfDNA levels to not be increased in the first t rimester[25]
Body mass index was significantly higher, and gestational age at delivery and birth weight were significantly lower in all patient groups compared to those in the control group (P < 0.05 for all)

Summary

Introduction

Hypertensive disorders of pregnancy (HDP) are classified into four categories: chronic hypertension, preeclampsia (PE), PE superimposed on chronic hypertension, and gestational hypertension (GH). Cell-free DNA (cfDNA) circulating in the maternal blood is a candidate b iomarker[12]. It may be maternal or fetal in origin. Fetal cfDNA is shed from the syncytiotrophoblast as an apoptotic fragment during normal cell turnover, and released into maternal circulation. Various authors have observed elevations in fetal cfDNA level, during the first and second trimesters, in patients who subsequently developed PE14–16, and suggested cfDNA as a predictive marker for early-onset PE or ‘any PE’17. A poorly perfused placenta in patients with PE may release circulating factors into maternal circulation, causing damage to maternal vascular endothelial cells and leading to multi-system d ysfunction[17]. A few previous studies had shown total cfDNA to be increased in patients with PE during the first or second trimester[22,23,24], whereas a recent case–control study of a relatively large sample size demonstrated the total cfDNA levels to not be increased in the first t rimester[25]

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Conclusion