Folate, Vitamin B12 and Homocysteine in Relation to Birth Defects and Pregnancy Outcome
Open accessAbstract
Increased folate intake reduces the risk of neural tube defects, other malformations and also possibly, pregnancy complications. Increasing evidence suggests that the beneficial effect of folate may be related to improved function of methionine synthase, a vitamin B12-dependent enzyme that converts homocysteine to methionine. In India, the majority of the population adheres to a vegetarian diet known to be deficient in vitamin B12. In such a population, increased folate intake may offer minimal protection against birth defects, whereas vitamin B12 administration should be considered. In this review, is described the metabolism of and interrelations between folate, vitamin B12 and homocysteine. This is followed by a brief discussion of some of the proposed mechanisms for their biological effects in relation to birth defects and pregnancy outcome.
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Folic acid is a key regulator of DNA synthesis, methylation processes, and epigenetic programming during early development, making it central to fetal organogenesis and long-term metabolic and neurocognitive health.
“In summary, folic acid is a key regulator of DNA synthesis, methylation processes, and epigenetic programming during early development, making it central to fetal organogenesis and long-term metabolic and neurocognitive health [109,110].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [110]
Folic acid deficiency inhibits DNA synthesis due to reduced purine basis, causing cell cycle arrest in the S phase and resulting in megaloblastic-type red blood cells with unusually large dimensions (macrocytes), fragile membranes, altered nucleus shapes and delayed maturation.
“Folic acid deficiency inhibits DNA synthesis due to reduced purine basis, causing cell cycle arrest in the S phase and resulting in megaloblastic-type red blood cells, with unusually large dimensions (macrocytes), fragile membranes, altered nucleus shapes and delayed maturation.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [110]
Low folic acid levels lead to the incorporation of uracil into DNA in place of thymine, resulting in double-strand breaks as well as chromosome instability, which can lead to apoptosis.
“Low folic acid levels lead to the incorporation of uracil into DNA in place of thymine, resulting in double-strand breaks as well as chromosome instability, which can lead to apoptosis [110].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [110]
Inadequate intake of folic acid produces hyperhomocysteinemia, which is a risk factor for cardiovascular diseases and diseases associated with cognitive deficiency.
“Inadequate intake of folic acid produces hyperhomocysteinemia, which is a risk factor for cardiovascular diseases and diseases associated with cognitive deficiency.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [110]
Folate and vitamin B12 act synergistically in one-carbon metabolism, and deficiency of vitamin B12 can impair folate-dependent DNA synthesis and methylation, potentially masking megaloblastic anemia while exacerbating epigenetic dysregulation during fetal development.
“Folate and vitamin B12 act synergistically in one-carbon metabolism, and deficiency of vitamin B12 can impair folate-dependent DNA synthesis and methylation, potentially masking megaloblastic anemia while exacerbating epigenetic dysregulation during fetal development [110,155].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [110]
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Sorted by citations
Diverse metabolic model parameters generate similar methionine cycle dynamics
Piazza, M., Feng, X.-J., Rabinowitz, J. D., & Rabitz, H. (2008) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2007.12.009 · Cited by 24 · see citing works
Schiera, G., Macajone, G., Volpes, S., Greco, L., Di Liegro, C. M., Serio, G., Caradonna, F., & Naselli, F. (2026) · Cells · doi:10.3390/cells15040366 · Cited by 8 · see citing works
- Authors
- Refsum, H.
- Affiliations
- University of Bergen (NO)
- Corresponding author
- Refsum, Helga
- ORCID
- Refsum, Helga
- Venue
- British Journal of Nutrition
- Publisher
- Cambridge University Press (CUP)
- Published
- 2001-05
- Volume
- 85
- Issue
- S2
- Pages
- S109
- ISSN
- 0007-1145 (ISSN-L)
- 1475-2662
- OpenAlex
- W2056160337
- Cited by
- 180
- References
- 0
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 5 · 2015: 12 · 2014: 6 · 2013: 9 · 2012: 13
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal Of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- folic acid, vitamin B12, homocysteine, neural tube defects, congenital malformations, pregnancy outcomes, pregnancy complications, methionine synthase, folate metabolism, vegetarian diet, folic acid supplementation, India
- MeSH terms
- Congenital Abnormalities, Deficiency Diseases, Developing Countries, Female, Folic Acid, Folic Acid Deficiency, Homocysteine, Humans, Infant, Newborn, Neural Tube Defects, Pregnancy, Pregnancy Complications, Pregnancy Outcome, Vitamin B 12, Vitamin B 12 Deficiency
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