Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial

Denice S Feig, Kellie Murphy, Elizabeth Asztalos, George Tomlinson, Johanna Sanchez, Bernard Zinman, Arne Ohlsson, Edmond A Ryan, I George Fantus, Anthony B Armson, Lorraine L Lipscombe, Jon F R Barrett, MiTy Collaborative Group, George Carson, Suzanne Williams, Sheila Kelly, Heather Clark, Diane Donat, Shital Gandhi, Barbara Cleave, Michele Strom, Lois Donovan, Carolyn Oldford, Catherine Young, Brenda Galway, Minnie Parsons, Ariane Godbout, Michele Mahone, Florence Weber, Marie-Josee Bedard, BiLan Wo, Sylvie Daigle, Amir Hanna, Maria Wolfs, Leanne De Souza, Robyn Houlden, Adriana Breen, Tina Kader, Luca Cefis, Erin Keely, Josee Champagne, Jennifer Klinke, Julie Lee, Peter Subrt, Francina Carr, Sharon Young, Peter Subrt, Francina Carr, Sharon Young, Sarah Kwong, Heather Rylance, Helene Long, Julie Lambert, Julia Lowe, Anna Rogowsky, Susan Jackson, Sora Ludwig, Laurie Slater, Lori Berard, David McIntyre, Anne Tremellen, Ruth McManus, Sara Meltzer, Natasha Garfield, Shari Segal, David Miller, Karen Coles, Carol Fergusson, Jill Newstead-Angel, Judy Brandt, Thomas Ransom, Darlene Baxendale, Evelyne Rey, Diane Francoeur, Sophie Perreault, Heather Rylance, Dory Sample, David Thompson, Sharon Thompson, JohnS Weisnagel, Camile Lambert, Valerie-Eve Julien, Marie-Christine Dube, Louise Rheaume, Afshan Zahedi, Grace Lee, Krystyna Szwiega, Asma Qureshi, Siobhan Tobin, Denice S Feig, Kellie Murphy, Elizabeth Asztalos, George Tomlinson, Johanna Sanchez, Bernard Zinman, Arne Ohlsson, Edmond A Ryan, I George Fantus, Anthony B Armson, Lorraine L Lipscombe, Jon F R Barrett, MiTy Collaborative Group, George Carson, Suzanne Williams, Sheila Kelly, Heather Clark, Diane Donat, Shital Gandhi, Barbara Cleave, Michele Strom, Lois Donovan, Carolyn Oldford, Catherine Young, Brenda Galway, Minnie Parsons, Ariane Godbout, Michele Mahone, Florence Weber, Marie-Josee Bedard, BiLan Wo, Sylvie Daigle, Amir Hanna, Maria Wolfs, Leanne De Souza, Robyn Houlden, Adriana Breen, Tina Kader, Luca Cefis, Erin Keely, Josee Champagne, Jennifer Klinke, Julie Lee, Peter Subrt, Francina Carr, Sharon Young, Peter Subrt, Francina Carr, Sharon Young, Sarah Kwong, Heather Rylance, Helene Long, Julie Lambert, Julia Lowe, Anna Rogowsky, Susan Jackson, Sora Ludwig, Laurie Slater, Lori Berard, David McIntyre, Anne Tremellen, Ruth McManus, Sara Meltzer, Natasha Garfield, Shari Segal, David Miller, Karen Coles, Carol Fergusson, Jill Newstead-Angel, Judy Brandt, Thomas Ransom, Darlene Baxendale, Evelyne Rey, Diane Francoeur, Sophie Perreault, Heather Rylance, Dory Sample, David Thompson, Sharon Thompson, JohnS Weisnagel, Camile Lambert, Valerie-Eve Julien, Marie-Christine Dube, Louise Rheaume, Afshan Zahedi, Grace Lee, Krystyna Szwiega, Asma Qureshi, Siobhan Tobin

Abstract

Background: The incidence of type 2 diabetes in pregnancy is rising and rates of serious adverse maternal and fetal outcomes remain high. Metformin is a biguanide that is used as first-line treatment for non-pregnant patients with type 2 diabetes. We hypothesize that metformin use in pregnancy, as an adjunct to insulin, will decrease adverse outcomes by reducing maternal hyperglycemia, maternal insulin doses, maternal weight gain and gestational hypertension/pre-eclampsia. In addition, since metformin crosses the placenta, metformin treatment of the fetus may have a direct beneficial effect on neonatal outcomes. Our aim is to compare the effectiveness of the addition of metformin to insulin, to standard care (insulin plus placebo) in women with type 2 diabetes in pregnancy.

Methods: The MiTy trial is a multi-centre randomized trial currently enrolling pregnant women with type 2 diabetes, who are on insulin, between the ages of 18-45, with a gestational age of 6 weeks 0 days to 22 weeks 6 days. In this randomized, double-masked, parallel placebo-controlled trial, after giving informed consent, women are randomized to receive either metformin 1,000 mg twice daily or placebo twice daily. A web-based block randomization system is used to assign women to metformin or placebo in a 1:1 ratio, stratified for site and body mass index. The primary outcome is a composite neonatal outcome of pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, or neonatal intensive care unit admission longer than 24 h. Secondary outcomes are large for gestational age, cord blood gas pH < 7.0, congenital anomalies, hyperbilirubinemia, sepsis, hyperinsulinemia, shoulder dystocia, fetal fat mass, as well as maternal outcomes: maternal weight gain, maternal insulin doses, maternal glycemic control, maternal hypoglycemia, gestational hypertension, preeclampsia, cesarean section, number of hospitalizations during pregnancy, and duration of hospital stays. The trial aims to enroll 500 participants.

Discussion: The results of this trial will inform endocrinologists, obstetricians, family doctors, and other healthcare professionals caring for women with type 2 diabetes in pregnancy, as to the benefits of adding metformin to insulin in this high risk population.

Trial registration: ClinicalTrials.gov Identifier: no. NCT01353391 . Registered February 6, 2009.

Keywords: Diabetes Mellitus; Diabetes Mellitus Type 2; Metformin; Pregnancy; Pregnancy in diabetics; Pregnancy outcome; Randomized controlled trial.

Figures

Fig. 1
Fig. 1
MiTy timeline of visits, measurements, blood samples and follow-up

References

    1. IDF Diabetes Atlas 6th Edition. .
    1. Lipscombe L, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario Canada 1995–2005: a population-based study. Lancet. 2007;369:750–756. doi: 10.1016/S0140-6736(07)60361-4.
    1. Feig DS, Palda VA. T2DM in pregnancy: a growing concern. Lancet. 2002;359:1690–1692. doi: 10.1016/S0140-6736(02)08599-9.
    1. Feig DS, Hwee J, Shah BR, Booth GL, Bierman AS, Lipscombe LL. Trends in Incidence of Diabetes in Pregnancy and Serious Perinatal Outcomes: A Large Population-Based Study in Ontario, Canada 1996–2010. Diabetes Care. 2014;37(6):1590–1596. doi: 10.2337/dc13-2717.
    1. Albrecht SS, Kuklina EV, Bansil P, Jamieson DJ, Whiteman MK, Kourtis AP, Posner SF, Callaghan WM. Diabetes trends among delivery hospitalizations in the US, 1994–2004. Diabetes Care. 2010;33:768–773. doi: 10.2337/dc09-1801.
    1. Bell R, Bailey K, Cresswell T, Hawthorne G, Critchley J, Lewis-Barned N, on behalf of the Northern Pregnancy Survey Steering Group Trends in prevalence and outcomes of pregnancy in women with pre-existing type I and type II diabetes. BJOG. 2008;115:445–452. doi: 10.1111/j.1471-0528.2007.01644.x.
    1. Clausen TD, Matheisen E, Ekbom P, Hellmuth E, Mandrup-Poulsen T, Damm P. Poor pregnancy outcome in women with type 2 diabetes. Diabetes Care. 2005;28(2):323–328. doi: 10.2337/diacare.28.2.323.
    1. Brydon P, Smith T, Proffitt M, Gee H, Holder R, Dunne F. Pregnancy outcome in women with type 2 diabetes needs to be addressed. Int J Clin Pract. 2000;54(7):418–419.
    1. Dunne F. Type 2 diabetes and pregnancy. Semin Fetal Neonatal Med. 2005;10(4):333–339. doi: 10.1016/j.siny.2005.04.007.
    1. Murphy HR, Steel SA, Roland JM, Morris D, Ball V, Campbell J, Temple RC, on behalf of East Anglia Study Group for improving Pregnancy Outcomes in Women with Diabetes (EASIPOD) Obstetric and perinatal outcomes in pregnancies complicated by Type 1 and Type 2 diabetes: influences of glycaemic control, obesity and social advantage. Diabet Med. 2011;28(9):1060–1067. doi: 10.1111/j.1464-5491.2011.03333.x.
    1. Holman N, Lewis-Barned N, Bell R, Stephens H, Modder J, Gardosi J, et al. Development and evaluation of a standardized registry for diabetes in pregnancy using data from the Northern, North West, and East Aglia regional audits. Diabet Med. 2011;28(7):797–804. doi: 10.1111/j.1464-5491.2011.03259.x.
    1. Knight KM, Pressman EK, Hackney DN, Thomburg LL. Perinatal outcomes in type 2 diabetic patients compared with non-diabetic patients matched by body mass index. J Matern Fetal Neonatal Med. 2012;25(6):611–615. doi: 10.3109/14767058.2011.587059.
    1. Boulet SL, Alexander GR, Salihu H, Pass M. Macrosomic birth in the United States: determinant, outcomes and proposed grades of risk. Am J Obstet Gynecol. 2003;188(5):1372–1378. doi: 10.1067/mob.2003.302.
    1. Wollschlaeger K, Nieder J, Kӧppe I, Hӓrtlein K. A study of fetal macrosomia. Arch Gynecol Obstet. 1999;263(1–2):51–55. doi: 10.1007/s004040050262.
    1. Spellacy WN, Miller S, Winegar A, Peterson PQ. Macrosomia-maternal characteristics and infant complications. Obstet Gynecol. 1985;66(2):158–161.
    1. Grassi AE, Giuliano MA. The neonate with macrosomia. Clin Obstet Gynecol. 2000;43(2):340–348. doi: 10.1097/00003081-200006000-00012.
    1. Overland EA, Vatten LJ, Eskild A. Risk of shoulder dystocia: associations with parity and offspring birthweight. A population study of 1,914,544 deliveries. Acta Obstet Gynecol Scand. 2012;91(4):483–488. doi: 10.1111/j.1600-0412.2011.01354.x.
    1. Asbjornsdottir B, Rasmussen SS, Kelstrup L, Damm P, Mathiesen ER. Impact of restricted maternal weight gain on fetal growth and perinatal morbidity in obese women with type 2 diabetes. Diabetes Care. 2013;36(5):1102–1106. doi: 10.2337/dc12-1232.
    1. Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542–546. doi: 10.1038/nature13270.
    1. Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011;152(12):4610–4619. doi: 10.1210/en.2011-1485.
    1. Seely EW, Solomon CG. Insulin resistance and its potential role in pregnancy-induced hypertension. J Clin Endocrinol Metab. 2003;88(6):2393–2398. doi: 10.1210/jc.2003-030241.
    1. Rowan JA, Hague WM, Gao W, Battin MR. Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(19):2003–2015. doi: 10.1056/NEJMoa0707193.
    1. Balsells M, Garcia-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. Glibenclamide, metformin and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ. 2015;350:h102. doi: 10.1136/bmj.h102.
    1. Catalano PM, Presley L, Minium J, Hauguel-de MS. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care. 2009;32(6):1076–1080. doi: 10.2337/dc08-2077.
    1. Su DF, Wang XY. Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2014;104(3):353–357. doi: 10.1016/j.diabres.2013.12.056.
    1. Zheng J, Shan PF, Gu W. The efficacy of metformin in pregnant women with polycystic ovary syndrome: a meta-analysis of clinical trials. J Endocrinol Invest. 2013;36(10):797–802.
    1. Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49(12):2208–2211. doi: 10.2337/diabetes.49.12.2208.
    1. Mitanchez D, Burguet A, Simeoni U. Infants born to mothers with gestational diabetes mellitus: mild neonatal effects, a long-term threat to global health. J Pediatr. 2014;164(3):445–450. doi: 10.1016/j.jpeds.2013.10.076.
    1. Rowan J, Rush E, Obolonkin V, Battin M, Trecia W. HagueW. Metformin in gestationaldiabetes: the offspring follow up (MiGTOFU): body composition at two years of age. Diabetes Care. 2011;60:2279–2284. doi: 10.2337/dc11-0660.
    1. Ibrahim MI, Hamdy A, Shafik A, Taha S, Anwar M. The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial. Arch Gynecol Obstet. 2014;289(5):959–965. doi: 10.1007/s00404-013-3090-7.
    1. Kramer MS, Platt RW, Wen SW, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics. 2001;108(2):1–7.
    1. Catalano PM, Thomas AJ, Avallone DA, Amini SB. Anthropometric estimation of neonatal body composition. Am J Obstet Gynecol. 1995;173:1176–1181. doi: 10.1016/0002-9378(95)91348-3.
    1. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549–556. doi: 10.2307/2530245.
    1. McNutt L, Wu C, Xue X, Hafner JP. Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J Epidemiol. 2003;157(10):940–943. doi: 10.1093/aje/kwg074.

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