Caffeine Intake and the Risk of First-Trimester Spontaneous Abortion
Sven Cnattingius, M.D., Ph.D., Lisa B. Signorello, Sc.D., Göran Annerén, M.D., Ph.D., Britt Clausson, M.D., Anders Ekbom, M.D., Ph.D., Elisabeth Ljunger, M.D., William J. Blot, Ph.D., Joseph K. McLaughlin, Ph.D., Gunnar Petersson, B.Sc., Anders Rane, M.D., Ph.D., and Fredrik Granath, Ph.D.
Background Some epidemiologic studies have suggested that the ingestion of caffeine increases the risk of spontaneous abortion, but the results have been inconsistent. Methods We performed a population-based, case–control study of early spontaneous abortion in Uppsala County, Sweden. The subjects were 562 women who had spontaneous abortion at 6 to 12 completed weeks of gestation (the case patients) and 953 women who did not have spontaneous abortion and were matched to the case patients according to the week of gestation (controls). Information on the ingestion of caffeine was obtained from in-person interviews. Plasma cotinine was measured as an indicator of cigarette smoking, and fetal karyotypes were determined from tissue samples. Multivariate analysis was used to estimate the relative risks associated with caffeine ingestion after adjustment for smoking and symptoms of pregnancy such as nausea, vomiting, and tiredness.
Results Among nonsmokers, more spontaneous abortions occurred in women who ingested at least 100 mg of caffeine per day than in women who ingested less than 100 mg per day, with the increase in risk related to the amount ingested (100 to 299 mg per day: odds ratio, 1.3; 95 percent confidence interval, 0.9 to 1.8; 300 to 499 mg per day: odds ratio, 1.4; 95 percent confidence interval, 0.9 to 2.0; and 500 mg or more per day: odds ratio, 2.2; 95 percent confidence interval, 1.3 to 3.8). Among smokers, caffeine ingestion was not associated with an excess risk of spontaneous abortion. When the analyses were stratified according to the results of karyotyping, the ingestion of moderate or high levels of caffeine was found to be associated with an excess risk of spontaneous abortion when the fetus had a normal or unknown karyotype but not when the fetal karyotype was abnormal. Conclusions The ingestion of caffeine may increase the risk of an early spontaneous abortion among nonsmoking women carrying fetuses with normal karyotypes
The New England Journal of Medicine, Volume 343:1839-1845, December 21, 2000
Caffeine is a naturally occurring compound that is metabolized more slowly in pregnant women than in nonpregnant women.1
Caffeine passes readily through the placenta to the fetus,1
but the biologic mechanisms by which caffeine could induce a spontaneous abortion are not known.2,3
The results of epidemiologic studies relating the ingestion of caffeine to the risk of spontaneous abortion have been inconclusive,4,5,6,7,8,9,10,11,12,13
partly because the relation between the consumption of coffee (usually the primary source of caffeine), symptoms of pregnancy (such as nausea or aversion to the odor or taste of coffee), and fetal viability is complex. In response to such symptoms, many women decrease their ingestion of caffeine during pregnancy. Because the symptoms are more common among women with viable pregnancies than among those with nonviable pregnancies, the ingestion of caffeine in early pregnancy may reflect, rather than affect, fetal viability.6,14
Most previous studies have not included in their analyses data on symptoms of pregnancy,4,5,8,11,12,13
and the few that have included these data have used fairly insensitive markers, such as the presence or absence of nausea or vomiting at any time during pregnancy.6,7,9,10
Moreover, only one study with a sufficient sample size focused on the first trimester of pregnancy,12
when changes in caffeine intake, pregnancy-related symptoms, and the majority of spontaneous abortions occur.
In epidemiologic studies, the range of caffeine ingestion has been narrow.5,6,7,8,10,11,13 Moreover, the assessment of exposure has been suboptimal, with the reporting of caffeine intake occurring long after the period in question or with little regard to changes in ingestion during pregnancy.4,5,6,8,9,10,12,13 Finally, studies of caffeine ingestion and spontaneous abortion have, with one exception,10 not distinguished between chromosomally normal and abnormal fetuses.
In Sweden, the consumption of coffee is high, and health care coverage is nationwide; it was therefore possible to investigate whether caffeine is associated with an elevated risk of early spontaneous abortion in the general population. The current study was designed to analyze caffeine intake, smoking status, symptoms of pregnancy, and the risk of spontaneous abortion. In addition, fetal tissue, when available, was collected for chromosomal analysis.