Neighborhood Environment and Poor Maternal Glycemic Control-Associated Complications of Gestational Diabetes Mellitus.

Introduction: Risk of complications due to gestational diabetes mellitus is increasing in the U.S., particularly among individuals from racial minorities. Research has focused largely on clinical interventions to prevent complications, rarely on individuals' residential environments. This retrospective cohort study aims to examine the association between individuals' neighborhoods and complications of gestational diabetes mellitus. Methods: Demographic and clinical data were extracted from electronic health records and linked to American Community Survey data from the U.S. Census Bureau for 2,047 individuals who had 2,164 deliveries in 2014-2018. Data were analyzed in 2021-2022 using Wilcoxon rank sum test and chi-square test for bivariate analyses and logistic regression for analysis of independent effects. All census tract-based variables used in the model were dichotomized at the median. Results: Bivariate analysis showed that the average percentage of adults earning <$35,000 was higher in neighborhoods where individuals with complications were living than in neighborhoods where individuals without complications were living (30.40%±12.05 vs 28.94%±11.71, p=0.0145). Individuals who lived in areas with ≥8.9% of residents aged >25 years with less than high school diploma had a higher likelihood of complications than those who lived in areas with <8.9% of such residents (33.43% vs 29.02%, p=0.0272). Individuals who lived in neighborhoods that had ≥1.8% of households receiving public assistance were more likely to have complications than those who lived in areas where <1.8% of households received public assistance (33.33% vs 28.97%, p=0.0287). Logistic regression revealed that the odds of deliveries with complications were 44% higher for individuals with obesity (OR=1.44; 95% CI=1.17, 1.77), 35% greater for individuals residing in neighborhoods with higher percentages of households living below the poverty level (OR=1.35; 95% CI=1.09, 1.66), and 28% lower for individuals from neighborhoods where a higher percentage of households had no vehicles available for transportation to work (OR=0.72; 95% CI=0.59, 0.89). Conclusions: Clinical interventions in concert with environmental changes could contribute to preventing maternal and neonatal complications of gestational diabetes mellitus.

A fetal rat model of ventricular noncompaction caused by intrauterine hyperglycemia.

BACKGROUND: This study aims to develop a fetal rat model of ventricular noncompaction (NVM) using streptozotocin (STZ)-induced gestational hyperglycemia and compare it with a retinoic acid (RA) model. METHODS: Female SD rats were categorized into STZ, RA, and normal control (NC) groups. The STZ group was given a high-fat diet pre-pregnancy and 35 mg/kg of 2% STZ postpregnancy. The RA group received a 90 mg/kg dose of RA on day 13 postpregnancy. Embryonic myocardial morphology was analyzed through HE staining, and embryonic cardiomyocyte ultrastructures were studied using electron microscopy. Diagnoses of NVM were based on a ratio of noncompact myocardium (N) to compact myocardium (C) >1.4, accompanied by thick myocardial trabeculae and a thin myocardial compaction layer. Kruskal-Wallis test determined N/C ratio differences among groups. RESULTS: Both STZ and RA groups displayed significant NVM characteristics. The left ventricular (LV) N/C in the STZ, RA, and NC groups were 1.983 (1.423-3.527), 1.640 (1.197-2.895), and 0.927 (0.806-1.087), respectively, with a statistically significant difference (P<0.001). The right ventricular (RV) N/C in the STZ, RA, and NC groups were 2.097 (1.364-3.081), 1.897 (1.337-2.662), and 0.869 (0.732-1.022), respectively, with a significant difference (P<0.001). Electron microscopy highlighted marked endoplasmic reticulum swelling in embryonic cardiomyocytes from both STZ and RA groups. CONCLUSION: Our model underscores the pivotal role of an adverse intrauterine developmental environment in the onset of NVM. This insight holds significant implications for future studies exploring the pathogenesis of NVM.

Maternal Hemoglobin A1c in the Third-Trimester May Underestimate Maternal Hyperglycemia and Its Impact on Offspring in Perinatal Demise Associated With Gestational Diabetes Mellitus: An Autopsy Case Series.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common metabolic disorder linked to adverse pregnancy outcomes. Recent research indicates that HbA1c is reliable in detecting maternal glycemia during the first trimester but may underestimate glucose intolerance in the late second to third trimesters. Therefore, it is reasonable to hypothesize that mothers with GDM, despite apparently normal HbA1c levels in the third trimester, may give birth to infants displaying characteristic features often seen in infants of diabetic mothers with suboptimal glycemic control. This study aimed to describe a case series of autopsy cases involving stillborn or deceased neonates delivered in the third trimester to mothers diagnosed with GDM and having normal HbA1c levels at or around the time of delivery. The primary focus was on identifying and documenting the characteristic features commonly associated with "infants of diabetic mothers" with suboptimal glycemic control in this series of cases. MATERIALS AND METHODS: We conducted a retrospective review of autopsy reports from our institution spanning 7.5 years. The study included cases that met the following criteria: (1) stillborn or infants who died in the early neonatal period, delivered in the third trimester; (2) mothers diagnosed with GDM; (3) normal maternal HbA1c levels of ≤6.1% at or around the time of delivery; (4) birthweight or femoral length exceeding the 90th percentile for gestational age; and (5) absence of genetic aberrations. We also examined these cases for other characteristic features associated with "infants of diabetic mothers." RESULTS: Ten autopsy cases met our inclusion criteria, including 9 stillbirths and 1 neonatal death. Gestational age at delivery ranged from 32 to 39 weeks (mean: 35.7 weeks). Femoral length exceeded the 90th percentile in all cases, and 6 cases had birthweights above the 90th percentile. Puffy facies were observed in 6 cases. Among the 9 cases with complete autopsies including internal examination, 6 exhibited excess adipose tissue, 4 had cardiomegaly, and 3 showed pancreatic islet hyperplasia. Hypoxic-ischemic encephalopathy was detected in 7 cases. No structural abnormalities were noted. DISCUSSION: Our findings demonstrated that fetuses and neonates born to mothers with apparently normal HbA1c levels in the third trimester could still display characteristic features commonly observed in infants of diabetic mothers with poor glycemic control, also known as "infants of diabetic mothers." This study underscores the potential of third-trimester maternal HbA1c measurements to underestimate maternal glycemia and its consequential impact on fetal development, as well as the subsequent manifestation of features of "infants of diabetic mothers."

Maternal Diabetes Deregulates the Expression of Mecp2 via miR-26b-5p in Mouse Embryonic Neural Stem Cells.

Maternal diabetes has been associated with a greater risk of neurodevelopmental disorders in offspring. It has been established that hyperglycemia alters the expression of genes and microRNAs (miRNAs) regulating the fate of neural stem cells (NSCs) during brain development. In this study, the expression of methyl-CpG-binding protein-2 (Mecp2), a global chromatin organizer and a crucial regulator of synaptic proteins, was analyzed in NSCs obtained from the forebrain of embryos of diabetic mice. Mecp2 was significantly downregulated in NSCs derived from embryos of diabetic mice when compared to controls. miRNA target prediction revealed that the miR-26 family could regulate the expression of Mecp2, and further validation confirmed that Mecp2 is a target of miR-26b-5p. Knockdown of Mecp2 or overexpression of miR-26b-5p altered the expression of tau protein and other synaptic proteins, suggesting that miR-26b-5p alters neurite outgrowth and synaptogenesis via Mecp2. This study revealed that maternal diabetes upregulates the expression of miR-26b-5p in NSCs, resulting in downregulation of its target, Mecp2, which in turn perturbs neurite outgrowth and expression of synaptic proteins. Overall, hyperglycemia dysregulates synaptogenesis that may manifest as neurodevelopmental disorders in offspring from diabetic pregnancy.

Sex differences in glycolipidic disorders after exposure to maternal hyperglycemia during early development.

PURPOSE: The aim of this review was to summarize sex differences in glycolipid metabolic phenotypes of human and animal models after exposure to maternal hyperglycemia and overview the underlying mechanisms, providing a new perspective on the maternal hyperglycemia-triggered risk of glycolipidic disorders in offspring. METHODS: A comprehensive literature search within PubMed was performed. Selected publications related to studies on offspring exposed to maternal hyperglycemia investigating the sex differences of glycolipid metabolism were reviewed. RESULTS: Maternal hyperglycemia increases the risk of glycolipid metabolic disorders in offspring, such as obesity, glucose intolerance and diabetes. Whether with or without intervention, metabolic phenotypes have been shown to exhibit sex differences between male and female offspring in response to maternal hyperglycemia, which may be related to gonadal hormones, organic intrinsic differences, placenta, and epigenetic modifications. CONCLUSION: Sex may play a role in the different incidences and pathogenesis of abnormal glycolipid metabolism. More studies investigating both sexes are needed to understand how and why environmental conditions in early life affect long-term health between male and female individuals.

GST T1, M1, and IRS-1 G972R Genetic Variants Association to Gestational Diabetes Mellitus (GDM) in Egyptian Women: Linkage to Maternal Hyperglycemia.

BACKGROUND: Gestational Diabetes Mellitus (GDM) shares in part the pathogenic mechanisms of multiple genetic interactions. Some of the T2D susceptibility genes are encountered in association with GDM. OBJECTIVE: We aimed to investigate GST T1, M1, and G972R IRS-I gene polymorphisms with the risk of developing GDM. METHODS: In this randomized case-control study, pregnant women with GDM were genotyped by PCR analysis for glutathione s-transferase-T1, M1 variant polymorphisms. RFLP was done for the G972R IRS 1 gene. Their newborns were additionally assayed for the whole of the clinical, laboratory, and genetic aspects. RESULTS: The T allele IRS-1rs1801278 TT genotype was more frequently detected in GDM mothers in comparison to healthy control ones [for TT homozygous variant; OR(CI 95%): 2.05(1.09-3.87, p: 0.025)]. Furthermore, GST T1 null was significantly presented in GDM mothers than those of control mothers [OR (CI95%: 0.29 (0.084-1.02), p:0.04]. Added to the significant correlation of glycemic indices to clinical parameters of infants born to GDM, the M1-null genotype of GST was significantly correlated (p<0.05) to abnormal values of respiratory rates and 1 minute-APGAR score noted for extra NICU care. CONCLUSION: Our results suggested that GST T1null and IRS-1 TT genotypic variants were claimed for GDM development among Egyptian women with a possible impact on their newly born infants.

Gestational diabetes: Implications for fetal growth, intervention timing, and treatment options.

Maternal gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy, which can adversely affect the short- and long-term health of mothers and newborns. In recent years, several studies have revealed the early impact of maternal hyperglycemia on fetal growth trajectory and birth weight abnormalities in GDM-exposed pregnancies. However, an intense debate continues regarding the mode and optimal timing of diagnosis and treatment of this condition. The purpose of this review is to provide a brief overview of the understanding of GDM and its implications for fetal growth, addressing the modulatory role of medical nutrition therapy and available pharmacological antidiabetic agents (i.e. insulin, metformin, and glyburide), and to identify gaps in current knowledge toward which future research should be directed.

Predictability of Macrosomic Birth based on Maternal Factors and Fetal Aneuploidy Screening Biochemical Markers in Hyperglycemic Mothers.

Background: Macrosomic birth weight has been implicated as a significant risk factor for developing various adult metabolic diseases such as diabetes mellitus and coronary heart diseases; it has also been associated with higher incidences of complicated births. This study aimed to examine the predictability of macrosomic births in hyperglycemic pregnant women using maternal clinical characteristics and serum biomarkers of aneuploidy screening performed in the first half of pregnancy. Methods: A retrospective observational study was performed on a cohort of 1,668 pregnant women who 1) had positive outcomes after undergoing 50-g oral glucose challenge test (OGCT) at two university-based hospitals and 2) underwent any one of the following maternal biomarker screening tests for fetal aneuploidy: triple test, quadruple test, and integrated test. Logistic regression-based models for predicting macrosomic births using maternal characteristics and serum biomarkers were developed and evaluated for prediction power. A nomogram, which is a graphical display of the best predictable model, was then generated. Results: The study cohort included 157 macrosomic birth cases defined as birth weight ≥3,820 g, which was equivalent to the top 10 percentile of the modeling cohort. Three primary models solely based on serum biomarkers achieved area under curves (AUCs) of 0.55-0.62. Expanded models, including maternal demographic and clinical factors, demonstrated an improved performance by 25% (AUCs, 0.69-0.73). Conclusion: Our prediction models will help to identify pregnancies with an elevated risk of macrosomic births in hyperglycemic mothers using maternal clinical factors and serum markers from routine antenatal screening tests. Prediction of macrosomic birth at mid-pregnancy may allow customized antenatal care to reduce the risk of macrosomic births.

Growth factors in the fetus and pre-adolescent offspring of hyperglycemic rats.

BACKGROUND: Maternal hyperglycemia influences childhood metabolic syndrome, including obesity and hyperglycemia. We tested the hypothesis that the maternal hyperglycemia influences growth factors in the fetal and pre-adolescent offspring. METHODS: Hyperglycemia was induced in pregnant rats on embryonic day (E)16 using streptozocin followed by implantation with insulin or placebo pellets at embryonic day 18 (E18). Fetuses at E20 and pre-adolescent pups at postnatal day 14 (P14) were studied: (1) normal untreated controls (CTL) at E20; (2) hyperglycemic placebo-treated (HPT) at E20; (3) hyperglycemic insulin-treated (HIT) at E20; (4) CTL at P14; and (5) HIT at P14. Fetal and pre-adolescent growth factors were determined. RESULTS: Biomarkers of hypoxia were elevated in the HPT group at E20. This group did not survive to term. Maternal insulin improved fetal survival despite lower fetal body weight at E20, however, at normal birth (postnatal day 0 (P0)) and at P14, body weights and blood glucose were higher than CTL. These high levels correlated with aberrant growth factors. Maternal hyperglycemia influenced glucose-6-phosphate dehydrogenase, glucagon, insulin, interleukin-10, and leptin genes. CONCLUSIONS: The impact of maternal hyperglycemia on pre-adolescent glucose and body weight was not a consequence of maternal overnutrition. This suggests an independent link which may affect offspring metabolic health in later life.

Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns.

BACKGROUND: Intrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes. DNA methylation is a potential mechanism underlying these associations. We examined whether maternal early-pregnancy glucose and insulin concentrations are associated with newborn DNA methylation. In a population-based prospective cohort study among 935 pregnant women, maternal plasma concentrations of non-fasting glucose and insulin were measured at a median of 13.1 weeks of gestation (95% range 9.4-17.4). DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Ilumina). We analyzed associations of maternal early-pregnancy glucose and insulin concentrations with single-CpG DNA methylation using robust linear regression models. Differentially methylated regions were analyzed using the dmrff package in R. We stratified the analyses on normal weight versus overweight or obese women. We also performed a look-up of CpGs and differently methylated regions from previous studies to be associated with maternal gestational diabetes, hyperglycemia or hyperinsulinemia, or with type 2 diabetes in adults. RESULTS: Maternal early-pregnancy glucose and insulin concentrations were not associated with DNA methylation at single CpGs nor with differentially methylated regions in the total group. In analyses stratified on maternal BMI, maternal early-pregnancy glucose concentrations were associated with DNA methylation at one CpG (cg03617420, XKR6) among normal weight women and at another (cg12081946, IL17D) among overweight or obese women. No stratum-specific associations were found for maternal early-pregnancy insulin concentrations. The two CpGs were not associated with birth weight or childhood glycemic measures (p values > 0.1). Maternal early-pregnancy insulin concentrations were associated with one CpG known to be related to adult type 2 diabetes. Enrichment among nominally significant findings in our maternal early-pregnancy glucose concentrations was found for CpGs identified in a previous study on adult type 2 diabetes. CONCLUSIONS: Maternal early-pregnancy glucose concentrations, but not insulin concentrations, were associated with DNA methylation at one CpG each in the subgroups of normal weight and of overweight or obese women. No associations were present in the full group. The role of these CpGs in mechanisms underlying offspring health outcomes needs further study. Future studies should replicate our results in larger samples with early-pregnancy information on maternal fasting glucose metabolism.

The Joint Associations of Maternal BMI and Glycemia with Childhood Adiposity.

CONTEXT: An obesogenic perinatal environment contributes to adverse offspring metabolic health. Previous studies have been limited by lack of direct adiposity measurements and failure to account for potential confounders. OBJECTIVE: Examine the joint associations of maternal midpregnancy body mass index (BMI) and glycemia with direct adiposity measures in 10-14 year old offspring. DESIGN AND SETTING: International, epidemiological study: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and HAPO Follow-up Study, conducted between 2000-2006 and 2013-2016, respectively. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 4832 children, adiposity measures for body mass index (BMI), body fat with air displacement plethysmography, skinfold thickness, and waist circumference were obtained at mean age 11.4 years. RESULTS: Maternal BMI and glucose, as continuous and categorical variables, were the primary predictors. In fully adjusted models controlling for child age, sex, field center, and maternal characteristics, maternal BMI had significant, positive associations with all childhood adiposity outcomes, while maternal glycemia had significant, positive associations with childhood adiposity outcomes except BMI. In joint analyses, and compared with a nonobese, nongestational diabetes mellitus (GDM) reference group, maternal obesity and GDM were associated with higher odds (maternal obesity odds ratio; OR [95% confidence interval; CI], GDM OR [95% CI]; combined OR [95% CI]) of childhood overweight/obese BMI (3.00 [2.42-3.74], 1.39 [1.14-1.71], 3.55 [2.49-5.05]), obese BMI (3.54 [2.70-4.64], 1.73 [1.29-2.30], 6.10 [4.14-8.99]), percent body fat >85th percentile (2.15 [1.68-2.75], 1.33 [1.03-1.72], 3.88 [2.72-5.55]), sum of skinfolds >85th percentile (2.35 [1.83-3.00], 1.75 [1.37-2.24], 3.66 [2.55-5.27]), and waist circumference >85th percentile (2.52 [1.99-3.21], 1.39 [1.07-1.80], 4.18 [2.93-5.96]). CONCLUSIONS: Midpregnancy maternal BMI and glycemia are independently and additively associated with direct adiposity measures in 10-14 year old children. The combination of maternal obesity and GDM is associated with the highest odds of childhood adiposity.

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels.

Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5'-C-phosphate-G-3' (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother-child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (ß = -2.69, p = 0.05) and fat distribution (ß = -0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (ß = -0.01, p = 0.04) and neonatal leptinemia (ß = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood.

Associations of maternal glycemia and prepregnancy BMI with early childhood growth: a prospective cohort study.

The prevalence of maternal and child overweight/obesity and gestational hyperglycemia has increased greatly in China in recent years. However, studies examining the relationship between maternal hyperglycemia, maternal prepregnancy body mass index (ppBMI), and offspring obesity in China are limited. Here, we conducted a prospective study of 6684 mother-child pairs in Wuhan, China in 2012-2015. Maternal glucose concentrations were measured at approximately 24-28 weeks of gestation; children's weight and length were measured at birth and at 6, 12, and 24 months of age; and BMI-for-age Z-scores (BMIZ) were calculated for different time points. We found that maternal fasting plasma glucose (FPG) concentrations were positively associated with offspring ponderal index and the risk of macrosomia at birth, but not with BMIZ or the risk of overweight/obesity at 6, 12, and 24 months of age. By contrast, maternal ppBMI was positively associated with both an increased risk of macrosomia at birth and overweight/obesity at 6, 12, and 24 months of age. Here, we observed an interaction effect of the association of FPG and ppBMI on offspring macrosomia and a mediating effect of gestational diabetes mellitus on the pathway between ppBMI and macrosomia. Our findings suggest that maternal ppBMI is a more pronounced predictor than gestational FPG concentrations in both the relation to BMIZ and the risk of overweight/obesity in early childhood.

High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction.

Offspring of diabetic mothers are susceptible to developing type 2 diabetes due to pancreatic islet dysfunction. However, the initiating molecular pathways leading to offspring pancreatic islet dysfunction are unknown. We hypothesized that maternal hyperglycemia alters offspring pancreatic islet transcriptome and negatively impacts offspring islet function. We employed an infusion model capable of inducing localized hyperglycemia in fetal rats residing in the left uterine horn, thus avoiding other factors involved in programming offspring pancreatic islet health. While maintaining euglycemia in maternal dams and right uterine horn control fetuses, hyperglycemic fetuses in the left uterine horn had higher serum insulin and pancreatic beta cell area. Upon completing infusion from GD20 to 22, RNA sequencing was performed on GD22 islets to identify the hyperglycemia-induced altered gene expression. Ingenuity pathway analysis of the altered transcriptome found that diabetes mellitus and inflammation/cell death pathways were enriched. Interestingly, the downregulated genes modulate more diverse biological processes, which includes responses to stimuli and developmental processes. Next, we performed ex and in vivo studies to evaluate islet cell viability and insulin secretory function in weanling and adult offspring. Pancreatic islets of weanlings exposed to late gestation hyperglycemia had decreased cell viability in basal state and glucose-induced insulin secretion. Lastly, adult offspring exposed to in utero hyperglycemia also exhibited glucose intolerance and insulin secretory dysfunction. Together, our results demonstrate that late gestational hyperglycemia alters the fetal pancreatic islet transcriptome and increases offspring susceptibility to developing pancreatic islet dysfunction.

Relationship between threatened miscarriage and gestational diabetes mellitus.

BACKGROUND: Both threatened miscarriage and gestational diabetes mellitus (GDM) are common complications of pregnancy. However, only one pilot study has reported that these complications are not related. We aimed to investigate whether threatened miscarriage is one of the risk factors of GDM. METHODS: An unmatched case-control study of 1567 pregnant Korean women who underwent a two-step approach to diagnose GDM was retrospectively conducted. The eligible women were classified into normal (n = 840), borderline GDM (n = 480), and GDM (n = 247) groups. We analyzed the associations with threatened miscarriage in all groups with adjustment for confounding factors. RESULTS: The proportion of women who experienced threatened miscarriage was significantly lower in the GDM group than in the normal group (adjusted odds ratio (OR), 0.38; 95% confidence interval (CI), 0.18-0.78). It was significantly lower in the maternal hyperglycemia group (borderline GDM and GDM groups) than in the normal group (adjusted OR, 0.66; 95% CI, 0.47-0.91). The proportion of women who experienced threatened miscarriage was also significantly lower in the GDM group than in the normal (adjusted OR, 0.35; 95% CI, 0.17-0.70) and borderline GDM groups (adjusted OR, 0.46; 95% CI, 0.22-0.94). Moreover, the proportion of women who experienced threatened miscarriage significantly decreased according to the severity of glucose intolerance (adjusted OR, 0.94; 95% CI, 0.76-1.16). CONCLUSION: This study demonstrates that threatened miscarriage is associated with decreased risk of GDM and the severity of glucose intolerance in Korean women. Additional studies are warranted to understand the pathophysiologic mechanisms that might exist between these frequent complications of pregnancy.

Cerebroplacental ratio in pregnancies complicated by gestational diabetes mellitus.

OBJECTIVE: To assess the relationship between the cerebroplacental ratio (CPR) and intrapartum and perinatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort study of women with a non-anomalous singleton pregnancy diagnosed with GDM who delivered at Mater Mothers' Hospital between 2007 and 2015. CPR was measured in 1089 cases between 34 + 0 and 36 + 6 weeks' gestation. CPR values were compared between groups categorized according to GDM treatment (by diet, oral hypoglycemic agent (OHA) or insulin). The association between CPR and intrapartum and perinatal outcomes was evaluated. RESULTS: No difference in CPR was observed between treatment groups. Fetuses with CPR < 10th centile were significantly more likely to have adverse composite perinatal outcome (odds ratio (OR) = 2.93 (95% CI, 1.95-4.40)), preterm delivery and low birth weight than fetuses with CPR ≥ 10th centile (all P < 0.001). These associations were present regardless of the type of GDM treatment. Fetuses of women with insulin-controlled GDM had poorer neonatal outcomes than did fetuses of women treated with OHA or dietary control alone. The risk of adverse outcome was significantly increased in the insulin-treated group (OR = 1.75 (95% CI, 1.34-2.28); P < 0.001), which also had higher rates of preterm delivery and higher birth weight. CONCLUSION: Regardless of the type of treatment, a low CPR is associated with poorer neonatal outcome in women with GDM. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Streptozotocin-Induced Maternal Hyperglycemia Increases the Expression of Antioxidant Enzymes and Mast Cell Number in Offspring Rat Ventral Prostate.

Gestational diabetes mellitus (GDM) has increased in recent years. Although the cellular and molecular mechanisms involved in GDM-increased risk factors to offspring remained poorly understood, some studies suggested an association between an increase in oxidative stress induced by maternal hyperglycemia and complications for both mothers and newborns. Here, we investigated the impact of maternal hyperglycemia followed by maternal insulin replacement during lactation on the expression of antioxidant enzymes and mast cell number in offspring ventral prostate (VP) at puberty. Pregnant rats were divided into three groups: control (CT); streptozotocin-induced maternal hyperglycemia (MH); and MH plus maternal insulin replacement during lactation (MHI). Male offspring were euthanized at postnatal day (PND) 60 and the VP was removed and processed for histology and Western blotting analyses. Maternal hyperglycemia delayed prostate maturation, and increased mast cell number catalase (CAT), superoxide dismutase (SOD), glutatione-s-transferase (GST-pi), and cyclooxygenase-2 (Cox-2) expression in the offspring of hyperglycemic dams. Maternal insulin replacement restored VP structure, mast cell number and antioxidant protein expression, except for Cox-2, which remained higher in the MHI group. Thus, an increase in oxidative stress induced by intrauterine hyperglycemia impacts prostate development and maturation, which persists until puberty. The overall improvement of maternal metabolism after insulin administration contributes to the restoration of prostate antioxidant enzymes and secretory function. Taken together, our results highlighted that imbalanced physiological maternal-fetal interaction contributes to the impairment of reproductive performance of the offspring from diabetic mothers. Anat Rec, 300:291-299, 2017. © 2016 Wiley Periodicals, Inc.

Unexpected regulation of miRNA abundance during adaptation of early-somite mouse embryos to diabetic pregnancy.

Maternal diabetes is one of major causes of congenital malformations in offspring, but the underlying mechanism is still unclear. MiRNAs play an important role in transcriptional and post-transcriptional regulation of gene expression. However, no miRNA expression profiling of hyperglycemic offspring are thus far available. Female mice were made diabetic with streptozotocin, treated with slow-release insulin tablets, and mated. MiRNA expression profiling with Next Generation Sequencing on the SOLiD5 platform was performed on 8 control and 5 hyperglycemic embryonic day (ED)8.5 and 9 control and 6 hyperglycemic ED9.5 embryos. Differential expression was analyzed with the Wald test. On ED8.5, the abundance of expressed miRNAs was similar in control and hyperglycemic ED8.5 embryos. The spectrum of expressed miRNAs had not changed in ED9.5 embryos, but the abundance of most miRNAs increased ∼5-fold in control embryos. However, hyperglycemic D9.5 embryos were unable to mount this increase in prevalence. Only 3 miRNAs were differentially expressed in control and hyperglycemic ED9.5 embryos, but their putative target genes were underrepresented in the Jackson database of genes causing cardiovascular or neural malformations.

Maternal hyperglycemia during labor and related immediate post-partum maternal and perinatal outcomes at the Yaoundé Central Hospital, Cameroon.

BACKGROUND: Data on the prevalence and complications of gestational diabetes are very scarce in Cameroon. The aim of this study was to evaluate the uptake of screening for gestational diabetes and assess the immediate post-partum outcome of hyperglycemic parturient mothers and perinatal outcome of their babies. METHODS: A prospective cohort study was held at the Maternity of the Yaoundé Central Hospital from March to June 2013. One hundred volunteer women in labor without overt diabetes mellitus and having fasted for 8 to 12 h were recruited. No intervention was given. A clinical examination was done and capillary glucose recorded. Parturient women were categorized into two groups (hyperglycemic and non-hyperglycemic subjects) based on glycemia results interpreted according to the International Association of Diabetes and Pregnancy Study Groups. Mothers' clinical examination was repeated and neonates examined immediately after delivery. Perinatal outcomes associated with maternal hyperglycemia during labor were assessed using relative risks. A p value <0.05 was considered statistically significant. RESULTS: One hundred women with a mean age of 27 (SD 6) years were recruited. Of them, 22 (22 %) had already been screened for gestational diabetes at baseline. Thirty-one (31 %) were diagnosed with hyperglycemia during labor, and this condition was highly associated with macrosomia in neonates (RR = 8.9, 95 % CI 2.70-29.32; p < 0.001). Other complications associated with maternal hyperglycemia during labor were perineal tears, cesarean section, and intrauterine fetal death, though the association was not statistically significant. CONCLUSIONS: The main finding of this study is that maternal hyperglycemia during labor is highly associated with macrosomia in neonates. About a third of mothers were concerned with hyperglycemia during labor, and gestational diabetes was insufficiently screened in this series.

Placental structural abnormalities have detrimental hemodynamic consequences in a rat model of maternal hyperglycemia.

INTRODUCTION: Human type 1 diabetic pregnancy is associated with placental structural and hemodynamic abnormalities. We hypothesized that in rat fetuses of hyperglycemic dams, placental and fetal blood flow velocity waveforms demonstrate compromised hemodynamics when compared to control fetuses, and these hemodynamic parameters correlate with placental structural abnormalities at near term gestation. METHODS: Streptozotocin-induced maternal hyperglycemia group comprised 10 dams with 107 fetuses and the control group 20 dams with 219 fetuses. Doppler-ultrasonographic examinations were performed at gestational days 13-14, 16-17, and 19-21. After the last examination, placentas were collected for morphologic, gene expression, and cytokine analysis. RESULTS: Umbilical artery (UA), descending aorta (DAO), and ductus venosus (DV) pulsatility indices (PI) were significantly higher at each study point in maternal hyperglycemia compared to controls. Placental size, glycogen storages, venous thrombosis formation, and fluid accumulation were increased in maternal hyperglycemia. Epidermal growth factor receptor (Edgfrb), platelet derived growth factor receptor beta polypeptide (Pdgfrb), and tumor necrosis factor receptor superfamily, member 12α (Tnfrsf12α) expressions were decreased. Interleukin (IL) -2 and -4 concentrations were decreased, and IL-1beta levels were increased in maternal hyperglycemia. UA PIs correlated positively with DV PIV, DAO PI, fluid accumulation, and glycogen storages. UA PIs correlated negatively with IL-4, Edgfrb, and Pdgfrb. DISCUSSION: In maternal hyperglycemia, placental and fetal hemodynamics were compromised during the last trimester of pregnancy compared to normoglycemic pregnancies. Placental structural, metabolic, and growth related gene expression, and inflammatory marker abnormalities were associated with hemodynamic compromise.