Amélie Taschereau

Background/Aims: Pregnancy is a window of opportunity for closer links with clinical care, and to identify women at risk of chronic disease. Because of the elevated risk of type 2 diabetes (T2D) associated with gestational diabetes mellitus (GDM), most existing prediction models for post-delivery T2D focus on women with GDM, leaving many parous women without clear risk stratification. This study aimed to develop a prediction model for prediabetes or T2D risk in the general population of parous women, based on clinical pregnancy variables. Methods: We assessed prediabetes/T2D five years after delivery in the Genetics of Glucose Regulation in Gestation and Growth (Gen3G) cohort (N=403). Using a machine-learning approach, we developed a risk prediction model from which we derived a simple, clinically usable risk index: the Gestational 4-variable Prediabetes/type 2 diabetes (G4PD) index. The G4PD index was then validated in the Project Viva cohort at three years (n=562) and seventeen years (n=541) after delivery. Results: The G4PD index included gestational weight gain, pre-gestational body mass index, first-trimester maternal age, and a GDM variable reflecting hyperglycemia severity during pregnancy. In Gen3G, the model achieved a cross-validated estimate of the area under the receiver operating characteristic curve (ROC-AUC) of 0.696. The G4PD index achieved ROC-AUC of 0.682 in the 17-year Project Viva dataset, with similar results in the 3-year dataset. Beyond overall discrimination, the model effectively stratified women into clinically meaningful risk categories, with those in the lowest group (< 2) exhibiting an expected risk of ~2% and ~15% at three and seventeen years after delivery, respectively, whereas those with the highest scores (≥ 7 or ≥ 5) expected substantially higher risks (~7% and ~37% at respective time points). Conclusion: The G4PD index, derived from clinical pregnancy variables, moderately predicts the risk of prediabetes/T2D over several years.

Purpose Initiated in 2010, the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort investigates the pathophysiology of impaired glycaemic regulation in pregnancy and evaluates its impact on both the mothers and her offspring health trajectory. Follow-up visits 3 and 5 years after delivery aimed to investigate pregnancy-related risk factors such as maternal obesity and gestational hyperglycaemia in relation to the mother’s metabolic health after pregnancy, and with offspring health outcomes such as risk of obesity and neurodevelopmental problems in early childhood. We also investigated molecular mechanisms involved in the fetal programming of these later health outcomes. Participants Of the 1024 women originally recruited in the first trimester of pregnancy, we have targeted the 854 who had complete glucose tolerance test data and the 724 newborns who provided placenta and/or cord blood samples for follow-up recruitment. Of these, 695 mother–child dyads agreed to be contacted for the prospective follow-up visits. 448 and 521 mother–child dyads completed the research visits at 3 and 5 years after delivery respectively. Findings to date At both visits, we collected the mother’s and child’s medical history, lifestyle (using validated questionnaires), sociodemographic status, anthropometric measurements, mother’s blood samples, child’s saliva samples and growth charts. At the 5-year-old visit, we additionally collected the mother’s and child’s urine and stool samples and the child’s blood samples; we performed a 75 g oral glucose tolerance test in the mothers and assessed the body composition in children using dual-energy X-ray absorptiometry. Using the Gen3G rich longitudinal data set, we have enhanced the understanding of the pathophysiology and characterisation of the heterogeneity of gestational diabetes mellitus, and we have shown that gestational hyperglycaemia and insulin resistance are associated with offspring epigenetics (DNA methylation) variations in the placenta, cord blood and blood at 5 years of age, as well as with offspring anthropometric, metabolic and neurodevelopmental outcomes in early childhood. Future plans We are currently conducting a prospective follow-up of mothers and their children 12 years after delivery to study how prenatal and early-life metabolic factors may programme childhood adiposity and obesogenic dietary behaviours. This follow-up should be completed by the end of 2026.

Plasminogen activator inhibitor (PAI-1) expression has been associated with a higher risk of development of obesity. DNA methylation (DNAm) is an epigenetic mechanism regulating gene transcription and likely involved in the fetal programming of childhood obesity. Our study aimed to assess the associations between PAI-1 gene (SERPINE1) DNAm, plasma PAI-1 levels, and adiposity at five years of age. We analyzed DNAm and anthropometric data from 146 girls and 177 boys from the Gen3G prospective birth cohort. We assessed adiposity using BMI z-scores, waist circumference, total skinfolds, and percentages of total, android, and trunk fat measured by dual-energy radiography (DXA). We estimated blood cell DNAm levels at 15 CpG sites within SERPINE1 using the methylationEPIC array. After correction for multiple testing, we found that lower DNAm in SERPINE1 intron 3 (cg11353706) was associated with greater adiposity levels in girls (waist circumference: r = −0.258, p = 0.002; skinfolds: r = −0.212, p = 0. 013; android fat: r = −0.215, p = 0.015; BMI z-score: r = −0.278, p < 0.001) and that lower DNAm in the SERPINE1 promoter (cg19722814) was associated with higher plasma PAI-1 levels in boys (r = −0.178, p = 0.021). Our study suggests that DNAm levels at the SERPINE1 gene locus are negatively correlated with adiposity, but not with plasma PAI-1 levels, in young girls only.