A systematic evaluation of the reproductive risks of caffeine

Abstract

The basic principles of Teratology are reviewed as well as the methodology utilized to evaluate the reproductive risks of environmental agents in general and caffeine in particular. While environmental factors account for approximately 10% of human congenital malformations, which include maternal disease states, maternal infection, mechanical factors or problems of constraint and exogenous chemicals, drugs and physical agents, prescription drugs and environmental chemicals in all likelihood account for a very small proponion of environmentally produced malformations. Since environmentally induced birth defects represent a cause of birth defects that is preventable, identifying drugs and chemicals with a significant teratogenic risk is worthy of pursuit. It is important to recognize that the most reliable estimate of risk of environmental teratogens will be derived from human epidemiological studies, and that laboratory toxicology studies may clarify some aspects of the epidemiological studies. Methods of evaluating alleged teratogenicity are presented. Appropriately designed animal developmental toxicology studies and the utilization of basic embryological and biologic concepts are utilized to evaluate the reproductive risk estimates obtained from human epidemiological studies dealing with embryonic death, growth retardation, congenital malformation, and functional deficits. Confusion in understanding these concepts can come from the misuse of the term teratogen and non-teratogen, which are defined in this publication. The The medical literature dealing with the reproductive risks of caffeine has been reviewed and evaluated, utilizing human epidemiological studies and animal studies. The basic science principles of teratology, developmental biology and genetics have been utilized to test the biological plausibility of the epidemiological findings and the conclusions of previous authors. Epidemiological studies included exposures to caffeine during pregnancy and the occurrence of congenital malformations, fetal growth retardation, small-for-date babies, miscarriages (spontaneous abortions), behavioral effects and maternal fertility. Other epidemiological studies have been concerned with the genetic effects of preconception exposures to caffeine. While there are epidemiological studies that report statistical associations to many of the reproductive parameters just mentioned, these findings lack consistency, since there are also many negative studies in the medical literature. The caffeine content of foods and beverages can vary considerably, which can interfere with obtaining valid conclusions from many human studies. Isolated epidemiological studies dealing with the risk of abonion, without evaluating other reproductive effects, are the most difficult to interpret, because they present special problems that are sometimes ignored in epidemiological studies, including caffeine studies. The animal studies are probably the most helpful in solving some of the dilemmas created by the epidemiological studies. It was the animal study reported in 1960 that focused our attention on the reproductive effects of caffeine. But the exposure reported by Nishimura in 1960 was 250 mg/kg in the mouse, equivalent to 175 cups of coffee on a mg/kg comparative basis. But animal studies have demonstrated a no-effect dose for teratogenicity,of 20 mg/kg (14 cups of coffee), supporting the view that ordinary use of caffeine-containing foods is below the threshold dose for teratogenicity. 1be difficulty is that we want to rely on epidemiological studies, but the findings have been inconsistent and contain methodological errors. Even more important is the fact that multiple confounding factors are present in many caffeine users and they make analyses difficult and prevent the investigators from reaching definitive conclusions. Lack of biological plausibility is a very important part of this analysis. For example, no one has described the clus~r of malformations associated with caffeine ingestion. Proven teratogens have an identifiable syndrome. 1be malfonnations described in the animal studies at very high doses fit the description of vascular disruptive types of malformations. But in the occasional epidemiological study reporting an increased relative risk in the caffeine exposed population, the malformations were not of the vascular disruptive type. It appears that caffeine is another chemical, among a long list of drugs and chemicals, that may have the potential for injuring the embryo. but the usual range ?f human exposures frQm food and beverages, is below the threshold dose that would result m reproductive effects.