Caffeine, selected metabolic gene variants, and risk for neural tube defects

Rebecca Jean Schmidt, Paul A. Romitti, Trudy L. Burns, Jeffrey C. Murray, Marilyn L. Browne, Charlotte M. Druschel, Richard S. Olney

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


BACKGROUND: Investigations of maternal caffeine intake and neural tube defects (NTDs) have not considered genetic influences. Caffeine metabolism gene effects were examined in the National Birth Defects Prevention Study. METHODS: Average daily caffeine was summed from self-reported coffee, tea, soda, and chocolate intake for mothers of 768 NTD cases, and 4143 controls delivered from 1997 to 2002. A subset of 306 NTD and 669 control infants and their parents were genotyped for CYP1A2*1F, NAT2 481C>T, and NAT2 590G>A. CYP1A2*1F was classified by fast or slow oxidation status, and NAT2 variants were categorized into rapid or slow acetylation status. Case-control logistic regression analyses, family-based transmission/disequilibrium tests and log-linear analyses, and hybrid log-linear analyses were conducted to produce odds ratios (ORs) or relative risks (RRs) and 95% confidence intervals (CIs) for caffeine intake and maternal and infant gene variants, and to examine interaction effects. RESULTS: NTDs were independently associated with infant slow NAT2 acetylator status (RR, 2.00; 95% CI, 1.10-3.64) and maternal CYP1A2*1F fast oxidation status (OR, 1.49; 95% CI, 1.10-2.03). Mothers who consumed caffeine, oxidized CYP1A2*1F quickly, and acetylized NAT2 slowly had a nonsignificantly elevated estimated risk for an NTD-affected pregnancy (OR, 3.10; 95% CI, 0.86-11.21). Multiplicative interaction effects were observed between maternal caffeine and infant CYP1A2*1F fast oxidizer status (Pinteraction = 0.03). CONCLUSIONS: The association identified between maternal CYP1A2*1F fast oxidation status and NTDs should be examined further in the context of the other substrates of CYP1A2. Maternal caffeine and its metabolites may be associated with increased risk for NTD-affected pregnancies in genetically susceptible subgroups.

Original languageEnglish (US)
Pages (from-to)560-569
Number of pages10
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Issue number7
StatePublished - 2010


  • Adverse effects
  • Caffeine
  • Cytochrome P450 CYP1A2
  • Effect modification
  • Embryo
  • Encephalocele
  • Gene-environment interaction
  • Mammalian
  • Maternal exposure
  • Metabolism
  • N-acetyltransferase NAT2
  • Neural tube defects
  • Spinal dysraphism

ASJC Scopus subject areas

  • Developmental Biology
  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Medicine(all)


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