Abstract
The aim of this work was to investigate the association of maternal HbA1c during mid-pregnancy with biomarkers of glucose-insulin homeostasis during early childhood (4-7years of age) and to assess whether and how offspring adiposity at birth and at age 4-7years mediates this relationship among 345 mother-child pairs in the Healthy Start Study. The exposure was maternal HbA1c (mmol/mol) measured at 20-34 gestational weeks and categorised into tertiles. The outcomes were offspring fasting glucose, 1/insulin, HOMA2-IR, and HOMA2-B at age 4-7years. The mediators were per cent fat mass (%FM) at birth, %FM at age 4-7years, and the sum of the two as a metric of cumulative adiposity. Mediation analyses were conducted via a counterfactual-based approach. All models accounted for maternal race/ethnicity, offspring age and sex. There was a significant total effect of maternal HbA1c on offspring glucose and 1/insulin. Specifically, we observed a positive trend across tertiles of HbA1c and offspring glucose (p trend <0.001), and an inverse trend across tertiles of HbA1c and offspring 1/insulin (p trend = 0.04). For instance, compared with offspring of women in the lowest tertile of HbA1c, those whose mothers were in the second and third tertiles had 0.04mmol/l (95% CI -0.05, 0.13) and 0.17mmol/l (95% CI 0.08, 0.26) higher fasting glucose concentrations at age 4-7years, respectively. Adjustment for pre-pregnancy BMI did not appreciably change the results. We found no evidence of mediation by offspring adiposity at any life stage. Offspring of women with higher HbA1c during pregnancy had higher fasting glucose and lower insulin sensitivity by early childhood. These relationships were largely unaffected by the child's own adiposity. Graphical abstract.
Highlights
Several studies show a dose–response relationship between maternal blood glucose levels and offspring adiposity starting at birth [1, 2] and biomarkers of glucose–insulin homeostasis as early as 7 years of age [3, 4]
Higher maternal HbA1c corresponded with higher fasting glucose (p trend = 0.03), HOMA2-IR (p trend
Offspring adiposity at birth or at age 4–7 years, or cumulatively across the two time points, did not play a substantial role in mediating the effect of maternal HbA1c on metabolic biomarkers in offspring. These findings suggest the existence of alternative pathways through which maternal blood glucose levels may impact offspring glucose–insulin homeostasis
Summary
Several studies show a dose–response relationship between maternal blood glucose levels (even below gestational diabetes mellitus [GDM] diagnostic criteria) and offspring adiposity starting at birth [1, 2] and biomarkers of glucose–insulin homeostasis as early as 7 years of age [3, 4]. Two recent studies from the Hyperglycemia and Adverse Pregnancy Outcomes [5] Follow-up Study (HAPO-FUS) investigated associations between maternal blood glucose and offspring metabolic biomarkers independent of adiposity [3, 6]. In both analyses, the association between maternal blood glucose and offspring biomarkers at 7–14 years of age was robust to adjustment for offspring BMI or sum of skinfolds, notwithstanding some slight attenuation in the estimate of interest, suggesting minimal mediation by offspring adiposity in late childhood and adolescence. Given that development of metabolic risk likely transpires from chronic excess adiposity, the dynamic changes in fat accrual across infancy and early childhood, and that these life stages are sensitive periods for development of obesity-related diseases, it is important to assess the role of adiposity during multiple life stages and consider the impact of cumulative adiposity over time
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