Maternal and neonatal outcomes according to the timing of diagnosis of gestational diabetes: A critical appraisal

Table 6 Hyperglycemia in early pregnancy and fetal damage: Proposed mechanisms

Gestational period in weeks	Foetal physiology	Maternal hyperglycemia effects
0-14 GW	Implantation; early embryo organogenesis; decidual histotropic function; early placental development; spiral artery plugging. Low oxygen environment and anaerobic metabolism of glucose (glycolysis) and protection of embryo from oxygen-free radical-mediated damage	Mothers with pregestational prediabetes. Have several metabolic abnormalities: Mild dysglycemia and hyperinsulinemia, changes in HDL-C and triglycerides, C-reactive protein, tissue plasminogen activator antigen, adipokines, and insulin-like growth factor binding protein 2. Needs to explore the influence of these parameters on fetal physiology in the perinatal period and the benefits of preventive strategies
		GDM diagnosed in the first trimester. Probable hyperglycemia-induced organogenesis, implantation and decidual dysfunctions, and placentation defects. Greater pro-oxidant and pro-inflammatory intrauterine milieu induced by hyperglycemia disturb the anaerobic environment, leading to fetal changes and miscarriage
14 GW onwards	Extravillous cytotrophoblast cells invade and remodel decidual cells to enable the entry of fully oxygenated maternal blood to reach the intervillous space and fetoplacental unit. Hematotropic nutrition and fetal growth and development. Placental-derived signals like hormones and extracellular vesicles induce adaptive responses in maternal physiology to support the fetoplacental unit. The mother-placenta interplay persists throughout pregnancy	Hyperglycemia and hyperinsulinemia-induced changes in spiral artery remodeling can interfere with oxygen and nutrient supply to the fetus. This will alter fetal growth dynamics throughout gestation. Hyperglycemia can induce epigenetic alterations affecting the signaling pathway. Insulin is detected in fetal circulation by 12 weeks, and maternal hyperglycemia can trigger a “fetal glucose steal phenomenon” to produce LGA babies. Fetal hyperinsulinemia at 17 GW is associated with insulin resistance and high free fatty acids in the offspring at age 5. This observation suggests that maternal hyperglycemia prior to 24 GW may trigger fetal programming for metabolic outcomes in the offspring. This is presumed to be due to epigenetic factors like DNA methylation, histone post-translational modifications, and non-coding RNAs

GDM: Gestational diabetes mellitus; GW: Gestational weeks; LGA: Large for gestational age; HDL-C: High density lipoprotein cholesterol.