Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies

Abstract

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity. Vitamin B12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.

Maternal but not fetoplacental health can be improved by metformin in a murine diet‐induced model of maternal obesity and glucose intolerance

“…This could therefore contribute to the observed reduction in fetal growth despite the correction of uterine blood flow by metformin. It has been hypothesised that metformin may also have epigenetic effects on the fetus that could have long-term health consequences via changes in activity of histone modification enzymes or DNA methylation (Bridgeman et al 2018;Owen et al 2021). This highlights the complexity of metformin use in utero and the need for further research in light of the lack of knowledge and understanding of metformin action in fetal tissues.…”

“…2018; Owen et al . 2021). This highlights the complexity of metformin use in utero and the need for further research in light of the lack of knowledge and understanding of metformin action in fetal tissues.…”

Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism

“…Secondly, metformin will interfere with the absorption of vitamin B12 and folic acid. Studies have shown that up to 30% of patients taking metformin have B12 deficiency ( 47 , 48 ). In this study, CS showed a good anti-DOP effect, similar to metformin.…”

Association of folate and vitamin B12 imbalance with adverse pregnancy outcomes among 11,549 pregnant women: An observational cohort study

“…Folate and Vitamin B12 participate in the one-carbon metabolism cycle and are essential for the regulation of fetal growth (17). Insufficient levels of folate or vitamin B12 during pregnancy are associated with an increased risk of neural tube defects, poorer cognitive function, spontaneous abortion, stillbirth, fetal growth restriction, preterm delivery, and low birthweight (18)(19)(20)(21)(22)(23)(24)(25)(26).…”

“…Moreover, an in vivo rodent study elucidated altered dietary ratios of folate and B12 could have more severe effects than individual deficiencies on the expression of transporters, related miRNAs, and DNA methylation in C57BL/6 mice, which play an important role in fetal development ( 44 ). Therefore, an imbalance between folate and vitamin B12 during pregnancy could theoretically cause adverse pregnancy outcomes through placental mechanisms ( 17 ). Our findings provide new insights for further study on the effect of maternal folate and vitamin B12 imbalance on birthweight alteration.…”