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Review

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

1
Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK
2
Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, University of Manchester, Manchester M13 9WL, UK
3
St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
4
Clinical and Population Sciences, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Adaikala Antonysunil
Int. J. Mol. Sci. 2021, 22(11), 5759; https://doi.org/10.3390/ijms22115759
Received: 1 May 2021 / Revised: 24 May 2021 / Accepted: 25 May 2021 / Published: 28 May 2021
(This article belongs to the Special Issue Micronutrients in Metabolic Health)
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. View Full-Text
Keywords: metformin; diabetes; placenta; folate; vitamin B12; one carbon metabolism; fetal growth; LGA; SGA; fetal programming metformin; diabetes; placenta; folate; vitamin B12; one carbon metabolism; fetal growth; LGA; SGA; fetal programming
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MDPI and ACS Style

Owen, M.D.; Baker, B.C.; Scott, E.M.; Forbes, K. Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. Int. J. Mol. Sci. 2021, 22, 5759. https://doi.org/10.3390/ijms22115759

AMA Style

Owen MD, Baker BC, Scott EM, Forbes K. Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. International Journal of Molecular Sciences. 2021; 22(11):5759. https://doi.org/10.3390/ijms22115759

Chicago/Turabian Style

Owen, Manon D., Bernadette C. Baker, Eleanor M. Scott, and Karen Forbes. 2021. "Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies" International Journal of Molecular Sciences 22, no. 11: 5759. https://doi.org/10.3390/ijms22115759

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