The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism

Hum Reprod Update. 2013 Nov-Dec;19(6):640-55. doi: 10.1093/humupd/dmt041. Epub 2013 Aug 19.


BACKGROUND Most reproductive failures originate during the periconceptional period and are influenced by the age and the lifestyle of parents-to-be. We advance the hypothesis that these failures can arise as a partial consequence of derangements to one-carbon (1-C) metabolism (i.e. metabolic pathways that utilize substrates/cofactors such as methionine, vitamin B12, folate). 1-C metabolic pathways drive the synthesis of proteins, biogenic amines and lipids required for early growth, together with the synthesis and methylation of DNA and histones essential for the regulation of gene expression. We review how deficiencies in periconceptional 1-C metabolism affect fertility and development together with underlying mechanisms derived from animal studies. METHODS A literature search was performed using PubMed and bibliographies of all relevant original research articles and reviews. RESULTS We define 'periconception' as a 5-6-month period in women embracing oocyte growth, fertilization, conceptus formation and development to Week 10 of gestation (coinciding with the closure of the secondary palate in the embryo). During this period significant epigenetic modifications to chromatin occur that correspond with normal development. Subtle variations in 1-C metabolism genes and deficiencies in 1-C substrates/cofactors together with poor lifestyle, such as smoking and alcohol consumption, disturb 1-C metabolism and contribute to subfertility and early miscarriage and compromise offspring health. Procedures used in assisted reproduction can also disturb these metabolic pathways and contribute to poor pregnancy outcomes. CONCLUSIONS Evidence presented indicates that parental nutrition and other lifestyle factors during the periconceptional period can affect reproductive performance via 1-C metabolic pathways. This knowledge provides opportunities for treatment and prevention of reproductive failures and future non-communicable diseases.

Keywords: B vitamins; epigenetics; fertility; folate; preconception care.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alcohol Drinking / adverse effects
  • Animals
  • Carbon / metabolism
  • Female
  • Fertilization*
  • Folic Acid / metabolism*
  • Humans
  • Metabolic Networks and Pathways / genetics
  • Pregnancy
  • Pregnancy Outcome*
  • Reproductive Techniques, Assisted / adverse effects
  • Smoking / adverse effects
  • Vitamin B 12 / metabolism*


  • Carbon
  • Folic Acid
  • Vitamin B 12