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Reduced insulin sensitivity (insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM). We conducted transcriptomic profiling of 434 human placentas and identified a positive association between insulin-like growth factor binding protein 1 gene (IGFBP1) expression in the placenta and insulin sensitivity at ~26 weeks gestation. Circulating IGFBP1 protein levels rose over the course of pregnancy and declined postpartum, which, together with high gene expression levels in our placenta samples, suggests a placental or decidual source. Higher circulating IGFBP1 levels were associated with greater insulin sensitivity (lesser insulin resistance) at ~26 weeks gestation in the same cohort and in two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts of pregnant women. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis., (© 2024. The Author(s).)

Context: Elevated body mass index (BMI) in pregnancy is associated with adverse maternal and fetal outcomes. The placental transcriptome may elucidate molecular mechanisms underlying these associations., Objective: We examined the association of first-trimester maternal BMI with the placental transcriptome in the Gen3G prospective cohort., Methods: We enrolled participants at 5 to 16 weeks of gestation and measured height and weight. We collected placenta samples at delivery. We performed whole-genome RNA sequencing using Illumina HiSeq 4000 and aligned RNA sequences based on the GTEx v8 pipeline. We conducted differential gene expression analysis of over 15 000 genes from 450 placental samples and reported the change in normalized gene expression per 1-unit increase in log2 BMI (kg/m2) as a continuous variable using Limma Voom. We adjusted models for maternal age, fetal sex, gestational age at delivery, gravidity, and surrogate variables accounting for technical variability. We compared participants with BMI of 18.5 to 24.9 mg/kg2 (N = 257) vs those with obesity (BMI ≥30 kg/m2, N = 82) in secondary analyses., Results: Participants' mean ± SD age was 28.2 ± 4.4 years and BMI was 25.4 ± 5.5 kg/m2 in early pregnancy. Higher maternal BMI was associated with lower placental expression of EPYC (slope = -1.94, false discovery rate [FDR]-adjusted P = 7.3 × 10-6 for continuous BMI; log2 fold change = -1.35, FDR-adjusted P = 3.4 × 10-3 for BMI ≥30 vs BMI 18.5-24.9 kg/m2) and with higher placental expression of IGFBP6, CHRDL1, and CXCL13 after adjustment for covariates and accounting for multiple testing (FDR < 0.05)., Conclusion: Our genome-wide transcriptomic study revealed novel genes potentially implicated in placental biologic response to higher maternal BMI in early pregnancy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth., (© 2023. The Author(s).)

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings., (© 2022. The Author(s).)

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth., (© 2021. The Author(s).)

Aim: The placenta undergoes DNA methylation (DNAm) programming that is unique compared with all other fetal tissues. We aim to decipher some of the physiologic roles of the placenta by comparing its DNAm profile with that of another fetal tissue. Materials & methods: We performed a comparative analysis of genome-wide DNAm of 444 placentas paired with cord blood samples collected at birth. Gene ontology term analyses were conducted on the resulting differentially methylated regions. Results: Genomic regions upstream of transcription start sites showing lower DNAm in the placenta were enriched with terms related to miRNA functions and genes encoding G-protein-coupled receptors. Conclusion: These results highlight genomic regions that are differentially methylated in the placenta in contrast to fetal blood.

Placental lipids transfer is essential for optimal fetal development, and alterations of these mechanisms could lead to a higher risk of adverse birth outcomes. Low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), and scavenger receptor class B type 1 (SCARB1) genes are encoding lipoprotein receptors expressed in the placenta where they participate in cholesterol exchange from maternal to fetal circulation. The aim of this study was thus to investigate the association between maternal lipid changes occurring in pregnancy, placental DNA methylation (DNAm) variations at LDLR, LRP1, and SCARB1 gene loci, and newborn's anthropometric profile at birth. Sixty-nine normoglycemic women were followed from the first trimester of pregnancy until delivery. Placental DNAm was quantified at 43 Cytosine-phosphate-Guanines (CpGs) at LDLR, LRP1, and SCARB1 gene loci using pyrosequencing: 4 CpGs were retained for further analysis. Maternal clinical data were collected at each trimester of pregnancy. Newborns' data were collected from medical records. Statistical models included minimally newborn sex and gestational and maternal age. Maternal total cholesterol changes during pregnancy (ΔT3-T1) were correlated with DNAm variations at LDLR (r = -0.32, p = 0.01) and LRP1 (r = 0.34, p = 0.007). DNAm at these loci was also correlated with newborns' cord blood triglyceride and leptin levels. Mediation analysis supports a causal relationship between maternal cholesterol changes, DNAm levels at LRP1 locus, and cord blood leptin concentration (pmediation = 0.02). These results suggest that LRP1 DNAm link maternal blood cholesterol changes in pregnancy and offspring adiposity at birth, which provide support for a better follow-up of blood lipids in pregnancy.

The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ∼26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index ( P < 6.94 × 10 -8 ). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1 Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy., (© 2019 by the American Diabetes Association.)

Studies have linked maternal pre-pregnancy obesity and hyperglycaemia with metabolic and neurodevelopmental complications in childhood. DNA methylation (DNAm) might enable foetal adaptations to environmental adversities through important gene loci. NEGR1 is involved in both energy balance and behaviour regulation. The aim of this study was to investigate associations between placental DNAm at the NEGR1 gene locus and childhood anthropometric and neurodevelopmental profiles in preschoolers. We analysed 276 mother-child dyads from Gen3G, a prospective birth cohort from Sherbrooke. At 3yo (40.4 ± 3.0 months), we measured body mass index (BMI) and the mothers reported on offspring neurobehavior using the Strengths and Difficulties Questionnaire (SDQ). We quantified DNAm levels at 30 CpGs at the NEGR1 locus using the MethylationEPIC Array in placental biopsies. DNAm at four CpGs located before NEGR1 second exon predicted child's BMI z-score (cg26153364: β=-0.16 ± 0.04; p =0.008, cg23166710: β=0.14 ± 0.08; p =0.03) and SDQ total score (cg04932878: β=0.22 ± 1.0; p = 3.0x10 -4 , cg16525738: β=-0.14 ± 0.18; p =0.01, cg23166710: β=-0.13 ± 0.36; p = 0.04), explaining 4.2% (p=0.003) and 7.3% ( p = 1.3 x 10 -4 ) of BMI-z and SDQ variances. cg23166710 was associated with both childhood phenotypes and correlated with NEGR1 placental expression (r=-0.22, p =0.04), suggesting its possible functional role. Together, maternal metabolic characteristics during pregnancy with NEGR1 DNAm levels explained 7.4% ( p =4.2 x 10 -4 ) of BMI-z and 14.2% ( p =2.8 x 10 -7 ) of SDQ variance at 3yo. This longitudinal study suggests that placental NEGR1 DNAm is associated with adiposity and neurodevelopment in preschool children and highlights its potential role in their comorbidity.

Illumina HumanMethylation450 BeadChip (450K) has been commonly used to investigate DNA methylation in human tissues. Recently, it has been replaced by Illumina HumanMethylationEPIC BeadChip (EPIC) covering over 850,000 CpGs distributed genome-wide. Many consortia have now datasets coming from both arrays and aspire to analyze the two together. The placenta shows a high number of intermediate methylation levels and is often investigated for obstetric/birth outcomes, and potentially for long-term programming in offspring. We performed a systematic comparison between the two arrays using 108 duplicate placental samples from Gen3G birth cohort. We find that placenta shows a high per-sample correlation between the arrays, and higher median correlations at individual CpGs than those reported for blood. We identify 26,340 probes with absolute difference in per cent methylation >10%. We conclude that EPIC and 450K placental data can be combined, and we provide two lists of CpGs that should be excluded to avoid misleading results.

Prenatal maternal smoking is a risk factor for lower birth weight. We performed epigenome-wide association analyses of placental DNA methylation (DNAm) at 720,077 cytosine-phosphate-guanine (CpG) sites and prenatal maternal smoking among 441 mother-infant pairs (2010-2014) and evaluated whether DNAm mediates the association between smoking and birth weight using mediation analysis. Mean birth weight was 3,443 (standard deviation, 423) g, and 38 mothers (8.6%) reported smoking at a mean of 9.4 weeks of gestation. Prenatal maternal smoking was associated with a 175-g lower birth weight (95% confidence interval (CI): -305.5, -44.8) and with differential DNAm of 71 CpGs in placenta, robust to latent-factor adjustment reflecting cell types (Bonferroni-adjusted P < 6.94 × 10-8). Of the 71 CpG sites, 7 mediated the association between prenatal smoking and birth weight (on MDS2, PBX1, CYP1A2, VPRBP, WBP1L, CD28, and CDK6 genes), and prenatal smoking × DNAm interactions on birth weight were observed for 5 CpG sites. The strongest mediator, cg22638236, was annotated to the PBX1 gene body involved in skeletal patterning and programming, with a mediated effect of 301-g lower birth weight (95% CI: -543, -86) among smokers but no mediated effect for nonsmokers (β = -38 g; 95% CI: -88, 9). Prenatal maternal smoking might interact with placental DNAm at specific loci, mediating the association with lower infant birth weight., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

DNA methylation is known to be responsive to prenatal exposures, which may be a part of the mechanism linking early developmental exposures to future chronic diseases. Many studies use blood to measure DNA methylation, yet we know that DNA methylation is tissue specific. Placenta is central to fetal growth and development, but it is rarely feasible to collect this tissue in large epidemiological studies; on the other hand, cord blood samples are more accessible. In this study, based on paired samples of both placenta and cord blood tissues from 169 individuals, we investigated the methylation concordance between placenta and cord blood. We then employed a machine-learning-based model to predict locus-specific DNA methylation levels in placenta using DNA methylation levels in cord blood. We found that methylation correlation between placenta and cord blood is lower than other tissue pairs, consistent with existing observations that placenta methylation has a distinct pattern. Nonetheless, there are still a number of CpG sites showing robust association between the two tissues. We built prediction models for placenta methylation based on cord blood data and documented a subset of 1,012 CpG sites with high correlation between measured and predicted placenta methylation levels. The resulting list of CpG sites and prediction models could help to reveal the loci where internal or external influences may affect DNA methylation in both placenta and cord blood, and provide a reference data to predict the effects on placenta in future study even when the tissue is not available in an epidemiological study.

Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (>850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-h post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal 2-h glycemia postload was strongly associated with lower DNA methylation of four CpG sites (false discovery rate [FDR] q <0.05) within the phosphodiesterase 4B gene ( PDE4B ). Additionally, three other individual CpG sites were differentially methylated relative to maternal glucose response within the TNFRSF1B , LDLR , and BLM genes (FDR q <0.05). DNA methylation correlated with expression of its respective genes in placental tissue at three out of four independent identified loci: PDE4B ( r = 0.31, P < 0.01), TNFRSF1B ( r = -0.24, P = 0.013), and LDLR ( r = 0.32, P < 0.001). In an independent replication cohort ( N = 65-108 samples), results were consistent in direction but not significantly replicated among tested CpG sites in PDE4B and TNFRSF1B Our study provides evidence that maternal glycemic response during pregnancy is associated with placental DNA methylation of key inflammatory genes whose expression levels are partially under epigenetic control., (© 2018 by the American Diabetes Association.)

Gestational diabetes mellitus (GDM) is associated with obesity in childhood. This suggests that consequences of in utero exposure to maternal hyperglycemia extend beyond the fetal development, possibly through epigenetic programming. The aims of this study were to assess whether placental DNA methylation (DNAm) marks were associated with maternal GDM status and to offspring body composition at 5 years old in a prospective birth cohort. DNAm levels were measured in the fetal side of the placenta in 66 samples (24 from GDM mothers) using bisDNA-pyrosequencing. Anthropometric and body composition (bioimpedance) were measured in children at 5 years of age. Mann-Whitney and Spearman tests were used to assess associations between GDM, placental DNAm levels at the lipoprotein lipase (LPL) locus and children's weight, height, body mass index (BMI), body fat, and lean masses at 5 years of age. Weight, height, and BMI z-scores were computed according to the World Health Organization growth chart. Analyses were adjusted for gestational age at birth, child sex, maternal age, and pre-pregnancy BMI. LPL DNAm levels were positively correlated with birth weight z-scores (r = 0.252, P = 0.04), and with mid-childhood weight z-scores (r = 0.314, P = 0.01) and fat mass (r = 0.275, P = 0.04), and negatively correlated with lean mass (r = -0.306, P = 0.02). We found a negative correlation between LPL DNAm and mRNA levels in placenta (r = -0.459; P < 0.001), which highlights the regulation of transcriptional activity by these epivariations. We demonstrated that alterations in fetal placental DNAm levels at the LPL gene locus are associated with the anthropometric profile in children at 5 years of age. These findings support the concept of fetal metabolic programming through epigenetic changes.

Purpose of the Review: This review focuses on the recent emergence of microRNAs (miRNAs) as metabolic and developmental regulators in pregnancy and their role in the development of gestational diabetes mellitus (GDM). MiRNAs are short and stable RNA sequences that repress protein synthesis through interference with messenger RNA translation., Recent Findings: The placenta produces numerous miRNAs with some of them being released in the maternal circulation. These miRNA genes are encoded into specific clusters and expressed preferentially by placental cells, in a time-dependent manner. They were shown to be dysregulated in plasma and placenta from women suffering from GDM and associated with pregnancy and birth-related outcomes. The discovery of pregnancy-related miRNAs and their respective characterization will provide us with important information as to their function in maternal and placental metabolic regulation. More studies are needed to determine whether they will be useful for early screening of GDM.

Background: Children exposed to gestational diabetes mellitus (GDM) are at a higher risk of developing obesity and type 2 diabetes. This susceptibility might involve brown adipose tissue (BAT), which is suspected to protect against obesity. The objective of this study is to assess whether fetal exposure to maternal hyperglycemia is associated with DNA methylation variations in genes involved in BAT genesis and activation., Methods: DNA methylation levels at the PRDM16, BMP7, CTBP2, and PPARGC1α gene loci were measured in placenta samples using bisulfite pyrosequencing in E-21 (n = 133; 33 cases of GDM) and the HumanMethylation450 array in Gen3G (n = 172, all from non-diabetic women) birth cohorts. Glucose tolerance was assessed in all women using an oral glucose tolerance test at the second trimester of pregnancy. Participating women were extensively phenotyped throughout pregnancy, and placenta and cord blood samples were collected at birth., Results: We report that maternal glycemia at the second and third trimester of pregnancy are correlated with variations in DNA methylation levels at PRDM16, BMP7, and PPARGC1α and with cord blood leptin levels. Variations in PRDM16 and PPARGC1α DNA methylation levels were also correlated with cord blood leptin levels. Mediation analyses support that DNA methylation variations at the PPARGC1α gene locus explain 0.8 % of the cord blood leptin levels variance independently of maternal fasting glucose levels (p = 0.05)., Conclusions: These results suggest that maternal glucose in pregnancy could produce variations in DNA methylation in BAT-related genes and that some of these DNA methylation marks seem to mediate the impact of maternal glycemia on cord blood leptin levels, an adipokine regulating body weight.

Placental lipoprotein lipase (LPL) is crucial for placental lipid transfer. Impaired LPL gene expression and activity were reported in pregnancies complicated by gestational diabetes mellitus (GDM) and intra-uterine growth restriction. We hypothesized that placental LPL DNA methylation is altered by maternal metabolic status and could contribute to fetal programming. The objective of this study was thus to assess whether placental LPL DNA methylation is associated with GDM and both maternal and newborn lipid profiles. Placenta biopsies were sampled at delivery from 126 women including 27 women with GDM diagnosed following a post 75 g-oral glucose tolerance test (OGTT) between weeks 24 and 28 of gestation. Placental LPL DNA methylation and expression levels were determined using bisulfite pyrosequencing and quantitative real-time PCR, respectively. DNA methylation levels within LPL proximal promoter region (CpG1) and intron 1 CpG island (CpGs 2 and 3) were lower in placenta of women with GDM. DNA methylation levels at LPL-CpG1 and CpG3 were also negatively correlated with maternal glucose (2-h post OGTT; r=-0.22; P=0.02) and HDL-cholesterol levels (third trimester of pregnancy; r=-0.20; p=0.03), respectively. Moreover, we report correlation between LPL-CpG2 DNA methylation and cord blood lipid profile. DNA methylation levels within intron 1 CpG island explained up to 26% (r⩽-0.51; P<0.001) of placental LPL mRNA expression variance. Overall, we showed that maternal metabolic profile is associated with placental LPL DNA methylation dysregulation. Our results suggest that site-specific LPL epipolymorphisms in the placenta are possibly functional and could potentially be involved in determining the future metabolic health of the newborn.

Aims: To determine whether placental IGF1R, IGFBP3, INSR and IGF1 DNA methylation and mRNA levels were dysregulated when exposed to maternal impaired glucose tolerance (IGT) and investigate whether the epigenetic profile is associated with feto-placental developmental markers., Patients & Methods: The IGT diagnosis was made according to the WHO criteria (IGT: n = 34; normal glucose tolerance [NGT]: n = 106). DNA methylation and mRNA levels were quantified using bisulfite pyrosequencing and qRT-PCR, respectively., Results: IGF1R and IGFBP3 DNA methylation levels were lower in placentas exposed to IGT compared with NGT (-4.3%; p = 0.021 and -2.5%; p = 0.006 respectively) and correlated with 2-h post-oral glucose tolerance test (OGTT) glycemia (r = -0.23; p = 0.010 and r = -0.20; p = 0.028, respectively). IGF1R mRNA levels were associated with newborns' growth markers (e.g., birth weight; r = 0.20; p = 0.032)., Conclusion: These results support the growth-promoting role of the IGF system in placental/fetal development and suggest that the IGF1R and IGFBP3 DNA methylation profiles are dysregulated in IGT, potentially affecting the fetal metabolic programming.

In utero environmental perturbations have been associated with epigenetic changes in the offspring and a lifelong susceptibility to cardiovascular diseases (CVD). DNA methylation at the ATP-binding cassette transporter A1 (ABCA1) gene was previously associated with CVD, but whether these epigenetic marks respond to changes in the maternal environment is unknown. This study was undertaken to assess the associations between the maternal metabolic profile and ABCA1 DNA methylation levels in placenta and cord blood. Placenta and cord blood samples were obtained at delivery from 100 women including 26 with impaired glucose tolerance (IGT) diagnosed following a 75 g-oral glucose tolerance test (OGTT) between week 24 and 28 of gestation. ABCA1 DNA methylation and mRNA levels were measured using bisulfite pyrosequencing and quantitative real-time PCR, respectively. We report that ABCA1 DNA methylation levels on the maternal side of the placenta are correlated with maternal high density lipoprotein cholesterol (HDL-C) levels (r<-0.21; P<0.04) and glucose levels 2 h post-OGTT (r = 0.25; P = 0.02). On the fetal side of the placenta, ABCA1 DNA methylation levels are associated with cord blood triglyceride levels (r = -0.28; P = 0.01). ABCA1 DNA methylation variability on both sides of the placenta are also associated with ABCA1 mRNA levels (r<-0.35; P = 0.05). As opposed to placenta, cord blood DNA methylation levels are negatively correlated with maternal glucose 2 h post-OGTT (r = -0.26; P = 0.02). In conclusion, the epivariations observed in placenta and cord blood likely contribute to an optimal materno-fetal cholesterol transfer. These in utero epigenetics adaptations may also potentially trigger the long-term susceptibility of the newborn to dyslipidemia and CVD.

Growing evidence suggests that epigenetic profile changes occurring during fetal development in response to in utero environment variations could be one of the mechanisms involved in the early determinants of adult chronic diseases. In this study, we tested whether maternal glycemic status is associated with the adiponectin gene (ADIPOQ) DNA methylation profile in placenta tissue, in maternal circulating blood cells, and in cord blood cells. We found that lower DNA methylation levels in the promoter of ADIPOQ on the fetal side of the placenta were correlated with higher maternal glucose levels during the second trimester of pregnancy (2-h glucose after the oral glucose tolerance test; r(s) ≤ -0.21, P < 0.05). Lower DNA methylation levels on the maternal side of the placenta were associated with higher insulin resistance index (homeostasis model assessment of insulin resistance) during the second and third trimesters of pregnancy (r(s) ≤ -0.27, P < 0.05). Finally, lower DNA methylation levels were associated with higher maternal circulating adiponectin levels throughout pregnancy (r(s) ≤ -0.26, P < 0.05). In conclusion, the ADIPOQ DNA methylation profile was associated with maternal glucose status and with maternal circulating adiponectin concentration. Because adiponectin is suspected to have insulin-sensitizing proprieties, these epigenetic adaptations have the potential to induce sustained glucose metabolism changes in the mother and offspring later in life.