• Open Access

Evaluation of the reproductive and developmental risks of caffeine


  • CDC

    Centers for Disease Control


    plasma clearance


    congenital malformations (birth defects)


    central nervous system


    binding protein involved in transcription regulation


    Food and Drug Administration


    gestation day


    Health Environmental Science Institute


    Human Health Services




    International Life Science Institute


    intrauterine growth retardation


    methyl mercury


    mean residence time


    mechanism of action


    no adverse effect level


    Organization of Teratology Information Specialists


    post conception day (s)






    spontaneous abortion (miscarriage)


    small for gestational age (less than the 10th percentile for gestational age)


    website http://apps.medical.washington.edu/teris/teris1a.aspx




    volume distribution


    World Health Organization.

    This Teratogen Update of the reproductive and developmental risks of caffeine is dedicated to Mildred S. Christian, better known to her friends and colleagues as Millie. This manuscript is the third publication that Millie and I will have coauthored. She spent the last year of her life working on this manuscript with her usual indefatigable perseverance. In a recent published essay the author quoted his father's philosophy of life who said, “The young may die, but the old have to.” Whatever her age, Millie was young. She was young in spirit, enthusiasm, creativity, and productivity. Millie was a brilliant toxicologist and had a broad intellectual grasp of science. Because of her expertise, she was frequently consulted by pharmaceutical and chemical companies to analyze preclinical studies that needed an objective experienced toxicologist. She received accolades and praise from the entire teratology and toxicology community. Dr. Christian completed her doctorate in the Teratology-Developmental Biology Training Program at the Jefferson Medical College of Thomas Jefferson University. She was a good graduate student and was already planning her career. After receiving her Ph.D. she pursued toxicology consulting as a career. She was the co-founder of Argus Research Laboratories (now a Division of Charles River Laboratories) and President and CEO of Argus International, Inc. She was an Adjunct Associate Professor in the Department of Anatomy and Developmental Biology at Jefferson Medical College, Thomas Jefferson University since 1992 and an Adjunct Professor in the Department of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences since 1997. She was a certified Diplomate in General Toxicology of The Academy of Toxicological Sciences. In addition, she was the Founding Editor of the International Journal of the American College of Toxicology and was its Editor-in-Chief for 10 years. Dr. Christian edited and/or contributed to several major textbooks and was the author of more than 100 papers and abstracts. Because of the high respect and admiration of Dr. Christian by the teratology community, she was elected President of the Teratology Society. Her year as President was a memorable experience. She accomplished so much for the Society that year because of her excellent administrative ability. Mildred S. Christian passed away on March 26, 2009, in Mechanicsville, Pennsylvania shortening the life of a wonderful human being and a tireless scientist. We all are saddened that both her productivity and her life have been shortened by her death. Above all she was a beautiful human being.


A risk analysis of in utero caffeine exposure is presented utilizing epidemiological studies and animal studies dealing with congenital malformation, pregnancy loss, and weight reduction. These effects are of interest to teratologists, because animal studies are useful in their evaluation. Many of the epidemiology studies did not evaluate the impact of the “pregnancy signal,” which identifies healthy pregnancies and permits investigators to identify subjects with low pregnancy risks. The spontaneous abortion epidemiology studies were inconsistent and the majority did not consider the confounding introduced by not considering the pregnancy signal. The animal studies do not support the concept that caffeine is an abortafacient for the wide range of human caffeine exposures. Almost all the congenital malformation epidemiology studies were negative. Animal pharmacokinetic studies indicate that the teratogenic plasma level of caffeine has to reach or exceed 60 µg/ml, which is not attainable from ingesting large amounts of caffeine in foods and beverages. No epidemiological study described the “caffeine teratogenic syndrome.” Six of the 17 recent epidemiology studies dealing with the risk of caffeine and fetal weight reduction were negative. Seven of the positive studies had growth reductions that were clinically insignificant and none of the studies cited the animal literature. Analysis of caffeine's reproductive toxicity considers reproducibility and plausibility of clinical, epidemiological, and animal data. Moderate or even high amounts of beverages and foods containing caffeine do not increase the risks of congenital malformations, miscarriage or growth retardation. Pharmacokinetic studies markedly improve the ability to perform the risk analyses. Birth Defects Res (Part B) 92:152–187, 2011. © 2011 Wiley-Liss, Inc.