Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial

Denice S Feig; J Johanna Sanchez; Kellie E Murphy; Elizabeth Asztalos; Bernard Zinman; David Simmons; Andrea M Haqq; I George Fantus; Lorraine Lipscombe; Anthony Armson; Jon Barrett; Lois Donovan; Paul Karanicolas; Siobhan Tobin; Kathryn Mangoff; Gail Klein; Yidi Jiang; George Tomlinson; Jill Hamilton; MiTy Kids Collaborative Group

doi:10.1016/S2213-8587(23)00004-9

Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial

Lancet Diabetes Endocrinol. 2023 Mar;11(3):191-202. doi: 10.1016/S2213-8587(23)00004-9. Epub 2023 Feb 3.

Authors

Denice S Feig¹, J Johanna Sanchez², Kellie E Murphy³, Elizabeth Asztalos⁴, Bernard Zinman⁵, David Simmons⁶, Andrea M Haqq⁷, I George Fantus⁸, Lorraine Lipscombe⁹, Anthony Armson¹⁰, Jon Barrett⁴, Lois Donovan¹¹, Paul Karanicolas⁴, Siobhan Tobin², Kathryn Mangoff², Gail Klein², Yidi Jiang², George Tomlinson¹², Jill Hamilton¹³; MiTy Kids Collaborative Group

Collaborators

MiTy Kids Collaborative Group:
D S Feig, A Galper, B Cleave, M Strom, K Poolman, D Fong, E Viguiliouk, L Legault, L Boutin, J Ho, H Virtanen, A Zahedi, K Szwiega, J Coolen, R Dias, E Sellers, B Fletcher, L Bourrier, A Haqq, H Rylance, S Hadjiyannakis, J Courtney, R McManus, I Halperin, D Miller, K Coles, D Simmons, J Nema, S J Weisnagel, M C Dubé, J P Chanoine, J Kwan, H D McIntyre, J Laurie, F Maguire, J Soper, T Bridger, R Houlden, A Breen, M McLean, A Duke, S Hendon, A Sigmund

Affiliations

¹ Department of Medicine, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada; Sinai Health System, Mount Sinai Hospital, Toronto, ON, Canada. Electronic address: d.feig@utoronto.ca.
² Sunnybrook Research Institute, Toronto, ON, Canada.
³ Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada; Sinai Health System, Mount Sinai Hospital, Toronto, ON, Canada.
⁴ Sunnybrook Research Institute, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁵ Department of Medicine, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada; Sinai Health System, Mount Sinai Hospital, Toronto, ON, Canada.
⁶ Department of Medicine, Western Sydney University, Sydney, NSW, Australia.
⁷ Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
⁸ Department of Medicine, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada; Sinai Health System, Mount Sinai Hospital, Toronto, ON, Canada; Department of Medicine and Research Institute, McGill University Health Center, McGill University, Montreal, QC, Canada.
⁹ Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Medicine, Women's College Hospital, Toronto, ON, Canada.
¹⁰ Department of Obstetrics and Gynecology, Dalhousie University, Halifax, NS, Canada.
¹¹ Department of Medicine and Department of Obstetrics and Gynecology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
¹² Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Medicine, University Health Network, Toronto, ON, Canada.
¹³ Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

PMID: 36746160
DOI: 10.1016/S2213-8587(23)00004-9

Abstract

Background: Metformin is increasingly being used during pregnancy, with potentially adverse long-term effects on children. We aimed to examine adiposity in children of women with type 2 diabetes from the Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) trial, with and without in-utero exposure to metformin, up to 24 months of age.

Methods: MiTy Kids is a follow-up study that included infants of women who participated in the MiTy randomised controlled trial, receiving either oral 1000 mg metformin twice daily or placebo. Caregivers and researchers remained masked to the type of medication (metformin or placebo) mothers received during their pregnancy. Anthropometric measurements, including weight, height, and skinfold thicknesses, were taken at 3, 6, 12, 18, and 24 months. At 24 months, linear regression was used to compare the BMI Z score and sum of skinfolds in the metformin versus placebo groups, adjusted for confounders. Fractional polynomials were used to assess growth trajectories. This study is registered with ClinicalTrials.gov, NCT01832181.

Findings: Of the 465 eligible children, 283 (61%) were included from 19 centres in Canada and Australia. At 24 months, there was no difference between groups in mean BMI Z score (0·84 [SD 1·52] with metformin vs 0·91 [1·38] with placebo; mean difference 0·07 [95% CI -0·31 to 0·45], p=0·72) or mean sum of skinfolds (23·0 mm [5·2] vs 23·8 mm [5·4]; mean difference 0·8 mm [-0·7 to 2·3], p=0·31). Metformin was not a predictor of BMI Z score at 24 months of age (mean difference -0·01 [95% CI -0·42 to 0·37], p=0·92). There was no overall difference in BMI trajectory but, in males, trajectories were significantly different by treatment (p=0·048); BMI in the metformin group was higher between 6 and 24 months. Children of women with type 2 diabetes were approximately 1 SD heavier than the WHO reference population.

Interpretation: Anthropometrics were similar in children exposed and those not exposed to metformin in utero; hence, overall, data are reassuring with regard to the use of metformin during pregnancy in women with type 2 diabetes and the long-term health of their children.

Funding: Canadian Institute for Health Research.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Canada
Child
Diabetes Mellitus, Type 2* / drug therapy
Female
Follow-Up Studies
Humans
Hypoglycemic Agents / therapeutic use
Infant
Metformin* / therapeutic use
Pregnancy

Substances

Metformin
Hypoglycemic Agents

Associated data

ClinicalTrials.gov/NCT01832181

Grants and funding

CIHR/Canada