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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2; Child Development; Child Obesity; Pregnancy in Diabetic

• Study Type: Observational
• Enrollment (Estimated): 220

Contacts and Locations

• Study Contact: Name: Gail Klein, MSc; Phone Number: 416-480-5632; Email: gail.klein@sunnybrook.ca
• Study Contact Backup: Name: Siobhan Tobin, HonBSc; Phone Number: 416-480-5631; Email: mitytykes@sunnybrook.ca

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia
      • Recruiting
      • Campbelltown Hospital
      • Contact: David Simmons, MD
  • Queensland
    • Brisbane, Queensland, Australia
      • Recruiting
      • Mater Misericordiae
      • Contact: Josephine Laurie, MD
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Recruiting
      • Alberta Children's Hospital
      • Contact: Jospehine Ho, MD
    • Edmonton, Alberta, Canada, T6G 2B7
      • Recruiting
      • Stollery Children's Hospital
      • Contact: Andrea Haqq, MD
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3N1
      • Completed
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Completed
      • Children's Health Research Institute of Manitoba (CHRIM)
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • Completed
      • IWK Health Centre
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • Recruiting
      • St Joseph's Health Care
      • Contact: Selina Liu, MD
    • Scarborough, Ontario, Canada, M1P 2V5
      • Recruiting
      • The Scarborough Hospital
      • Contact: Afshan Zahedi, MD
    • Toronto, Ontario, Canada
      • Recruiting
      • Mount Sinai Hospital
      • Contact: Denice Feig, MD
  • Quebec
    • Montréal, Quebec, Canada, H1T 2M4
      • Recruiting
      • Hospital Maisonneuve-Rosemont
      • Contact: Laurent Legault, MD
    • Quebec City, Quebec, Canada, G1V 4G2
      • Completed
      • Chuq-Chul

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Offspring of women with type 2 diabetes who participated in the MiTy trial will be recruited for participation.

Description

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).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Metformin exposed in utero; Offspring of mothers who were exposed to metformin during pregnancy in the MiTy trial.
Placebo exposed in utero; Offspring of mothers who were not exposed to metformin during pregnancy in the MiTy trial.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: Canadian Institutes of Health Research (CIHR); Sunnybrook Research Institute
• Investigators: Principal Investigator: Denice Feig, MD, Mount Sinai Hospital, Toronto, ON, Canada

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2022
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: August 11, 2021
• First Submitted That Met QC Criteria: August 23, 2021
• First Posted (Actual): August 27, 2021

Study Record Updates

• Last Update Posted (Estimated): January 15, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Pregnancy Complications; Obesity; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Diabetes Mellitus, Type 2; Pediatric Obesity; Pregnancy in Diabetics
• Other Study ID Numbers: CTO 3632

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No