Yasmin Hammami

Background: Neural tube defects (NTDs) remain a leading cause of neonatal mortality, occurring in 2 per 1,000 births globally and nearly 300,000 cases annually.¹ Despite folic acid fortification, 40–50% of NTDs persist, underscoring the insufficiency of folate monotherapy.^1,2 Folate-dependent methylation regulates the genes and cellular processes needed for the neural folds to fuse properly, so disrupted methylation increases the risk of NTDs. Neural tube closure completes by Day 28 post-conception, placing high demands on the one-carbon methylation cycle, a biochemical network that adds methyl groups to DNA to regulate gene expression.^1,3 Choline, an essential methyl donor, supports DNA methylation through its oxidation to betaine, bypassing the folate cycle to generate S-adenosylmethionine (SAM), the universal substrate for DNA methyltransferases (DNMTs).^2,3 90% of pregnant individuals consume below the Adequate Intake (AI) of 450 mg/day, reaching only ~70% of the AI, decreasing DNMT activity during neurulation.^3,4,5 Genetic variants such as MTHFR C677T polymorphisms further compromise folate-mediated remethylation, amplifying dependence on the choline-betaine pathway.¹

Objective: This review examined the mechanisms by which maternal choline, through one-carbon metabolism and epigenetic programming, influences fetal DNA methylation, NTD risk, and long-term neurodevelopmental outcomes.

Search Methods: A literature search was conducted in PubMed from 2018 to 2023 using the following MeSH terms: “choline,” “neural tube defects,” “one-carbon metabolism,” “DNA methylation,” “prenatal supplementation,” “DNMT,” “SAM,” “folate,” “neurodevelopment,” and “epigenetics.”

Results: Korsmo et al. (2022) demonstrated in a mouse model high-fat diet decreased fetal DNA methylation and DNMT1 expression in fetal brain and liver. Maternal choline supplementation rescued both, confirming the choline → SAM → DNMT1 pathway is critical for fetal genomic stability, though benefits were not maintained postnatally without continued choline.⁴ Kadam et al. (2023) translated this to humans, showing in 76 pregnant women maternal plasma choline positively correlated with cord blood SAM/SAH ratio (r = 0.44, p = 0.016), and higher choline intake was associated with increased corticotropin-releasing hormone promoter methylation (r = 0.13, p = 0.007) and decreased fetal cortisol (r = −0.36, p = 0.021), independent of gestational diabetes.⁶ Petersen et al. (2019), analyzing over 3,000 pregnancies from the post-folic acid fortification Slone Birth Defects Study, identified a dose-response relationship between one-carbon cofactor intake and NTD risk, with women consuming five cofactors including choline achieving a 51% risk reduction beyond folate alone.⁵ Caudill et al. (2018) demonstrated in a double-blind randomized control trial infants of mothers consuming 930 mg/day choline during the third trimester had significantly faster information processing speeds at 4, 7, 10, and 13 months compared to those receiving 480 mg/day.⁷ Bahnfleth et al. (2022) confirmed these benefits persisted at age 7, with 930 mg/day children achieving higher Sustained Attention Task scores (p = 0.02) and less vigilance decrement.⁸

Conclusion: This review establishes maternal choline as a vital component of fetal nutrition for fetal methylation potential, with time-specific effects on neural tube closure and long-term neurocognitive programming. The current AI of 450 mg/day appears insufficient for optimal epigenetic programming; evidence supports targeting intakes closer to 930 mg/day. A multi-cofactor prenatal strategy integrating choline, folate, B12, and methionine is needed to overcome the folate plateau and reduce residual NTD risk.⁵ Future randomized controlled trials targeting the periconceptional and first-trimester windows are needed to determine whether a comprehensive one-carbon strategy can further reduce NTD incidence and optimize offspring neurodevelopment.

Works Cited:

1. Kancherla V. Neural tube defects: a review of global prevalence, causes, and primary prevention. Childs Nerv Syst ChNS Off J Int Soc Pediatr Neurosurg. 2023;39(7):1703-1710. doi:10.1007/s00381-023-05910-7.
2. Obeid R, Derbyshire E, Schön C. Association between Maternal Choline, Fetal Brain Development, and Child Neurocognition: Systematic Review and Meta-Analysis of Human Studies. Adv Nutr. 2022;13(6):2445-2457. doi:10.1093/advances/nmac082.
3. Bekdash RA. Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection. Int J Mol Sci. 2023;24(3):2346. doi:10.3390/ijms24032346.
4. Korsmo HW, Dave B, Trasino S, et al. Maternal Choline Supplementation and High-Fat Feeding Interact to Influence DNA Methylation in Offspring in a Time-Specific Manner. Front Nutr. 2022;9. doi:10.3389/fnut.2022.841787.
5. Petersen JM, Parker SE, Crider KS, Tinker SC, Mitchell AA, Werler MM. One-Carbon Cofactor Intake and Risk of Neural Tube Defects Among Women Who Meet Folic Acid Recommendations: A Multicenter Case-Control Study. Am J Epidemiol. 2019;188(6):1136-1143. doi:10.1093/aje/kwz040.
6. Kadam I, Dalloul M, Hausser J, et al. Associations between nutrients in one-carbon metabolism and fetal DNA methylation in pregnancies with or without gestational diabetes mellitus. Clin Epigenetics. 2023;15(1):137. doi:10.1186/s13148-023-01554-1.
7. Caudill MA, Strupp BJ, Muscalu L, Nevins JEH, Canfield RL. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study. FASEB J Off Publ Fed Am Soc Exp Biol. 2018;32(4):2172-2180. doi:10.1096/fj.201700692RR.
8. Bahnfleth CL, Strupp BJ, Caudill MA, Canfield RL. Prenatal choline supplementation improves child sustained attention: A 7-year follow-up of a randomized controlled feeding trial. FASEB J Off Publ Fed Am Soc Exp Biol. 2022;36(1):e22054. doi:10.1096/fj.202101217R.