Maternal Glycemia during pregnancy and Early Offspring Development: A Prospective Birth Cohort Study

Context The association of maternal gestational diabetes mellitus (GDM) with neurodevelopmental outcomes remains controversial and evidence that maternal increasing levels of glucose during pregnancy associated with the risk for impaired neurodevelopment were limited. Objective To identify the continuous association of increasing maternal glucose levels with neurodevelopmental disorders in offspring and explore the potential contribution of cord metabolites to this association. Methods The prospective birth cohort study included 1036 mother-child pairs. Primary predictors were maternal exposure GDM and maternal glucose values at a 75-g oral-glucose-tolerance test (OGTT) at 24–28 weeks during pregnancy. Primary neurodevelopmental outcomes at 12 mo in offspring were assessed by the ASQ-3. Results Maternal GDM was associated with failing the communication domain in offspring in the adjusted models [RR with 95% CI: 1.97(1.11, 3.52)]. Increasing levels of fasting plasma glucose (FPG), 1 h plasma glucose (1-h PG) and 2 h plasma glucose (2-h PG) with one SD change were at higher risks in failing the personal social domain of ASQ [RRs with 95% CI for FPG: 1.49(1.09, 2.04); for 1-h PG: 1.70(1.27, 2.29); for 2-h PG: 1.36(1.01, 1.84)]. The linear association was also demonstrated. Compared with girls, boys exposed to higher maternal glucose levels were inclined to the failure of the personal social domain. Mediation analysis showed the contribution of maternal GDM to failure of communication domain mediated by C-peptide. Conclusions Maternal glucose levels below those diagnostic of diabetes are continuously associated with impaired neurodevelopment in offspring at 12 mo.

IMPACT OF GESTATIONAL DIABETES MELLITUS ON CHILD BIRTH

GestationalDiabetesMellitus(GDM) is an irregular glucose tolerance condition that developsfirst and is recognized during pregnancy.The Oral Glucose Tolerance Test (OGTT) is the gold standard for the diagnosis of this disorder from 24 to 28 weeks. A number of adverse results, including gestational hypertension, cardiovascular disease and preeclampsia, havebeen associated with pregnant women. As for maternal glucose levels in the second or third trimester the risk of adverse outcomes drastically increases, even within ranges previously considered normal for pregnancy. Excessive gestational weight gain in women with GDM, it is very normal and closely correlated with lifestyle factors during pregnancy. High fat consumption particularly saturated fat, trans fat and cholesterol, increases GDM risk. A higher intake of added sugar and lower intake of vegetable and fruit fiber are independently linked to increased fasting glucose. Animal protein consumption is positive and vegetable protein is inversely related to the risk of GDM.Since fetuses and infants are particularly vulnerable to the effects of toxic compounds, attempts should be made during the years well before childbearing to reduce the exposure of girls and women to dioxins in food, so that fewer quantities of these compounds accumulate in their bodies and are passed on through the placenta and breast milk.The key sources of exposure for most people are fats in meat, food, fatty fish, whole milk and full-fat milk products and their intake should be reduced.

The Association between Glucose Levels and Adverse Pregnancy Outcomes in Nondiabetic Twin Pregnancies

Objective The aim of this study is to determine if hyperglycemia in twin pregnancies without gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes. Study Design Retrospective cohort study of twin pregnancies in a single Maternal–Fetal Medicine practice between 2005 and 2019 who underwent two-step GDM screening at 24 to 28 weeks. We excluded women with pregestational or gestational diabetes. We examined the association between maternal glycemia and adverse pregnancy outcomes. Glycemia was defined as the 1-hour GCT in all women, and each of the four values of the 3-hour OGTT in women who failed the GCT (≥130 mg/dL). Primary outcomes were preeclampsia, cesarean delivery, and neonatal hypoglycemia in either twin. Statistical tests used included Pearson's correlation, Student's t-test, Mann–Whitney U test, Chi-square test for trend, and logistic regression. Results A total of 847 women underwent a GCT and 246 women underwent an OGTT. Increasing maternal glucose levels had no positive association with adverse outcomes. Women with preeclampsia, cesarean delivery, and neonatal hypoglycemia did not have higher mean GCT or OGTT values than women without these outcomes. There was no increased risk of adverse outcomes with increasing quartiles of the GCT or OGTT values. Conclusion In women with twin pregnancies without GDM, elevated maternal glucose levels are not associated with preeclampsia, cesarean delivery, or neonatal hypoglycemia. The altered physiology of twin gestations may modify the effect of maternal hyperglycemia on perinatal outcomes as compared with singleton pregnancies. Current approaches to screening for and treating GDM during pregnancy might not adequately account for these unique considerations among twins.

Pre-pregnancy maternal fasting plasma glucose levels in relation to time to pregnancy among the couples attempting first pregnancy

STUDY QUESTION What is the relationship between pre-pregnancy maternal glucose levels and fecundability in Chinese couples? SUMMARY ANSWER Elevated pre-pregnancy maternal glucose levels were associated with fecundability, as reflected by prolonged time to pregnancy (TTP) among the couples with no prior gravidity. STUDY DESIGN, SIZE, DURATION Based on the National Free Pre-conception Check-up Projects supported by the Chinese government, 2 226 048 eligible couples attempting first pregnancy and participating in the project from 2015 to 2016 were included. They were followed-up for 1 year or until they reported pregnancy. PARTICIPANTS/MATERIALS, SETTINGS, METHODS The Kaplan–Meier method was used to estimate the cumulative pregnancy rate in each menstrual cycle, and the discrete-time analogue of the Cox models was used to estimate the fecundability odds ratios (FORs) and 95% CIs by different pre-pregnancy maternal glucose levels (impaired fasting glucose (IFG) or diabetes as compared to normal). MAIN RESULTS AND THE ROLE OF CHANCE The cumulative pregnancy rate for 12 cycles of the normal fasting plasma glucose (FPG) level group was 42.29%, significantly higher than that of the IFG (35.52%) and diabetes groups (31.52%). After adjusting for confounding factors, the FORs were 0.82 (95% CI: 0.81–0.83) and 0.74 (95% CI: 0.72–0.76) for the IFG and diabetes groups, respectively, as compared to the normal group. The association between pre-pregnancy maternal FPG levels and the FORs was non-linear, and the optimal FPG level for greatest fecundability (shortest TTP) was 3.90–4.89 mmol/L. LIMITATIONS, REASONS FOR CAUTION The findings from this register-based cohort study require cautious interpretation given that information bias would be inevitable for single FPG measurements and for TTP calculations that were based on telephone follow-up information. Additionally, because couples who achieved pregnancy during their first menstrual cycle in the study were excluded, the pregnancy rates reported were low and possibly biased. WIDER IMPLICATIONS OF THE FINDINGS The current report suggests that elevated pre-pregnancy maternal glucose levels were associated with prolonged TTP. Early evaluation and preventive treatment for female partners with IFG or diabetes in a pre-pregnancy examination are necessary. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the National Key Research and Development Program of China (grants No. 2016YFC1000300 and 2016YFC1000307), the National Natural Science Foundation of China (grant No. 81872634), the CAMS Innovation Fund for Medical Sciences (grant No. 2018-I2M-1-004), the National Human Genetic Resources Sharing Service Platform (grant No. 2005DKA21300) and the National Population and Reproductive Health Science Data Center (grant No. 2005DKA32408), People’s Republic of China. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A

Placenta DNA Methylation Adaptation to Maternal Glucose Tolerance in Pregnancy

ABSTRACTMaternal hyperglycemia during pregnancy is associated with fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study of term placentas and prenatal maternal glucose response 2-hour post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal glucose levels post-load were strongly associated with lower DNA methylation of 4 CpGs (FDR q<0.05) within the Phosphodiesterase 4B gene (PDE4B). Additionally, three other CpGs were differentially methylated relative to maternal glucose response within the TNFRSF1B; LDLR; and BLM genes (FDR q<0.05). Methylation levels correlated with expression in placental tissue for all 4 CpG sites in PDE4B (rs: 0.26–0.35, P<0.01), LDLR (rs: 0.22, P=0.03) and at TNFRSF1B (rs: -0.25, P=0.01). Our study provides evidence that maternal glucose response during pregnancy is associated with DNA methylation of genes within the placenta that are partially under epigenetic control.

The identification and treatment of women with hyperglycaemia in pregnancy: an analysis of individual participant data, systematic reviews, meta-analyses and an economic evaluation

BackgroundGestational diabetes mellitus (GDM) is associated with a higher risk of important adverse outcomes. Practice varies and the best strategy for identifying and treating GDM is unclear.AimTo estimate the clinical effectiveness and cost-effectiveness of strategies for identifying and treating women with GDM.MethodsWe analysed individual participant data (IPD) from birth cohorts and conducted systematic reviews to estimate the association of maternal glucose levels with adverse perinatal outcomes; GDM prevalence; maternal characteristics/risk factors for GDM; and the effectiveness and costs of treatments. The cost-effectiveness of various strategies was estimated using a decision tree model, along with a value of information analysis to assess where future research might be worthwhile. Detailed systematic searches of MEDLINE®and MEDLINE In-Process & Other Non-Indexed Citations®, EMBASE, Cumulative Index to Nursing and Allied Health Literature Plus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database, Maternity and Infant Care database and the Cochrane Methodology Register were undertaken from inception up to October 2014.ResultsWe identified 58 studies examining maternal glucose levels and outcome associations. Analyses using IPD alone and the systematic review demonstrated continuous linear associations of fasting and post-load glucose levels with adverse perinatal outcomes, with no clear threshold below which there is no increased risk. Using IPD, we estimated glucose thresholds to identify infants at high risk of being born large for gestational age or with high adiposity; for South Asian (SA) women these thresholds were fasting and post-load glucose levels of 5.2 mmol/l and 7.2 mmol/l, respectively and for white British (WB) women they were 5.4 and 7.5 mmol/l, respectively. Prevalence using IPD and published data varied from 1.2% to 24.2% (depending on criteria and population) and was consistently two to three times higher in SA women than in WB women. Lowering thresholds to identify GDM, particularly in women of SA origin, identifies more women at risk, but increases costs. Maternal characteristics did not accurately identify women with GDM; there was limited evidence that in some populations risk factors may be useful for identifying low-risk women. Dietary modification additional to routine care reduced the risk of most adverse perinatal outcomes. Metformin (Glucophage,®Teva UK Ltd, Eastbourne, UK) and insulin were more effective than glibenclamide (Aurobindo Pharma – Milpharm Ltd, South Ruislip, Middlesex, UK). For all strategies to identify and treat GDM, the costs exceeded the health benefits. A policy of no screening/testing or treatment offered the maximum expected net monetary benefit (NMB) of £1184 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year (QALY). The NMB for the three best-performing strategies in each category (screen only, then treat; screen, test, then treat; and test all, then treat) ranged between –£1197 and –£1210. Further research to reduce uncertainty around potential longer-term benefits for the mothers and offspring, find ways of improving the accuracy of identifying women with GDM, and reduce costs of identification and treatment would be worthwhile.LimitationsWe did not have access to IPD from populations in the UK outside of England. Few observational studies reported longer-term associations, and treatment trials have generally reported only perinatal outcomes.ConclusionsUsing the national standard cost-effectiveness threshold of £20,000 per QALY it is not cost-effective to routinely identify pregnant women for treatment of hyperglycaemia. Further research to provide evidence on longer-term outcomes, and more cost-effective ways to detect and treat GDM, would be valuable.Study registrationThis study is registered as PROSPERO CRD42013004608.FundingThe National Institute for Health Research Health Technology Assessment programme.