| Backgrounds and ObjectivesGestational diabetes mellitus (GDM), a common medical complication of pregnancy, is defined as "any degree of glucose intolerance with onset or first recognition during pregnancy". It could bring serious hazards to the maternal and offspring short and long term health. In recent years, the incidence of GDM has been increasing rapidly. Intrauterine hyperglycemia exposure in GDM patients could increase the risk of childhood, adolescent and adult obesity, which has drawn much attention. However, the conclusion about the association of GDM with offspring obesity is not entirely consistent, and the present studies mainly focus on childhood and adolescent obesity, lack of study on infant obesity; and it’s still lack of research about the association of GDM with offspring obesity in the Chinese population. To our knowledge, there was the first study on whether there was the difference on the degree of effect of different time-point blood glucose levels during pregnancy (blood glucose during the first and second trimester, fasting plasma glucose during the second trimester (FPG-2nd) and 1 h or 2 h plasma glucose in oral glucose tolerance test (OGTT)) on offspring obesity. So far, the biological mechanism of GDM and offspring obesity is still not clear, but the high glucose environment in utero might affect offspring obesity throught epigenetic changes. Peroxisome proliferator-activated receptor y (PPAR-y) plays an important role in regulating metabolism and adipogenesis, and leptin, adiponectin, lipoprotein lipase (LPL) and adipocyte fatty acid binding protein (AFABP) are the main obesity related factors on the pathway of PPAR-y; Trim28 is the latest discovery of ON/OFF switches gene for obesity. They might play a very important role in the changes of fetal programming. To our knowledge, there was the first study on the associations among GDM, the DNA methylation of PPAR-y and Trim28 and offspring obesity and the associations among GDM, the expression level of obesity related factors and offspring obesity after birth. Therefore, this study was carried out in Zhoushan Maternal and Child Health Hospital, Zhejiang. We explored the associations of GDM with the risk of infant (0,6,12,18 and 24 months) obesity in a prospective cohort study design; and explored the associations among GDM, the DNA methylation of PPAR-y (and the expression level of obesity related factors) and Trim28, and infant (0,6,12 and 18 months) obesity with a 1:1 matched design based on the prospective cohort study. This study aimed to illustrate the association of GDM with offspring obesity and its molecular mechanism.Materials and MethodsThis prospective cohort study was conducted in Zhoushan Maternal and Child Health Hospital, Zhejiang, from August 2011 to May 2015. Participants’ social-demographic characteristics, life behavior and other information were obtained through epidemiological questionnaires. Glycosylated hemoglobin (HbAlC) and FPG during the first trimester (FPG-1st), FPG-2nd and 1 h or 2 h plasma glucose were extracted from medical records of physical examination for pregnant women. Pregnant and perinatal complications, infant length and weight and other data were collected from maternal and child health system. Singleton, full-term newborns and their mothers without other pregnant and perinatal complications were selected as participants. Multivariate linear regression and Logistic regression model were used to assess the associations of GDM and infant (0,6,12,18 and 24 months) obesity related indicators.Based on the above-mentioned prospective cohort study, a 1:1 matched design was carried out. GDM group and control group (N=50) matched by maternal age, pre-pregnancy BMI, gestational age at delivery, sex and season of blood sampling, after excluding pregnant women with smoking, drinking and drug abuse, were selected. The sample of umbilical cord blood was collected from each subject at childbirth. The SEQUENOM MassArray(?) REpiTYPER platform was used to detect PPAR-y and Trim28 DNA methylation levels in white blood cell of umbilical cord blood. Leptin, adiponectin, LPL and AFABP in umbilical cord plasma were detected by enzyme linked immunosorbent assay method. Multivariate linear regression and Logistic regression model were used to explore the associations among GDM, the DNA methylation of PPAR-y (and the expression level of obesity related factors) and Trim28, and infant (0,6, 12 and 18 months) obesity.ResultsA total of 1232 pregnant women, of which GDM had 234 cases, accounting for 19%, were included in the prospective cohort study. After adjustment for confounding factors, GDM, FPG-2nd,1 h plasma glucose and 2 h plasma glucose were significantly associated with higher birth weight and birth weight for gestational age Z score, and increased risk of macrosomia (P<0.05); GDM and higher 2 h plasma glucose were significantly associated with increased risk of large for gestational age (LGA; OR= 1.79,95%CI:1.11-2.89; OR=2.71,95%CI:1.33-5.53). However, we did not find associations of FPG-1st and HbAlC with birth weight related indicators(P>0.05). In addition, compared with abnormal FPG-2nd, abnormal 1 h or 2 h plasma glucose had significantly higher birth weight and birth weight for gestational age Z score, and increased risk of macrosomia. Abnormal FPG-2nd and abnormal 1 h or 2 h plasma glucose had significantly joint effect on birth weight (P=161.4 g,P=0.0192) and birth weight for gestational age Z score (P=0.42, P=0.0121), and risk of macrosomia (OR =3.24,95%CI:1.21-8.67)and LGA (OR=5.73,95%CI:2.20-14.90), compared with any one of them. Compared with abnormal FPG-1st or HbA1C, GDM had significantly higher birth weight and birth weight for gestational age Z score. Abnormal FPG-1st or HbAlC and GDM had significantly joint effect on birth weight (P=125.8 g,P=0.0010) and birth weight for gestational age Z score (β=0.30, P=0.0013), and risk of macrosomia (OR=2.34,95%CI:1.28-4.30) and LGA (OR=2.53,95%CI:1.37-4.67), compared with any one of them. Besides, GDM was significantly associated with lower BMI (β=-0.31 kg/m2,P=0.0113)and BMI for age Z score (β=-0.19,P=0.0116), and decreased risk of overweight/obesity (OR=0.59,95%CI:0.33-1.04; P=0.0686) in infants aged 6 months. However, we did not find associations of plasma glucose during pregnancy with weight, weight gain, weight for age Z score, BMI, changes in BMI, BMI for age Z score, overweight and obesity in infants aged 12,18 and 24 months (P> 0.05).In the 1:1 matched prospective cohort study, GDM and higher FPG-2nd were significantly associated with higher Trim28 DNA methylation level at CpG10-11 locus, which was also significantly associated with higher BMI and BMI for age Z score in infants aged 18 months (P<0.05). GDM and higher FPG-2nd were also associated with higher average methylation level of Trim28 gene, although this association was not statistically significant; and the higher average Trim28 DNA methylation level was also significantly associated with increased risk of macrosomia (OR=1.37,95%CI: 1.03-1.81) and higher BMI and BMI for age Z score in infants aged 12 and 18 months (P< 0.05). Meanwhile, GDM was also significantly associated with higher BMI (β =0.67 kg/m2,P=0.0177) and BMI for age Z score (β=0.58,P=0.0221) in infants aged 18 months. However, we did not find associations among plasma glucose during pregnancy, Trim28 DNA methylation level at other CpG sites and infant obesity, and among plasma glucose during pregnancy, PPAR-y DNA methylation level, obesity related factors levels on PPAR-y pathway (leptin, adiponectin, LPL and AFABP) and infant obesity(P>0.05).Conclusions1. GDM were significantly associated with higher birth weight and increased risk of macrosomia and LGA, and lower BMI and decreased risk of overweight/obesity in infants aged 6 months. Abnormal FPG-2nd and abnormal 1 h or 2 h plasma glucose, abnormal FPG-1st or HbAlC and GDM had significantly joint effect on birth weight and risk of macrosomia and LGA. However, we did not find associations of plasma glucose during pregnancy with obesity related indicators in infants aged 12, 18 and 24 months. Our results suggest that pregnant women should be reasonable diet during pre-pregnancy and pregnancy, strengthen the monitoring of blood glucose levels in the first and second trimester and treat GDM timely, to decrease the risk of adverse pregnancy outcomes and offspring obesity.2. Our results also suggest that GDM might increase BMI in infants aged 18 months through the increase of Trim28 DNA methylation level at CpG 10-11 locus and the average Trim28 DNA methylation level. Nevertheless, we did not find associations among plasma glucose during pregnancy, PPAR-y DNA methylation level, obesity related factors levels on PPAR-y pathway (leptin, adiponectin, LPL and AFABP) and infant obesity. However, the results of molecular mechanism need to be validated by a large sample of epidemiological studies. |
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