EMERGE Mothers and Kids

Primary outcomes

1. To assess if treatment of GDM with metformin during pregnancy compared to placebo reduces the risk of disorders of glucose metabolism at follow up..

   Time frame: Up to 10 years post the index pregnancy

   This will be evaluated using a 75g oral glucose tolerance test (OGTT) and a haemoglobin A1c (HbA1c). Cutoffs for diabetes, imparied fasting gluocse and impaired glucose tolerance will be in line with the American Diabetes Association diagnostic criteria (ADA 2023).

2. To assess if treatment of GDM with metformin during pregnancy compared to placebo reduces the risk of metabolic syndrome.

   Time frame: Up to 10 years post the index pregnancy

   Metabolic syndrome is defined as the presence of >3 of the following risk factors (International Diabetetes Foundation 2009)

   • Fasting glucose >5.6 mmol/L or diagnosed diabetes
   • High density lipoprotein (HDL) cholesterol of <1.3 mmol/L or drug treatment for low HDL cholesterol
   • Triglyceride level of >1.7 mmol/L or drug treatment for elevated triglycerides
   • Waist circumference of >80cm
   • Hypertension with a blood pressure of > 130/85 mmHg or drug treatment for hypertension

3. To assess if treatment of GDM with metformin during pregnancy compared to placebo reduces rates of OW and OB at follow up.

   Time frame: Up to 10 years post the index pregnancy

   Definitions of overweight and obesity are a body mass index of >25 kg/m2 and >30 kg/m2, respectively.

4. To assess if treatment of GDM with metformin during pregnancy compared to placebo reduces the risk of hypertension.

   Time frame: Up to 10 years post the index pregnancy

   Hypertension is defined as a blood pressure of > 130 mmHg systolic or >80 mmHg diatolic (Whelton 2017).

5. To examine the associations of GDM diagnosis, sum of fasting, 1-hour, and 2-hour glucose z-scores after 75-g load, insulin sensitivity, and lipid levels at 24-32 weeks' gestation with lipid levels at up to 10 years postpartum.

   Time frame: Up to 10 years post the index pregnancy

   Lipid levels will be assessed by measuring a fasting sample and will be analysed using local assays.

6. To determine whether treatment with metformin during pregnancy, in women with GDM, leads to a reduction in adiposity in the offspring at follow up as measured by anthropometric measurements and sum of skinfolds.

   Time frame: Up to 10 years post the index pregnancy

   Obesity will be defined as a BMI of >95th percentile or BMI > 30 kg/m2 (whichever is lower) for children 2 years and older. Overweight will be defined as a BMI of >85th percentile.

   Weight for height gender specific growth charts will be used for children <2 years of age and a weight-for-height which is >95th centile will be considered obese. Overweight wil be defined as a BMI of >85th percentile.