The Effect of In-utero Exposure to Metformin in 5-11 Year Old Offspring of Mothers in the MiTy Trial

Study Overview
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Brief Summary
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The incidence of diabetes in pregnancy is rising, with rates of 1 in 7 pregnancies globally. Metformin is used for type 2 diabetes (T2DM) outside of pregnancy and is now increasingly prescribed during pregnancy. There are some concerns as metformin crosses the placenta and effects on offspring exposed during pregnancy are unknown. Animal and human evidence indicate that metformin may create an atypical in-utero environment similar to under-nutrition which has been associated with adult obesity. This is supported by studies in children of mothers treated with metformin in other populations where an increase in childhood obesity was found at 4-9 years of age. We now have evidence from the MiTy trial, that offspring of metformin-exposed women with T2DM have less large infants and are less adipose at birth, but are also more likely to be small for gestational age (SGA). These effects could lead to benefit or harm in the long-term. Offspring of MiTy mothers are currently being followed up to 2 years. Given that long-term effects may not be evident until 5 years of age, it is imperative to follow these children longer. Goals/Research Aims:To determine whether in-utero exposure to metformin, in offspring of women with T2DM, is beneficial or harmful in the long-term. Research Questions: 1. In offspring of women with T2DM, how does treatment with metformin during pregnancy affect a) adiposity b) growth over time c) metabolic syndrome d) cognitive and behavioral measures:2. What factors predict altered childhood adiposity and insulin resistance in these offspring? Primary Outcome: Body mass index (BMI) z-score. Secondary Outcomes: 1) other measures of adiposity (i.e. skinfolds, 2) growth over time 3) measures of insulin resistance 4) adipocytokines 5)neurodevelopment Expected Outcomes Given these increasing concerns, this study will inform the best treatment for pregnant mothers with diabetes by studying the long-term outcomes of children exposed to metformin during pregnancy.

Official Title
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A Multi-centre Follow up Study of the Effect of In-utero Exposure to Metformin in 5-11 Year Old Offspring of Mothers in the MiTy Trial

Conditions
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Diabetes Mellitus, Type 2, Pregnancy in Diabetic, Child Obesity, Child Development

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liveborn offspring of women who participated in the MiTy trial. Exclusion Criteria: Offspring with major congenital anomalies that would affect growth or development (these children have already been excluded from MiTy Kids).
Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Metformin exposed in utero<br>Offspring of mothers who were exposed to metformin during pregnancy in the MiTy trial. | |
| Placebo exposed in utero<br>Offspring of mothers who were not exposed to metformin during pregnancy in the MiTy trial. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Mass Index (BMI) z-score | Using WHO or other appropriate growth charts | 5-11 years of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skinfold measurements | triceps, subscapular and suprailiac skinfold thicknesses | 5-11 years of age | 
| Sum of skinfold measurements: | sum of triceps, subscapular and suprailiac skinfold thicknesses | 5-11 years of age | 
| Triceps skinfolds z-scores | Using WHO or other appropriate growth charts | 5-11 years of age | 
| Ratio of the central to peripheral skinfold ratio | ratio of the central (suprailiac) to peripheral (triceps) skinfold ratio; | 5-11 years of age | 
| Overweight and obesity status | Defined using WHO or other appropriate growth charts | 5-11 years of age | 
| Waist circumference | Waist circumference measurement | 5-11 years of age | 
| Waist to height ratio | Waist and height measurements | 5-11 years of age | 
| Growth trajectory | Longitudinal growth outcomes will be assessed using adiposity measurements from the MiTy trial (newborns) and at 3, 6, 12, 18 and 24 months from the MiTy Kids trial, to ages 5-11 years in the MiTy Tykes trial. | 5-11 years of age | 
| Fat mass | Using the Tanita SC-240 bioimpedance analyzer (BIA) | 5-11 years of age | 
| Percentage of body fat | Using the Tanita SC-240 bioimpedance analyzer (BIA) | 5-11 years of age | 
| Measures of insulin resistance and metabolic syndrome | The following measurements combined will contribute to the assessment of insulin resistance and metabolic syndrome: fasting glucose, fasting insulin, fasting insulin-to-glucose ratio, and the HOMA-IR, serum levels of leptin, adiponectin and lipids | 5-11 years of age | 
| Neurocognitive development | Attention Deficit Hyperactivity Disorder (ADHD)-5 Rating scale | 5-11 years of age | 
| Neurocognitive development | Children's Communication Checklist (CCC-2) | 5-11 years of age | 
| Neurocognitive development | Social Responsiveness Scale (SRS-2) | 5-11 years of age |