Prevention of Gestational Diabetes Mellitus (GDM); Targeting Early Pregnancy Intervention to Women at Risk

Abstract

Background: Gestational diabetes mellitus (GDM) is a common metabolic disorder of pregnancy, particularly among women living with obesity. GDM is associated with increased risk of short- and long-term adverse consequences for both the mother and her infant. Identification of women at high risk of developing GDM would facilitate targeted intervention in those who would benefit the most. This thesis comprises different studies, each aimed at enhancing the understanding, prediction and prevention of GDM in women who are at increased risk of the condition. Overarching aim: To identify pregnant women at higher risk of developing GDM and test the feasibility and efficacy of diet and/or metformin to improve glucose homeostasis and pregnancy outcomes. Methods: This thesis consists of a systematic review and meta-analysis in addition to three distinct studies. These are outlined below: i) ii) iii) Study (1): studies evaluating behavioural/pharmacological interventions or dietary supplements in the preconception period and in pregnant women with greater risk of developing GDM were assessed and evidence synthesised using a systematic review and meta-analysis. Study (2): Using a prospective cohort (the GDM validation study), the performance of two pragmatic GDM prediction tools (model 1 and model 2) was compared in women with obesity. Study (3): A secondary analysis was performed using data collected from women who took part in the UPBEAT study (UK Pregnancy Better Eating and Activity Trial). This analysis compared metabolic profiles in women identified as high-risk of developing GDM using the prediction tool, stratified by GDM diagnosis. Analyte 13 iv) data, measured using a nuclear magnetic resonance platform and conventional assays, were compared between women who developed GDM and those who did not in early (15+0 –18+6 weeks’ gestation) and mid-pregnancy (23+2 –30+0 weeks’ gestation). Study (4): A preliminary feasibility and Patient-Centred outcomes analysis of UPBEAT- Taking it Forward (TIF) was carried out. UPBEAT-TIF is an ongoing randomised controlled trial (RCT) of lifestyle advice with or without metformin compared to standard antenatal care in individuals identified as high-risk of developing GDM using the prediction tool. Results: i) Study (1): The systematic review and meta-analysis identified eighty-four RCTs (preconception=2, pregnancy=82). The review provided evidence that interventions targeted at women at risk of GDM may be an effective strategy for GDM prevention and highlighted the need for further studies using validated prediction tools or multiple risk factors to target high-risk women for intervention before and during pregnancy (Quotah et al., 2024). ii) Study (2): Model 2 incorporating non-biochemical factors (age/mid-arm circumference/systolic-blood pressure), haemoglobin A1c (HbA1c), glucose and triglycerides demonstrated a higher performance in predicting GDM compared to model 1 with non-biochemical factors, HbA1c and adiponectin (AUC 0.755 vs AUC 0.637; p=0.006). Model 2 could facilitate early detection among women with obesity and increased risk, enabling timely implementation of targeted lifestyle or pharmacological interventions for those who are most likely to benefit. However, external validation of the models' performance is underway. 14 iii) Study (3): The secondary analysis revealed biochemical differences between women with obesity identified as high-risk using the predictive tool who went on to develop GDM compared to those identified as high risk who did not. These differences were found both early in gestation and at the time of GDM diagnosis. The identified differences may be related to defective β-cell secretory function (Quotah et al., 2022). iv) Study (4): The preliminary feasibility analysis of UPBEAT-TIF RCT demonstrated that a targeted intervention in women at increased risk of GDM is a feasible approach. Preliminary analysis of outcomes did not support the use of lifestyle interventions with or without metformin to improve glucose concentrations among women who are at increased risk of GDM. The unexpectedly low rates of GDM across all groups, including the controls, warrant additional explorations. At the time of writing, recruitment to the study had not yet reached the predefined sample size. Conclusion: Overall, this thesis makes innovative contributions to understanding GDM pathophysiology and identifying high-risk women in order to assess the potential benefit of interventions. Intervention studies in the preconception period and in early pregnancy that target women at increased risk of GDM using multiple risk factors or validated prediction tools are warranted, as a strategy towards prevention of GDM and improved maternal and infant health among those who would benefit the most.