No major role for periconceptional folic acid use and its interaction with the MTHFR C677T polymorphism in the etiology of congenital anorectal malformations

Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):483-92. doi: 10.1002/bdra.23256. Epub 2014 May 20.


Background: Both genetic and nongenetic factors are suggested to be involved in the etiology of congenital anorectal malformations (ARM). Maternal periconceptional use of folic acid supplements were inconsistently suggested to play a role in the prevention of ARM. Therefore, we investigated independent associations and interactions of maternal periconceptional folic acid supplement use and the infant and maternal MTHFR (methylenetetrahydrofolate reductase) C677T polymorphisms with the risk of ARM and subgroups of ARM.

Methods: A case-control study was conducted among 371 nonsyndromic ARM cases and 714 population-based controls born between 1990 and 2012 using maternal questionnaires and DNA samples from mother and child. Cases were treated for ARM at departments of Pediatric Surgery of the Radboud university medical center, Sophia Children's Hospital-Erasmus MC Rotterdam, and the University Medical Center Groningen in The Netherlands and hospitals throughout Germany.

Results: No association with folic acid use was present (odds ratio = 1.1; 95% confidence interval: 0.8-1.4) for ARM as a group. Infant and maternal MTHFR C677T polymorphisms were weakly associated with isolated ARM in particular. Lack of folic acid supplement use in combination with infants or mothers carrying the MTHFR C677T polymorphism did not seem to increase the risk of ARM or subgroups of ARM. The relative excess risks due to interaction did not clearly indicate interaction on an additive scale either.

Conclusion: This first study investigating interactions between periconceptional folic acid supplement use and infant and maternal MTHFR C677T polymorphisms in the etiology of ARM did not provide evidence for a role of this gene-environment interaction.

Keywords: MTHFR; anal atresia; folic acid; interaction; multivitamins; pregnancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anal Canal / abnormalities*
  • Anal Canal / surgery
  • Anorectal Malformations
  • Anus, Imperforate / epidemiology*
  • Anus, Imperforate / genetics
  • Anus, Imperforate / surgery
  • Case-Control Studies
  • Dietary Supplements*
  • Female
  • Folic Acid / administration & dosage*
  • Gene Expression
  • Gene-Environment Interaction
  • Humans
  • Infant, Newborn
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Netherlands / epidemiology
  • Odds Ratio
  • Perinatal Care
  • Polymorphism, Genetic*
  • Pregnancy
  • Rectum / abnormalities*
  • Rectum / surgery
  • Risk Factors
  • Surveys and Questionnaires


  • Folic Acid
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)