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

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

Randomized Controlled Trial

. 2023 Mar;11(3):191-202.

doi: 10.1016/S2213-8587(23)00004-9. Epub 2023 Feb 3.

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 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, Affiliations

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

Randomized Controlled Trial

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 et al. Lancet Diabetes Endocrinol. 2023 Mar.

. 2023 Mar;11(3):191-202.

doi: 10.1016/S2213-8587(23)00004-9. Epub 2023 Feb 3.

Authors

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests DSF has received honoraria from Novo Nordisc for serving on an advisory board and from Sanofi for lectures, unrelated to this current work. AMH is a principal investigator for clinical trials from Levo Therapeutics and Rhythm Pharmaceuticals; is on the Pfizer Canada Somatrogon advisory board and the Rhythm Pharmaceuticals Bardet-Biedl Syndrome advisory board; and has received funding from the Canadian Institutes of Health Research and W Garfield Weston Foundation's Weston Family Microbiome Initiative for unrelated work. IGF declares grants from the Division of Endocrinology and Metabolism, McGill University. JB received honoraria for presentations from Ferring Pharmaceuticals. LL is a member of the Board of Directors of Diabetes Canada (volunteer) and receives salary support as Director of the University of Toronto Novo Nordisk Network for Healthy Populations (donation from Novo Nordisk to University of Toronto). JJS received funding from the Canadian Institutes of Health Research to support her postdoctoral fellowship salary, and grant funds were also used to attend the American Diabetes Association 2022 meeting. JH received research funding from Levo Therapeutics, SunLife, Rhythm Pharmaceuticals, Mead Johnson, Pfizer, and Foundation for Prader-Willi Research; served as a consultant for Novo Nordisk Canada; received an honoraria for speaking from Pfizer; and is the medical director for SickKids Team Obesity Management Program. All other authors declare no competing interests.

Comment in

Big babies, small babies: metformin exposure in pregnancy.
Kusinski LC, Meek CL. Kusinski LC, et al. Lancet Diabetes Endocrinol. 2023 Mar;11(3):145-146. doi: 10.1016/S2213-8587(23)00034-7. Epub 2023 Feb 3. Lancet Diabetes Endocrinol. 2023. PMID: 36746162 No abstract available.

Cited by

Metformin use and preeclampsia risk in women with diabetes: a two-country cohort analysis.
Gordon H, Salim N, Tong S, Walker S, De Silva M, Cluver C, Mehdipour P, Hiscock R, Sutherland L, Doust A, Bergman L, Wikström AK, Lindquist A, Hesselman S, Hastie R. Gordon H, et al. BMC Med. 2024 Sep 27;22(1):418. doi: 10.1186/s12916-024-03628-0. BMC Med. 2024. PMID: 39334302 Free PMC article.
Additional preconception considerations for patients with diabetes.
[No authors listed] [No authors listed] Aust Prescr. 2024 Jun;47(3):95-96. doi: 10.18773/austprescr.2024.022. Aust Prescr. 2024. PMID: 38962380 Free PMC article. No abstract available.
Initiation of metformin in early pregnancy results in fetal bioaccumulation, growth restriction, and renal dysmorphology in a primate model.
Bolte E, Dean T, Garcia B, Seferovic MD, Sauter K, Hummel G, Bucher M, Li F, Hicks J, Qin X, Suter MA, Barrozo ER, Jochum M, Shope C, Friedman JE, Gannon M, Wesolowski SR, McCurdy CE, Kievit P, Aagaard KM. Bolte E, et al. Am J Obstet Gynecol. 2024 Sep;231(3):352.e1-352.e16. doi: 10.1016/j.ajog.2024.06.002. Epub 2024 Jun 11. Am J Obstet Gynecol. 2024. PMID: 38871238 Free PMC article.
Drug Therapies for Diabetes.
Weinberg Sibony R, Segev O, Dor S, Raz I. Weinberg Sibony R, et al. Int J Mol Sci. 2023 Dec 5;24(24):17147. doi: 10.3390/ijms242417147. Int J Mol Sci. 2023. PMID: 38138975 Free PMC article. Review.
15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes-2024.
American Diabetes Association Professional Practice Committee. American Diabetes Association Professional Practice Committee. Diabetes Care. 2024 Jan 1;47(Suppl 1):S282-S294. doi: 10.2337/dc24-S015. Diabetes Care. 2024. PMID: 38078583 Review.

See all "Cited by" articles

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

Grants and funding

CIHR/Canada

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Associated data

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical