Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion

N Engl J Med. 1999 Nov 25;341(22):1639-44. doi: 10.1056/NEJM199911253412202.


Background: Whether the consumption of caffeine during pregnancy increases the risk of spontaneous abortion is controversial. Prior studies have determined caffeine consumption by questionnaire. We used a biologic marker, such as serum paraxanthine, a metabolite of caffeine, to measure the dose of caffeine.

Methods: In a nested case-control study, we measured serum paraxanthine in 591 women who had spontaneous abortions at less than 140 days' gestation and in 2558 matched women from the same clinic who gave birth to live infants at 28 weeks' gestation or later and who had serum drawn on the same day of gestation as the women who had abortions. The women were enrolled in the Collaborative Perinatal Project during the period from 1959 to 1966, and serum paraxanthine was measured over 30 years later.

Results: A total of 487 women who had spontaneous abortions (82 percent) and 2087 controls (82 percent) had quantifiable serum paraxanthine concentrations. However, the mean serum paraxanthine concentration was higher in the women who had spontaneous abortions than in the controls (752 vs. 583 ng per milliliter, P<0.001). The odds ratio for spontaneous abortion was not significantly elevated in the women who had serum paraxanthine concentrations of 1845 ng per milliliter or lower, corresponding to the 95th percentile of the matched women. However, the adjusted odds ratio for spontaneous abortion among women with serum paraxanthine concentrations higher than 1845 ng per milliliter, as compared with women who had concentrations below 50 ng per milliliter, was 1.9 (95 percent confidence interval, 1.2 to 2.8).

Conclusions: Only extremely high serum paraxanthine concentrations are associated with spontaneous abortion. This suggests that moderate consumption of caffeine is unlikely to increase the risk of spontaneous abortion.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abortion, Spontaneous / chemically induced*
  • Adult
  • Caffeine / administration & dosage
  • Caffeine / adverse effects*
  • Caffeine / blood
  • Case-Control Studies
  • Female
  • Humans
  • Odds Ratio
  • Pregnancy
  • Retrospective Studies
  • Risk Factors
  • Theophylline / blood*


  • Caffeine
  • Theophylline
  • 1,7-dimethylxanthine