27th April 2024, A/Prof Chee L Khoo
Metformin has microvascular (and perhaps, macrovascular) benefits in people with type 2 diabetes (T2D). It crosses the placenta and as with all medications used in pregnancy, we always worry about its potential effects on the offspring in utero. We worry about the metabolic effects of reduced nutrients to the growing baby in there. Current recommendations (RACGP handbook) says that the pros and cons of metformin in pregnancy for women with diabetes (not GDM) are unclear (1).
Current guidelines from the current RACGP Handbook on the management of T2D says “Women on other glucose-lowering medications should switch to insulin prior to conception, as there are no safety data for the use of other glucose-lowering medications agents in pregnancy” and “Women on metformin and/or sulfonylureas pre-conception may continue on these agents, if glycaemic control is adequate, until pregnancy is achieved”. These recommendations are based on the Canadian 2018 guidelines (2).
The Canadian position on metformin was based on three small randomised trials on women with T2D (although one trial did not mentioned whether some women had GDM and not DIP) and two meta-analyses of metformin in women with GDM. That was 6 years ago now and they were waiting on more evidence. Well, some of that data has been published.
The Metformin in women with type 2 diabetes in pregnancy (MiTy) was a prospective, multicentre, international, randomised, placebo-controlled trial aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes (3). This was published in the Lancet in October 2020.
Between May 2011 and October 2018, 502 pregnant women with T2D on insulin were randomised to receive metformin 1000mg bd or placebo added to insulin. Insulin was titrated in both groups to achieve fasting glucose <5.3 mmol/L and postprandial <6.7 mmol/L. Women on metformin and insulin achieved better HBA1c (5.9 vs 6.1%), required less insulin (1.1U/kg/day vs 1.5U/kg/day), gained less weight (7.2kg vs 9.0kg) and had fewer caesarean sections (53% vs 63%) compared with the placebo group.
Infants exposed to metformin weighed on average 200 g less, were less frequently extremely LGA (>97th percentile), less frequently had macrosomia (birth weight >4 kg), and had less adiposity (measured by sum of skinfolds and abdominal circumference). Although there was a reduction in LGA cases and adiposity measures in the metformin group, there was also an increase in the percentage of infants who were small for gestational age (SGA) (birth weight <10%) (12.9% vs. 6.6%).
That was in 2020. The same group then did a sub-analysis in 2022 to look at maternal factors which may predict SGA (4). Perhaps, we may be better informed about which women may not benefit from metformin during pregnancy. 460 infants were eligible for this study. There were 30 infants with SGA in the metformin group (12.9%) and 15 in the placebo group. In women with T2D and chronic hypertension +/- nephropathy, there was high percentage of SGA with metformin use (odds ratio of 3.05). The absolute increased risk of SGA in women with those co-morbidities and metformin was 25% vs 9.8% compared with on metformin but did not have those co-morbidities.
Pretty reassuring so far. When the original MiTy trial completed in 2020, the researchers followed up the infants for another 24 months. Care givers and researchers were blinded to which mother (and thence, infants) were exposed to metformin during the pregnancy.
The MiTy Kids follow up study collected anthropometric measurements, including weight, height, and skinfold thicknesses, were taken at 3, 6, 12, 18, and 24 months (5). 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. Anthropometrics were similar in children exposed and those not exposed to metformin in utero. It would seem that the use of metformin during pregnancy in women with type 2 diabetes did not affect the long-term health of their children.
The final clinical trial in this series about metformin in diabetes in pregnancy came from The MOMPOD Randomized Clinical Trial (Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes) which published in JAMA in Dec 2023 (6). 794 women with pre-existing T2D were enrolled in this randomised clinical trial comparing insulin and metformin with insulin with placebo. There were no different in composite neonatal outcomes between the two groups. There was a reduction in odds of a large-for-gestational-age infant. In other words, metformin is “safe” in women with T2D in pregnancy.
In summary, it would seem that metformin is beneficial for both mother and infant in women with T2D diabetes in pregnancy. The HbA1c is lower, the insulin dosage is lower, maternal weight gain is lower and the incidence of caesarean section was also lower. There were few LGA infants although there were more SGA in women who had chronic hypertension +/- nephropathy. There has been at least 2 RCTs confirming the safety of metformin for the infants. The recommendation is likely to be changed when the new RACGP Handbook comes out later in the year. For now, we need to inform our women with T2D that metformin does cross the placenta. More data has become available to reassure us of the benefits and safety of metformin to both mother and child.
References:
- https://www.racgp.org.au/getattachment/41fee8dc-7f97-4f87-9d90-b7af337af778/Management-of-type-2-diabetes-A-handbook-for-general-practice.aspx
- https://guidelines.diabetes.ca/cpg/chapter36. Accessed on 21/04/2024
- Feig DS, Donovan LE, Zinman B, et al.; MiTy Collaborative Group. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2020;8:834–844
- Feig DS, Zinman B, Asztalos E, Donovan LE, Shah PS, Sanchez JJ, Tomlinson G, Murphy KE. Determinants of Small for Gestational Age in Women With Type 2 Diabetes in Pregnancy: Who Should Receive Metformin? Diabetes Care. 2022 Jul 7;45(7):1532-1539.
- Feig DS, Sanchez JJ, Murphy KE, Asztalos E, Zinman B, Simmons D, Haqq AM, Fantus IG, Lipscombe L, Armson A, Barrett J, Donovan L, Karanicolas P, Tobin S, Mangoff K, Klein G, Jiang Y, Tomlinson G, Hamilton J; MiTy Kids Collaborative Group. 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.
- Boggess KA, Valint A, Refuerzo JS, et al. Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial. JAMA. 2023;330(22):2182–2190.