Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta-Analysis

Mol Nutr Food Res. 2020 May;64(9):e1900696. doi: 10.1002/mnfr.201900696. Epub 2020 Feb 20.


Scope: The effectiveness of maternal folate in reducing the risk of congenital malformations during pregnancy is well established. However, the role of the paternal folate status is scarcely investigated. The aim of this study is to investigate the evidence of associations between the paternal folate status and sperm quality, sperm epigenome, and pregnancy outcomes.

Methods and results: Databases are searched up to December 2017 resulting in 3682 articles, of which 23 are retrieved for full-text assessment. Four out of thirteen human and two out of four animal studies show positive associations between folate concentrations and sperm parameters. An additional meta-analysis of four randomized controlled trials in subfertile men shows that the sperm concentration increases (3.54 95% confidence interval (CI) [-1.40 to 8.48]) after 3-6 months of 5 mg folic acid use per day compared to controls. Moreover, two out of two animal and one out of three human studies show significant alterations in the overall methylation of the sperm epigenome. One animal and one human study show associations between low folate intake and an increased risk of congenital malformations.

Conclusions: This systematic review and meta-analysis shows evidence of associations between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight.

Keywords: congenital malformations; epigenetics; fertility; folate; folic acid supplements; placenta; sperm quality.

Publication types

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

MeSH terms

  • Animals
  • Dietary Supplements
  • Epigenesis, Genetic
  • Female
  • Folic Acid / blood*
  • Folic Acid / pharmacology*
  • Humans
  • Male
  • Pregnancy
  • Pregnancy Outcome*
  • Spermatozoa / drug effects
  • Spermatozoa / physiology*


  • Folic Acid