Maternal one-carbon metabolism during the periconceptional period and human foetal brain growth: A systematic review

Eleonora Rubini, Inge M.M. Baijens, Alex Horánszky, Sam Schoenmakers, Kevin D. Sinclair, Melinda Zana, András Dinnyés, Régine P.M. Steegers-Theunissen*, Melek Rousian

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

21 Citations (Scopus)
41 Downloads (Pure)


The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (>17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (<7 nmol/L) associated with a reduced foetal brain volume. Preconceptional folic acid supplement use and specific dietary patterns (associated with increased B vitamins and low homocysteine) increased foetal head size. Although early pregnancy maternal folate appears to be the most independent predictor of foetal brain growth, there is insufficient data to confirm the link between maternal folate and offspring risks for neurodevelopmental diseases.

Original languageEnglish
Article number1634
Number of pages23
Issue number10
Publication statusPublished - 17 Oct 2021

Bibliographical note

Funding Information:
This review has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 812660 (DohART-Net) and grant agreement no. 739593 (HCEMM) (for A.D.). K.D.S. was in receipt of funding from the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/K017810/1).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


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