Metformin during Pregnancy: Effects on Offspring Development and Metabolic Function

Abstract

Maternal obesity during pregnancy and gestational diabetes mellitus (GDM) are both associated with of several postnatal diseases in the offspring, including obesity, early onset hypertension, diabetes mellitus, and reproductive alterations. Metformin is an oral drug that is being evaluated to treat GDM, obesity-associated insulin resistance, and polycystic ovary syndrome (PCOS) during pregnancy. The beneficial effects of metformin on glycemia and pregnancy outcomes place it as a good alternative for its use during pregnancy. In this line of thought, improving the metabolic status of the pregnant mother by using metformin should avoid the consequences of insulin resistance on the offspring's fetal and postnatal development. However, some human and animal studies have shown that metformin during pregnancy could amplify these alterations and be associated with excessive postnatal weight gain and obesity. In this minireview, we discuss not only the clinical and experimental evidence that supports the benefits of using metformin during pregnancy but also the evidence showing a possible negative impact of this drug on the offspring's development.

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers

“…Metformin inhibits complex I in the mitochondria, leading to a reduction in mitochondrial respiration and ATP production, and has been shown to activate AMPK effectively [ 53 ]. In addition to its use in treating type 2 diabetes mellitus, metformin is currently also being increasingly used for treating gestational diabetes, as randomized controlled trial evidence is emerging, demonstrating its safety and efficacy during pregnancy [ 88 , 89 , 90 ]. Since metformin is able to prevent diabetes in pre-diabetic populations and may reduce gestational weight gain in women with moderate-to-severe obesity with and without diabetes, it is currently also being intensively discussed as a preventive therapy option for overweight pregnant women in order to improve metabolic dysfunction and prevent associated negative consequences for the offspring.…”

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…Over the past years, the focus has been on the validity of the use of MF for the treatment of GDM and the prevention of GDM-associated preeclampsia, which is of great importance for a normal pregnancy and the birth of healthy offspring [ 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 ]. GDM is recognized on average in 10–20% of pregnant women, and the incidence is largely depends on diagnostic criteria and genetic, environmental and ethnic factors [ 319 , 320 , 321 ].…”

“…In contrast to women with T2DM, the use of MF in obese pregnant women who do not have severe IR, hyperglycemia and dyslipidemia is not effective. Most clinical studies indicate that MF does not significantly affect the pregnancy and the health of newborns in obese pregnant women [ 318 , 388 , 389 , 390 ]. The use of MF in pregnant women with overweight or obesity at the end of the first and beginning of the second trimesters does not significantly improve the outcomes of pregnancy and childbirth [ 390 ].…”

A Glimpse at the Size of the Fetal Liver—Is It Connected with the Evolution of Gestational Diabetes?

“…The use of metformin in patients with GDM should not neglect the negative impact of this drug on the offspring's development or the high risk of maternal hypoglycemia. Therefore, metformin should be prescribed with precaution considering that it is not associated with an improvement in insulin sensitivity and there is a need to clarify whether it can cause any harm to the offspring in the long term [44][45][46][47]. This is particularly worrying given that the offspring of females with untreated GDM are prone to develop obesity, diabetes, and CVD, an important factor that will contribute towards the burden of diabetes reaching 439 million patients worldwide (approximately 70% of adults aged 54-60) by 2030 [2,48].…”