Stillbirth and slow metabolizers of caffeine: comparison by genotypes

Int J Epidemiol. 2006 Aug;35(4):948-53. doi: 10.1093/ije/dyl116. Epub 2006 Jun 16.


Background: Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. The polymorphism of these genes facilitates the detection of fast and slow metabolizers, and if caffeine is causally related to stillbirth, we expect slow metabolizers to have a higher risk of stillbirth at any given intake of caffeine. Gluthatione S-transferase alpha1 (GSTA1) may also be active in the metabolism of caffeine as it conjugates glutathione to aromatic amines. Our study, therefore, included analyses of the association between GSTA1 and stillbirth.

Methods: A nested case non-case study among women who participated in the Danish National Birth Cohort: 142 cases of singleton stillbirths and 157 controls of singleton live births.

Results: Slow oxidizer status (CYP1A2), slow acetylator status (NAT2), and low activity of GSTA1 were not individually associated with the risk of stillbirth [odds ratio (OR) = 1.06, 95% confidence interval (95% CI) 0.67-1.67, OR = 0.95, 95% CI 0.60-1.51, and OR = 1.42, 95% CI 0.88-2.28, respectively]. We did, however, observe that subjects with a combination of slow CYP1A2, slow NAT2, and low GSTA1 genes had almost a 2-fold risk of stillbirth compared with subjects with other combinations of genotypes.

Conclusions: We found no link between any single genotype and the risk of stillbirth. An association between a combination of genotypes and stillbirth was discovered. Caffeine may be causally related to stillbirth, but larger studies using Mendelian randomization are needed to verify this.

Publication types

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

MeSH terms

  • Acetyltransferases / genetics
  • Caffeine / metabolism*
  • Case-Control Studies
  • Cytochrome P-450 CYP1A2 / genetics
  • Female
  • Genotype
  • Glutathione Transferase / genetics
  • Humans
  • Logistic Models
  • Odds Ratio
  • Polymorphism, Genetic
  • Pregnancy
  • Risk Assessment / methods
  • Stillbirth*


  • Caffeine
  • Cytochrome P-450 CYP1A2
  • Acetyltransferases
  • Glutathione Transferase