Teratogen update: Evaluation of the reproductive and developmental risks of caffeine

<jats:title>Abstract</jats:title><jats:p>Caffeine is a methylated xanthine that acts as a mild central nervous system stimulant. It is present in many beverages, including coffee, tea, and colas, as well as chocolate. Caffeine constitutes 1–2% of roasted coffee beans, 3.5% of fresh tea leaves, and ∼2% of mate leaves (Spiller, '84; Graham, '84a,b). Many over‐the‐counter medications, such as cold and allergy tablets, headache medicines, diuretics, and stimulants also contain caffeine, although they lead to relatively minimal intake (FDA, '86). In epidemiological studies, it is assumed that one cup of coffee contains ≤100 mg of caffeine, and soft drinks, such as colas, contain 10–50 mg of caffeine per 12‐ounce serving. The per‐capita consumption of caffeine from all sources is estimated to be about 3–7 mg/kg per day, or ∼200 mg/day (Barone and Roberts, '96). Consumption of caffeinated beverages during pregnancy is quite common (Hill et al., '77) and is estimated to be approximately 144 mg/day, or 2.4 mg/kg for a 60‐kg human (Morris and Weinstein, '81). However, pregnant women appear to consume slightly less than do other adults, approximately 1 mg/kg per day (Barone and Roberts, '96). This decrease may be interrelated with taste aversion (Hook, '76; Little, '82). The medical literature contains many varied references that appear to indicate that human adverse reproductive/developmental effects are produced by caffeine. If caffeine indeed causes such effects, the reproductive consequences could be very serious because caffeine‐containing foods and beverages are consumed by most of the human populations of the world, and consumption in the United States is estimated to be 4.5‐kg/person/year (Narod et al., '91). Therefore, the medical literature dealing with developmental and reproductive risks of caffeine was reviewed, and the biological plausibility of the epidemiological and animal findings, as well as the methods and conclusions of previous investigators, were evaluated. The epidemiological studies describe exposures of women to caffeine during pregnancy, as well as the occurrence of congenital malformations, fetal growth retardation, small‐for‐date babies, miscarriages (spontaneous abortions), behavioral effects, and maternal fertility problems that presumably resulted from the caffeine consumption. A few epidemiological studies were concerned with the genetic effects of preconception exposures to caffeine. Animal studies, conducted mostly in pregnant rats and mice, were designed to produce malformations. The objectives of the present review are to summarize the findings from the various clinical and animals studies, objectively discuss the merits and/or faults inherent in the studies and establish a global reproductive risk assessment for caffeine consumption in humans during pregnancy. It should be noted that evaluation of the developmental risks of caffeine based solely on epidemiological studies is difficult because the findings are inconsistent. Even more important, is the fact that caffeine users are subject to multiple confounding factors that make analyses difficult and prevent investigators from reaching definitive conclusions. For example, the caffeine content of foods and beverages can vary considerably, which can interfere with obtaining valid interpretations from many human studies. Isolated epidemiological studies dealing with the risk of abortion, without evaluating other developmental and reproductive effects, are the most difficult to interpret, because they present special problems that are sometimes ignored in epidemiological studies. The results of animal studies are probably most helpful in solving some of the dilemmas created by the epidemiological studies. An animal study reported in 1960 first focused our attention on the potential developmental effects of caffeine. However, the exposure reported by Nishimura and Nakai ('60) was an intraperitoneal dosage of 250 mg/kg in the mouse, an extremely high dosage that would result in a blood plasma level that could never be obtained from consuming caffeine containing products. More recent animal studies have demonstrated, that depending on the method of administration and species, the developmental NOEL in rodents is approximately 30 mg/kg per day, the teratogenic NOEL is 8,100 mg/kg per day, and the reproductive NOEL approximately 80–120 mg/kg per day. Lack of biological plausibility to support the concept that caffeine has been responsible for human malformations is another important part of this analysis. For example, no one has described the Caffeine “teratogenic syndrome,” a cluster of malformations associated with caffeine ingestion. Proven human teratogens have an identifiable syndrome. The malformations described in the animal studies at very high doses fit the description of vascular disruptive types of malformations. However, in the occasional epidemiological study reporting an increased relative risk in a caffeine‐exposed population, the malformations were not of the vascular disruptive type. Thus, the overall conclusion is that caffeine is a chemical, among a long list of drugs and chemicals, that may have the potential to injure the embryo if used in marked excess. However, the usual range of human exposures to caffeine from food and beverages is below the threshold dose that would result in developmental/teratogenic or reproductive effects. Klebanoff et al. ('99), in the only study that has dealt with actual blood levels of caffeine metabolites, reached this conclusion with regard to caffeine consumption and spontaneous abortion. They concluded “that moderate consumption of caffeine is unlikely to increase the risk of spontaneous abortion.” Therefore, clinical teratology counselors, dysmorphologists, and genetic counselors can counsel prepregnant or pregnant women who do not smoke or drink alcohol and who consume moderate amounts of caffeine (<5–6 mg/kg per day spread throughout the day) that they do not have an increase in any reproductive risks. Any individual who consumes large amounts of caffeine is at greater risk of becoming a smoker and of drinking alcoholic beverages to excess. Therefore, such an individual may have an increased risk of reproductive problems. Teratology 64:51–78, 2001. © 2001 Wiley‐Liss, Inc.</jats:p>