Current findings on the treatment of gestational diabetes and DM2 in pregnancy with metformin

Hyperglycemia in pregnancy – prevalence, risks, and treatment

The prevalence of obesity, GDM, and DM2 has been rising in recent decades, which necessitates effective, reliable, and safe treatment of hyperglycemia even during pregnancy. ¹ Risks associated with hyperglycemia in pregnancy include spontaneous miscarriage, preeclampsia, congenital fetal abnormalities, fetal loss, macrosomia, the need for cesarean section, neonatal hypoglycemia, and neonatal respiratory distress syndrome.

Based on international data, hyperglycemia occurs in nearly 17% of pregnancies. According to the International Diabetes Federation (IDF), it can be divided into GDM (80.3%), pregestational diabetes (10.6%), and diabetes diagnosed during pregnancy (9.1%). Treatment involves lifestyle modifications (nutritional intervention, physical activity, weight reduction), and if inadequate, pharmacotherapy is added. Although insulin is considered the gold standard, it is associated with the risk of hypoglycemia, weight gain, financial cost, the need for meticulous patient education, and poorer compliance due to injectable administration. The only approved oral medications for hyperglycemia in pregnancy are metformin and glibenclamide, as long-term safety data are lacking for other compounds.

Recommendations for pharmacotherapy of diabetes in pregnancy vary. For example, the American Diabetes Association (ADA) and the Canadian Diabetes Association (CDA) recommend insulin as the first choice, while the guidelines of the UK National Institute for Health and Clinical Excellence (NICE) recommend metformin as the first choice.² The guidelines of the Czech Diabetes Society ČLS JEP mention both alternatives.^{3, 4}

Overview of studies from 2022

Metformin is widely used in pregnant women today. Its benefits and safety in GDM and DM2 during pregnancy are assessed in two recent review articles.^{1, 2} The 2022 review by Irish authors provides strong evidence that metformin administration is safe in early pregnancy without the risk of congenital malformations. For women with DM2, metformin leads to less weight gain and a reduced insulin dose. In newborns, it reduces the incidence of hypoglycemia and macrosomia, but may increase the incidence of small-for-gestational-age (SGA) infants. There is also evidence of an increased risk of obesity and altered fat distribution in children later in life.

Review of 16 RCTs from 2023

Data on the efficacy and safety of metformin in pregnancy for both mothers and children are detailed in a review published at the end of 2023. It includes 16 randomized controlled trials (RCTs) published between 2008 and 2022. Eight studies on women with GDM and two studies on patients with DM2 compared metformin to insulin. Another six studies focused on non-diabetic indications of metformin (polycystic ovary syndrome /PCOS/, obesity, pregestational insulin resistance, preeclampsia) and metformin was compared to placebo. Metformin doses ranged from 500 to 3000 mg/day.²

Results in mothers with GDM and DM2

The analyzed studies show less weight gain in women treated with metformin, regardless of whether they had GDM, DM2, or PCOS. The difference in average weight gain ranges from 0.5 to 1.8 kg.

Several studies indicate that metformin leads to glycemic control comparable to or even better than insulin during pregnancy. Some studies also found a trend towards a reduced risk of gestational hypertension with metformin use, although not all results were consistent.

Metformin use was associated with a lower proportion of cesarean sections performed (in women with GDM and DM2).²

Results in newborns

Several studies showed a higher proportion of SGA newborns in mothers with GDM treated with metformin. Metformin was also linked to more frequent preterm births and lower birth weights, although this finding was inconsistent and dependent on the indication for metformin use. In women with DM2, metformin usage did not correlate with SGA or preterm births. Regarding the average birth weight, it was lower in newborns of mothers treated with metformin, with a lower incidence of macrosomia (birth weight > 4000 g). Numerous studies have documented that metformin treatment of GDM reduces the risk of hypoglycemia in neonates. However, the results are inconsistent. Collectively, the studies indicate that metformin use during pregnancy is not associated with an increased frequency of neonatal ICU admissions, respiratory distress syndrome, or lower Apgar scores at 5 minutes.²

Results in children later in life

Evidence suggests a predisposition of children from pregnancies exposed to metformin to obesity in childhood and metabolic syndrome in adulthood. However, they do not confirm the conclusions of experimental studies that metformin exposure during intrauterine development leads to a smaller testicular volume in boys.²

Conclusion

Metformin is an alternative to insulin in the treatment of diabetes during pregnancy with equivalent efficacy for glycemic control at a significantly lower cost. Its oral administration is an advantage over insulin, increasing adherence to treatment. Metformin exposure during pregnancy may reduce weight gain and the incidence of gestational hypertension in mothers, without increasing congenital anomaly rates or hypoglycemia risk in newborns. However, a higher incidence of childhood obesity and a predisposition to metabolic syndrome in adulthood were observed in children exposed to metformin during intrauterine development.

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Sources: 
1. Newman C., Dunne F. P. Metformin for pregnancy and beyond: the pros and cons. Diabet Med 2022; 39 (3): e14700, doi: 10.1111/dme.14700.
2. Paschou S. A., Shalit A., Gerontiti E. et al. Efficacy and safety of metformin during pregnancy: an update. Endocrine 2024 Feb; 83 (2): 259−269, doi: 10.1007/s12020-023-03550-0.
3. ČDS. Doporučený postup péče o diabetes mellitus v těhotenství 2014. Available at: www.diab.cz/dokumenty/standard_tehotenstvi.pdf
4. ČGPS, ČDS, ČNS. Gestational Diabetes Mellitus. Recommended screening procedure, gynecological, perinatological, diabetological and neonatological care 2017. Available at: www.diab.cz/dokumenty/DP_GDM_2017.pdf