The role of maternal DNA methylation in pregnancies complicated by gestational diabetes

Abstract

Diabetes in pregnancy is associated with adverse pregnancy outcomes and poses a serious threat to the health of mother and child. Although the pathophysiological mechanisms that underlie the association between maternal diabetes and pregnancy complications have not yet been elucidated, it has been suggested that the frequency and severity of pregnancy complications are linked to the degree of hyperglycemia. Epigenetic mechanisms reflect gene-environment interactions and have emerged as key players in metabolic adaptation to pregnancy and the development of complications. DNA methylation, the best characterized epigenetic mechanism, has been reported to be dysregulated during various pregnancy complications, including pre-eclampsia, hypertension, diabetes, early pregnancy loss and preterm birth. The identification of altered DNA methylation patterns may serve to elucidate the pathophysiological mechanisms that underlie the different types of maternal diabetes during pregnancy. This review aims to provide a summary of existing knowledge on DNA methylation patterns in pregnancies complicated by pregestational type 1 (T1DM) and type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). Four databases, CINAHL, Scopus, PubMed and Google Scholar, were searched for studies on DNA methylation profiling in pregnancies complicated with diabetes. A total of 1985 articles were identified, of which 32 met the inclusion criteria and are included in this review. All studies profiled DNA methylation during GDM or impaired glucose tolerance (IGT), while no studies investigated T1DM or T2DM. We highlight the increased methylation of two genes, Hypoxia‐inducible Factor‐3α (HIF3α) and Peroxisome Proliferator-activated Receptor Gamma-coactivator-Alpha (PGC1-α), and the decreased methylation of one gene, Peroxisome Proliferator Activated Receptor Alpha (PPARα), in women with GDM compared to pregnant women with normoglycemia that were consistently methylated across diverse populations with varying pregnancy durations, and using different diagnostic criteria, methodologies and biological sources. These findings support the candidacy of these three differentially methylated genes as biomarkers for GDM. Furthermore, these genes may provide insight into the pathways that are epigenetically influenced during maternal diabetes and which should be prioritized and replicated in longitudinal studies and in larger populations to ensure their clinical applicability. Finally, we discuss the challenges and limitations of DNA methylation analysis, and the need for DNA methylation profiling to be conducted in different types of maternal diabetes in pregnancy.

Assessing the effect of childbearing on blood DNA methylation through comparison of parous and nulliparous females

“…Pregnancy has also been linked to changes in DNA methylation (DNAm) -the addition or removal of methyl groups to cytosine-phosphate-guanine (CpG) sites on DNA, frequently in promoter regions -which regulate gene expression. DNAm changes throughout pregnancy are considered as an important part of gene regulation and normal cellular control mechanisms [14,16]. Fradin et al investigated DNAm changes in maternal blood of a longitudinal cohort of pregnant women from early pregnancy (up to 18 weeks) to late pregnancy (35 weeks and later) and found a gain of methylation in genes involved in morphogenesis, such as ezrin, and a loss of methylation in genes promoting maternal-infant bonding [22].…”

Doppler ultrasound of the ductus venosus in diabetic pregnancies

“…Preterm births, congenital abnormalities, perinatal death, and large for gestational age (LGA) babies are among the prevalent unfavorable perinatal outcomes linked to diabetes during pregnancy (3). Heart-related abnormalities make up the largest percentage of fetal abnormalities and are the main cause of perinatal death (4).…”