Centers for Disease Control
congenital malformations (birth defects)
central nervous system
binding protein involved in transcription regulation
Food and Drug Administration
Health Environmental Science Institute
Human Health Services
International Life Science Institute
intrauterine growth retardation
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)
World Health Organization.
Evaluation of the reproductive and developmental risks of caffeine†
Article first published online: 2 MAR 2011
© 2011 Wiley-Liss, Inc.
Birth Defects Research Part B: Developmental and Reproductive Toxicology
Volume 92, Issue 2, pages 152–187, April 2011
How to Cite
Brent, R. L., Christian, M. S. and Diener, R. M. (2011), Evaluation of the reproductive and developmental risks of caffeine. Birth Defects Research Part B: Developmental and Reproductive Toxicology, 92: 152–187. doi: 10.1002/bdrb.20288
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.
- Issue published online: 11 APR 2011
- Article first published online: 2 MAR 2011
- Manuscript Accepted: 23 JAN 2011
- Manuscript Revised: 18 JAN 2011
- Manuscript Received: 29 SEP 2010
- International Life Sciences Institute
- Re-use of this article is permitted in accordance with the Terms and Conditions set out at [http://wileyonlinelibrary.com/author resources/onlineopen.html]
- 1991. Methodological issues for the assessment of clusters of adverse pregnancy outcomes in the workplace: the cause of video display terminal users. J Occup Med 33:1091–1096. , .
- 1980. Effect of caffeine on rat offspring from treated dams. Toxicol Lett 7:71–77. , , , .
- 2000. Maternal caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain. Pediatr Res 48:177–183. , , , .
- 2002. Interactions of caffeine and restraint stress during pregnancy in mice. Exp Biol Med 227:779–785. , , , , .
- 1990. Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci USA 87:7772–7776. , .
- 2005. Combined effects of caffeine and malnutrition on the newborn rat's myocardium. Food Chem Toxicol 43:451–456. , , , et al.
- 1993. Transplacental transfer of genotoxins and transplacental carcinogenesis. Environ Health Perspect 101:33–38. .
- 2001. Caffeine does not affect excitotoxic brain lesions in newborn mice. Eur J Paediatr Neurol 5:161–165. , , , .
- 2010. Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: The Generation R Study. Am J Clin Nutr 91:1691–1698. , , , et al.
- 2003. The effect of smoking and caffeine on the fetus and placenta in pregnancy. Clin Exp Obstet Gynecol 30:57–59. , , , .
- 1987. Caffeine-cigarette interaction on fetal growth. Am J Obstet Gynecol 157:1236–1240. , .
- 2007. Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial. BMJ 334:409. Epub 2007 Jan 26. (Repeated in Preterm Birth Section). , , , .
- 1986. Mechanism of known environmental teratogens: drugs and chemicals. In: BrentRL, BeckmanDA, editors. Clinics in perinatology. Vol 13. Philadelphia: W. B. Saunders. p 615–648. , .
- 1997. Developmental toxicity. In: MassaroEJ, editor. Handbook of human toxicology. Chapter 24. New York: CRC Press. p 1007–1084. , , .
- 1974. Chromosomal errors and reproductive failure. Basic Life Sci 4(Pt. A):73–90. .
- 1965. On the systematic and specific teratogenic effect of caffeine in rodents. C R Soc Biol 159:2199. , , , et al.
- 1970. Ectrodactyly caused by caffeine in rodents. Role of specific and genetic factors. C R Seances Soc Biol Fil 164:1488–1489. , , .
- 2007. Oral clefts and life style factors: a case-cohort study based on prospective Danish data. Eur J Epidemiol 22:173–181. , , , et al.
- 2007. The effects of methylmercury on motor activity are sex- and age-dependent, and modulated by genetic deletion of adenosine receptors and caffeine administration. Toxicology 241:119–133. , , , et al.
- 2003. Consequences of in utero caffeine exposure on respiratory output in normoxic and hypoxic conditions and related changes of Fos expression: a study on brainstem-spinal cord preparations isolated from newborn rats. Pediatr Res 53:266–273. , , , et al.
- 2003. Genetic effects of radiotherapy for childhood cancer. Health Phys 85:65–80. , , , et al.
- 1978. Coffee, risk factor during pregnancy. Louvain Med 97:279–284. , , , .
- 1975 Retrospective and prospective epidemiological studies of 1,500 karyotyped spontaneous abortions. Teratology 12:11–26. , , .
- 2003. Caffeine as a performance-enhancing drug in rats: sex, dose, housing, and task considerations. Percept Mol Skills 97:259–270. , , , et al.
- 2008. Assessing caffeine exposure in pregnant women. Br J Nutr 100:875–882. , , , et al.
- 2003. Association of maternal caffeine consumption with decrements in fetal growth. Am J Epidemiol 157:456–466. , , , et al.
- 1976. Environmental factors: miscellaneous. In: BrentRL, HarrisM, editors. Prevention of embryonic, fetal and perinatal disease. Vol 3. Bethesda, MD: DHEW Publication No. (NIH) 76-853. p 211–218. .
- 1978. Method of evaluating alleged human teratogens. (Editorial) Teratology 17:183. .
- 1985. Methods of evaluating and alleged teratogenicity of environmental agents. In: MaroisM, editor. Prevention of physical and mental congenital defects part c: basic and medical science, education and future strategies. New York: Alan R. Liss, Inc. p 191–195. .
- 1986a. The law and congenital malformations. In: BrentRL, BeckmanDA, editors. Clinics in perinatology. Vol. 13. W.B. Saunders, Philadelphia, PA. p 615–648. .
- 1986b. Evaluating the alleged teratogenicity of environmental agents. In: Brent, RL, BeckmanDA, editors. Clinics in perinatology. Vol 13. Philadelphia, PA: W.B. Saunders. p 609–613. .
- 1994. Commentary: cardiovascular birth defects and prenatal exposure to female sex hormones: importance of utilizing proper epidemiological methods and teratologic principles. Teratology 49:159–161. .
- 1995a. Bendectin review of the medical literature of a comprehensively studied human non-teratogen and the most prevalent tortogen-litigen. Reprod Toxicol 9:337–349. .
- 1995b. The application of the principles of toxicology and teratology in evaluating the risks of new drugs for the treatment of drug addiction in women of reproductive age. In: ChiangCN, FinneganLP, editors. Research monograph series 149: medications development for the treatment of pregnant addicts and their infants. Rockville, MD: National Institute on Drug Abuse. p 130–184. .
- 1997. Review of the scientific literature pertaining to the reproductive toxicity of Bendectin. In: FaigmanDL, KayeDH, SaksMJ, SandersJ, editors. Modern scientific evidence: the law and science of expert testimony. Vol 2. Chapter 29. St. Paul, MN: West Publishing Group. p 373–393. .
- 1999. The utilization of developmental basic science principles in the evaluation of reproductive risks from pre- and postconception environmental radiation exposures. Teratology 59:182–204. Paper presented at the Thirty-Third Annual Meeting of the National Council on Radiation Protection and Measurements, The Effects of Pre- and Postconception Exposure to Radiation, April 2–3, 1997, Arlington, Virginia. .
- 2003. Commentary on Bendectin and birth defects: hopefully, the final chapter. Birth Defects Res 67:79–87. .
- 2004. Environmental causes of human congenital malformations: the pediatrician's role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. In: BrentRL, WeitzmanM, editors. Pediatric supplement: vulnerability, sensitivity and resiliency of infants. Vol. 113. Pediatrics: Children and Adolescents to Environmental Agents. p 357–968. .
- 2005. Non-genital malformations following exposure to progestational drugs: the final chapter of an erroneous allegation. Birth Defects Part A 73:906–918. .
- 2007. Lauriston S. Taylor Lecture: fifty years of scientific research: the importance of scholarship and the influence of politics and controversy. Health Phys 93:348–379. .
- 2008. Environmental and genetic causes of human congenital malformations: the physician's role in dealing with these complex clinical problems caused by environmental and genetic factors. In: StuddJ, TanSL, ChervenakFA, editors. Progress in obstetrics and gynecology 18. Chapter 5. Edinburgh, England: Elsevier Ltd. p 61–84. .
- 1986. The relationship of animal experiments in predicting the effects of intrauterine effects in the human. In: KriegelH, SchmahlW, GerberGB, StieveFE, editors. Radiation risks to the developing nervous system. New York: Gustav Fisher. p 367–397. , , .
- 1990. Environmental teratogens. Bull N Y Acad Med 66:123–163. , .
- 1988. Clinical and basic science lessons from the thalidomide tragedy: what have we learned about the causes of limb defects? Teratology 38:241–251. , .
- 2006. Maternal exposure to caffeine and risk of congenital anomalies: a systematic review. Epidemiology 17:324–331. .
- 2007. Maternal caffeine consumption and risk of cardiovascular malformations. Birth Defects Res A Clin Mol Teratol 79:533–543. , , , et al.
- 2002. Effects of prenatal exposure to combination of acetaminophen, isopropylantipyrine and caffeine on intrauterine development in rats. Hum Exp Toxicol 21:25–31. .
- 2003. Intrauterine growth retardation and lack of teratogenic effects of prenatal exposure to the combination of paracetamol and caffeine in Wistar rats. Reprod Toxicol 17:51–58. .
- 2004. Developmental effects of propyphenazone in analgesic and antipyretic combination with caffeine or paracetamol. Hum Exp Toxicol 23:235–244. .
- 2000. The effects of short-time caffeine administration on skeleton development in Wistar rats. Folia Morphol (Warsz) 59:91–95. , , , et al.
- 2001. Combined effects of acetaminophen, isopropylantipyrine and caffeine on pregnant and nonpregnant liver. Hum Exp Toxicol 20:569–575. , , .
- 1981. An introduction to purinergic receptors. In: BurnstockG, editor. Purinergic receptors. London/New York: Chapman and Hall. pp. 1–45. , .
- 1962. Adenosine 3′,5′-phosphate in biological materials. I. Purification and properties of cyclic 3′,5′nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′,5-phosphate in human urine. J Biol Chem 237:1244–1250. , .
- 1996. Role of CYP1A2 in caffeine pharmacokinetics and metabolism: studies using mice deficient in CYP1A2. Pharmacogenetics 6:291–296. , , , et al.
- 2003 What do we know about the reproductive and developmental risks of herbal and alternate remedies? Birth Defects Res B Dev Reprod Toxicol 68:492–493. , .
- 1999. Long-term genetic and reproductive effects of ionizing radiation and chemotherapeutic agents on cancer patients and their offspring. Teratology 59:210–215. .
- CARE Study Group. 2008. Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ 337:a2332.
- 2009. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res (Part A) 85:63–69. , , , et al.
- 2004. Multiple effects of theobromine on fetus development and postnatal status of the immune system. Int J Tissue React 26:53–60. , , , et al.
- 2001. Teratogen update: evaluation of the reproductive and developmental risks of caffeine. Teratology 64:51–78. , .
- 2002. Effect of caffeine exposure during pregnancy on birth weight and gestational age. Am J Epidemiol 155:429–436. (Repeated in Preterm Birth Section). , , , et al.
- 2007. The effects of caffeine on the preterm sheep ductus arteriosus. Peditr Res 62;167–169. , .
- 2000. Caffeine intake and the risk of first trimester spontaneous abortion. N Engl J Med 343:1839–1845. , , , et al.
- 2009. National Birth Defects Prevention Study. Maternal caffeine intake during pregnancy and orofacial clefts. Birth Defects Res A Clin Mol Teratol 85:842–849. , , , .
- Teratogenic potential of caffeine in rats. In: Alternative dietary practices and nutritional abuses in pregnancy. Proceedings of a Workshop. Washington, DC: National Academy Press. p 97–107. , , , . 1981.
- 1983. A study of the teratogenic potential of caffeine ingested in drinking water. Food Chem Toxic 21:763. , , , .
- 1995. Effects of maternal stress on methylmercury-induced developomental toxicity in mice. Physiol Behav 58:979–983. , , , .
- 1999. Prenatal effects of caffeine and restraint stress in mice. Proc Soc Exp Biol Med 220:106–111. , , , .
- 2001. Interactions in developmental toxicology: combined action of restraint stress, caffeine, and aspirin in pregnant mice. Teratology 63:144–151. , , , .
- Committee on Toxicity. 2001. COT statement on the reproductive effects of caffeine. London: Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment, 2001, http://cot.food.gov.uk/cotstatements/cotstatementsyrs/cotsatemnt0s2001/caffeine
- 1996. Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study. BMJ 313:1358–1362. , , , et al.
- 2005. Maternal caffeine intake impairs MK-801-induced hyperlocomotion in young rats. Eur J Pharmacol 509:155–159. , , , et al.
- 2008. Maternal caffeine intake affects acetylcholinesterase in hippocampus of neonate rats. Int J Dev Neurosci 26:339–343. , , , et al.
- 2005. Theophylline pharmacokinetics: comparison of Cyp1a1 (− / −) and Cyp 1a2(− / −) knockout mice, humanized hCYP1A1_1A2 knock-in mice lacking either the mouseCyp1a1 or Cyp1a2 gene, and cypl(+ / +) wild-type mice. Pharmacogenet Genomics 15:503–511. , , , et al.
- 2007. Transient inhibition of astrocytogenesis in developing mouse brain following postnatal caffeine exposure. Pediatr Res 62:604–609. , , , et al.
- 2007. Caffeine use affects pregnancy outcome. J Child Adolesc Substance Abuse 17:41–49. , , , et al.
- 1992Reproductive effects of caffeine: a review and theoretical analysis. Epidemiol Rev 14:83–100. , .
- 1999. The pharmacokinetics of theophylline in premature neonates during the first few days after birth. Ther Drug Monit 21:598–603. , , , .
- 1982. Studies on the teratogenic effects of different oral preparations of caffeine in mice. Toxicol 23:57. , , .
- 2003. High dose caffeine administered to pregnant rats causes histopathological changes in the cornea of newborn pups. Med Sci Monit 9:BR168–BR173. , , , et al.
- 2004. Excessive maternal caffeine exposure during pregnancy is cataractogenic for neonatal crystalline lenses in rats: a biomicroscopic and histopathologic study. Acta Ophthalmol Scand 82:552–556. , , , et al.
- 1974. Anencephalus and maternal tea drinking: evidence for a possible association. Proc R Soc Med 67:356–360. .
- 1991. Caffeine consumption during pregnancy and fetal growth. Am J Public Health 81:458–461. , , , .
- 1998. Rate of caffeine metabolism and risk of spontaneous abortion. Am J Epidemiol 147:503–510. , , , et al.
- Food and Drug Administration (FDA). 1980. Caffeine and pregnancy. FDA Drug Bull 10:19–20.
- Food and Drug Administration (FDA). 1986. See Johnson CB, Shibko SI, Taylor JM.Caffeine. Review of toxicological studies, 1980-present (September 1986), FDA Review.
- 1998. Evaluation of the developmental toxicity of caffeine and caffeine metabolites using the frog embryo teratogenesis assay—Xenopus (FETAX). Food Chem Toxicol 36:591–600. , , , et al.
- 1972. Adverse effects of prolonged administration of caffeine on rat fetus. Toxicol Appl Pharmacol 22:449. , .
- 2006. Effect of postnatal exposure to caffeine on the pattern of adenosine A1 receptor distribution in respiration-related nuclei of the rat brainstem. Auton Neurosci 126–127:339–346. , , , et al.
- 2006. Risks of repeated miscarriage. Paediat Perinat Epidemiol 20:119–126. , , , et al.
- 2003. The effect of caffeine consumption and nausea on the risk of miscarriage. Paediatr Perinat Epidemiol 17:316–323. , , , et al.
- 2000. Maternal caffeine and its effect on the fetus. Am J Med Genet 93:253. .
- 1973. Effect on the offspring of repeated caffeine administration to pregnant rats. J Repro Fertil 34:495. , .
- 1991. Somatic development of the infant monkey following in utero exposure to caffeine. Fundam Appl Toxicol 17:454–465. , .
- 1994. In utero caffeine exposure affects feeding pattern and variable ratio performance in infant monkeys. Fundam Appl Toxicol 22:41–50. , .
- 1988. Adverse pregnancy outcome in the monkey (Macaca fasicularis) after chronic caffeine exposure. Pharmacol Exp Therap 245:1048. , , , .
- 2010 Caffeine intake during pregnancy, late miscarriage and stillbirth. Eur J Epidemiol 25:275–280. , , , et al.
- 1941. Congenital cataract following German measles in he mother. Trans Ophthalmol Soc Aust 3:35–46. .
- 2001. Maternal caffeine intake and intrauterine growth retardation. Epidemiology 12:447–455. Erratum in: Epidemiology 12:517. , , , et al.
- 2006. Caffeine metabolites in umbilical cord blood, cytochrome P-450 1A2 activity, and intrauterine growth restriction. Am J Epidemiol 163:1035–1041. Epub 2006 Apr 26. , , , et al.
- 1977. Birth defects and drugs in pregnancy. Littleton, MA: Jon Wright-PSG, p 11, 366–370, 436, 440, 477, 493. , , .
- 1967. The overall problem in man. In: BenirschkeK, editor. Comparative aspects of reproductive failure. Berlin: Springer. p 11–41. .
- 2000. Caffeine, carnitine and choline supplementation of rat decreases body fat and serum leptin serum leptin concentraton as does excercise. J Nutr 130:152–157. , .
- 2006. Chronic intake of caffeine during gestation down regulates metabotropic glutamate receptors in maternal and fetal rat heart. Amino Acids 30:257–266. , , , et al.
- 2007. Caffeine intake and small-for-gestational-age birth: modifying effects of xenobiotic-metabolising genes and smoking. Paediatr Perinat Epidemiol 21:300–309. .
- 1982. Blood levels of caffeine and results of fetal examination after oral administration of caffeine to pregnant rats. J Appl Toxicol 2:307. , , , et al.
- 1985. Caffeine and human reproduction. Rev Environ Health 5:151–167. , .
- 2000. The effect of sex and age on caffeine pharmacokinetics in cattle. Res Vet Sci 69:33–37. , .
- 2001.The effect of short-term starvation or waterdeprivation on caffeine pharmacokinetics in calves. Res Vet Sci 70:109–113. , , .
- 2009. Maternal consumption of coffee and caffeine-containing beverages and oral clefts: a population-based case-control study in Norway. Am J Epidemiol 169:1216–1222. , , , et al.
- 2000. Monitoring of cytochrome P-450 1A activity by determination of the urinary pattern of caffeine metabolites in Wistar and hyperbilirubinemic Gunn rats. Toxicology 144:229–236. , , , et al.
- 1980. Anatomic and chromosomal anomalies in 639 spontaneous abortuses. Hum Genet 55:87–98. , , , et al.
- 2006. Association of cytochrome P450 1B1 polymorphism with first-trimester miscarriage. Fertil Steril 86:1498–1503. , , , et al.
- 2007. Cardiovascular developmental insights from embryos. Ann N Y Acad Sci 1101:377–388. , , , .
- 1984. Maternal coffee drinking and unusually high concentrations of caffeine in the newborn. J Toxicol Clin Toxicol 22:473–483. , .
- 2004. Consequences of smoking and caffeine consumption during pregnancy in women with type 1 diabetes. J Matern Fetal Neonatal Med 15:44–50. , , , et al.
- 1998. Serum caffeine and paraxanthine as markers for reported caffeine inake in pregnancy. Ann Epidemiol 8:107–111. , , , et al.
- 1999. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N Engl J Med 341:1639–1644. , , , et al.
- 2002. Maternal serum caffeine metabolites and small-for-gestational age birth. Am J Epidemiol 155:32–37. , , , .
- 1985 Environmental causes of aneuploidy: why so elusive? Basic Sci 36:149–164. , .
- 1980. Environmental influences on early reproductive loss in a current New York City study. In: PorterIM, HookEM, editors. Human embryonic and fetal death. New York: Academic Press. p 225. , , , .
- 2002. A prospective study of the effects of female and male caffeine consumption on the reproductive endpoints of IVF and gamete intra-Fallopian transfer. Hum Reprod 17:1746–1754. , , .
- 1964. Zur pranatalen toxiziat von diphenylpyralin-8-chlortheophyllinat unterberuck-sichtgung von erfahrungen mit thalidomide und cafffein. Arzeimittelforschung 14:415–424. , .
- 1999. The influence of anesthetic concentrations of enflurane and ethanol on caffeine metabolism in mice. Exp Toxicol Pathol 51:347–351. , , .
- 1970. Cytomegalovirus isolations associated with pregnancy wastage. Am J Obstet Gynecol 106:885–892. , , , et al.
- 1983. Coffee consumption during pregnancy and selected congenital malformations: A nationwide case-control study. Am J Public Health 73:1397–1399. , , , .
- 2002. Differences in caffeine and paraxanthine metabolism between human andmurine CYP1A2. Biochem Pharmacol 63:2159–2167. , , , .
- 2004. Changes in caffeine consumption as a signal of pregnancy. Reprod Toxicol 18:625–633. , , .
- 2002. Adenosine A1 receptor down-regulation in mothers and fetal brain after caffeine and theophylline treatments to pregnant rats. J Neurochem 82:625–634. , , , et al.
- 2005a. Chronic caffeine or theophylline intake during pregnancy inhibits A1 receptor function in the rat brain. Neuroscience 131:481–489. , , , .
- 2005b. Effect of chronic gestational treatment with caffeine or theophylline on Group I metabotropic glutamate receptors in maternal and fetal brain. J Neurochem 94:440–451. , , .
- 1969. Uber deneinfluss von coffein und anderen methylxanthinen auf die fortpflanzung von Wistar-ratten. In: HeimF, AmmonHPT, editors. Caffein und anderemethylxanthine. Stuttgart: Erlangen, Schattauer. p 209–215. , .
- 2002. A review of the literature relating caffeine consumption by women to their risk of reproductive hazards. Food Chem Toxicol 40:127–131. , .
- 2002. A population-based prospective cohort study of personal exposure to magnetic fields during pregnancy and the risk of miscarriage. Epidemiology 13:9–20. , , , et al.
- 1982. No association between coffee consumption and adverse outcomes of pregnancy. N Engl J Med 306:141–145. , , , et al.
- 1981. Receptor-mediated stimulation and inhibition of adenylate cyclases: the fat cell as a model system. Adv Cyclic Nucleotide Res 14:163–171. , , .
- 2000. Effects of added caffeine on results following articial insemination with fresh and refrigerated rabbit semen. Anim Reprod Sci 58:147–154. , .
- 2006. Nausea and vomiting in pregnancy: maternal characteristics and risk factors. Paediatr Perinat Epidemiol 20:270–278. , , , .
- 2000. Caffeine decreases the occurrence of cadmium-induced forelimb ectrodactyly in C57BL/6J mice. Teratology 62:325–331. , .
- 2007. Risk factors for first trimester miscarriage-results from a UK-population-based-case-control study. Br J Obstet Gynaecol 114:170–186. , , , .
- 1987. The association between low birth weight and caffeine consumption during pregnancy. Am J Epidemiol 126:813–821. , .
- 1997. Caffeine decreases glial cell number and increases hyaluronan secretion in newborn rat brain cultures. Pediatric Brain Res 34:716–719. , , , et al.
- 1987. Caffeine induces cardiac and other malformations in the rat. Am J Med Genet Supl 3:433–443. , , , et al.
- 1974. Kaffee und alkoholkonsum,risikofaktoren in der schwangerschaft. Geburtsh Frauenheilkd 34:1018–1022. , .
- 2001. Influence of hepatic regeneration after partial hepatectomy on theophylline pharmacokinetics in rats. Eur J Drug Metab Pharmacokinet 26:53–58. , , , et al.
- 1997. Effects of theophylline on renal function in premature infants. Am J Perinatol 14:45–49. , , , et al.
- 1989. Parvovirus B19 infection and pregnancy. Contemp Ob Gyn 34:56–70. .
- 2009. Maternal exposure to tobacco smoke, alcohol and caffeine, and risk of anorectal atresia, National Birth Defects Prevention Study 1997–2003. Paediatr Perinat Epidemiol 23:9–17. , , , et al.
- 2008. Modest maternal caffeine exposure affects developing embryonic cardiovascular function and growth. Am J Physiol Heart Circ Physiol 294:H2248–H2256. , , , et al.
- 2003. Caffeine in fertilization in medium is not essential for bovine IVF by fullycapacitated spermatozoa. J Reprod Dev 49:507–512. , .
- 2008. Maternal smoking, alcohol consumption, and caffeine consumption during pregnancy in relation to a son's risk of persistent cryptorchidism: a prospective study in the Child Health and Development Studies cohort, 1959–1967. Am J Epidemiol 167:257–261. , , et al.
- 1987. Cancer in offspring of long-term survivors of childhood and adolescent cancer. The Lancet 2:813–817. , , , et al.
- 1986. Effects of chronic ingestion of caffeine on mammary growth and reproduction in mice. Life Sci 39:351. , .
- 1988. Reproductive and teratologic riska of caffeine. Anat Anz Jena 167:265–270. , .
- 2000. Maternal risk factors in cleft lip and palate: case control study. Br J Oral Maxillofac Surg 38:23–25. , , , .
- 2003. Effects of caffeine on human health. Food Addit Contam 20:1–30. , , , et al.
- 1999. Changing perspectives on the genetic doubling dose of ionizing radiation for humans, mice, and Drosophila. Teratology 59:216–222. .
- 1990. The comparative radiation genetics of humans and mice. Am Rev Genet 24:327–362. , .
- 1994. Consequences on the newborn of chronic maternal consumption of coffee during gestation and lactation: a review. J Am Coll Nutr 13:6–21. , .
- 1971. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. BMJ 1:523–527. , .
- 1960. Congenital malformations in offspring of mice treated with caffeine. Proc Soc Exp Biol Med 104:140–142. , .
- 1981. The effect of brewed and instant coffee on reproduction and teratogenesis in the rat. Toxicol Appl Pharmacol 58:171. .
- 1989. The developmental toxicology of caffeine. In: , editor. Issues and reviews in teratology. Vol 14. New York: Plenum Press. p 305–350. .
- 2004. Caffeine suppresses the expression of the Bel-2 mRNA in BeWo cell culture and rat placenta. J Nutr Biochem 15:342–349. , , , et al.
- 1991a. Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring. Med Pediat Oncol 19:459–466. , , , et al.
- 1991b. Second malignant neoplasms in patients treated for childhood leukemia. Acta Paediatr Scand 80:1220–1228. , , , et al.
- 1984. Calculating risk ratios for spontaneous abortions: the problems of induced abortions. Int J Epidemiol 13:347–350. .
- 1991. Coffee consumption, birthweight, and reproductive failures. Epidemiology 2:370–374. , , .
- 2003. Maternal characteristics and lifestyle factors and the risk of delivering high birth weight infants. Obstet Gynecol 102:115–120. , , , .
- 1978. Evaluation of the teratogenic potential of fresh-brewed coffee and caffeine in the rat. Toxicol Appl Pharmacol 44:1–16. , , , et al.
- 2005. Maternal coffee drinking in pregnancy and risk of small for gestational age birth. Eur J Clin Nutr 59:299–330. , , , et al.
- 1991. Effects on birthweight of alcohol and caffeine consumption in smoking women. J Epidemiol Community Health 45:159–163. , , .
- 1997. Comparative pharmacokinetics of caffeine and three metabolites in clinically normal horses and donkeys. Am J Vet Res 58:881–884. , , , .
- 2010A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: a 2000–2009 update. Food Chem Toxicol 48:2449–2576. , , .
- 2002. Time-of-day dependent pharmacodynamics and pharmacokinetic profiles of caffeine in rats. Naunyn Schmiedebergs Arch Pharmacol 365:318–325. , , , et al.
- 1981. The role of adenosine and its nucleotides in central synaptic transmission. Prog Neurobiol 16:187–239. , .
- 1985. Nutritional teratogens: a survey of epidemiology literature. Prog Clin Biol Res 163B:419–429. .
- 1987. Effects of caffeine administration during pregnancy on fetal development and subsequent functions in the adult rat: prolonged effects on a second generation. J Toxicol Environ Health 22:1. , , .
- 2001. Effects of caffeine and its reactive metabolites theophylline and theobromine on the differentiating testis. Reprod Fertil Dev 13:435–441. , , , .
- 1993. Reproductive effects of caffeine. Experimental studies in animals. In: , editor. Monographs of the Mario Negri Institute for pharmacological research. Milan/New York: Caffeine, Coffee and Health, Raven Press. p 317–342. , .
- 1980. Carcinogenicity testing of drugs. JAMA 243:1035. .
- 2003. Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion. Acta Obstet Gynecol Scand 82:182–188. .
- 1990. Automated behavioral procedures for infant monkeys. Neurotoxicol Teratol 12:429–439. , .
- 1982. Selected birth defects in relation to caffeine-containing beverages. JAMA 247:1429–1432. , , , .
- 2004. Involvement of adenosinergic A1 systems in the occurrence of respiratory perturbations encountered in newborns following an in utero caffeine exposure. a study on brainstem-spinal cord preparations isolated from newborn rats. Neuroscience 127:505–518. , , , et al.
- 2000. Caffeine induces in vivo premature appearance of telencephalic vesicles. Dev Brain Res 121:213–217. , , , .
- 2001. Caffeine-induced telencephalic vesicle evagination in early post-implantation mouse embryos involves cAMP-dependent protein kinase (PKA) inhibition. Cereb Cortex 11:343–349. , , , et al.
- 2007. The effects of methylmercury on motor activity are sex- and age-dependent and modulated by genetic deletion of adenosine receptors and caffeine administration. Toxicology 241:119–133. , , , et al.
- 2005. Mate drinking during pregnancy and risk of preterm and small for gestational age birth. J Nutr 135:1120–1123. , , .
- 2005. Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. Mol Hum Reprod 11:357–360. , , , et al.
- 1970. The effect of adenosine and adenine nucleotides on the cyclic adenosine 3′,5′-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol 6:13–23. , .
- 2008. Invited commentary: disaggregating preterm birth to determine etiology. Am J Epidemiol 168:990–992. .
- 2000. Chemically induced birth defects. 3rd ed. Revised and expanded. New York and Basil: Marcel Dekker Inc. 1096p. .
- 2009. National birth defects prevention study: maternal caffeine consumption and risk of neural tube defects. Birth Defects Res A Clin Mol Teratol 85:879–889. , , , et al.
- 1999. High-performance liquid chromatographic method for simultaneous determination of [1-methyl- 14C]caffeine and its eight major metabolites in rat urine. J Chromat B 726:195–201. , , , et al.
- editors. 1995. Reproductive effects of chemical, physical, and biological agents. Baltimore, MD: The Johns Hopkins University Press. , , ,
- 1986. Human teratogenicity. In: BarnessL, editor. Advances in pediatrics. Vol 33. Chicago: Year Book Medical Publishers. p 225–268. .
- 1994. Proof'' of human teratogenicity. Teratology 50:97–98. .
- 1993. Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA and serotonin receptors and calcium channels in mouse brain. Cell Mol Neurobiol 13:247–261. , , , .
- 2004. Maternal caffeine consumption and spontaneous abortion: a review of the epidemiologic evidence. Epidemiology 15:229–239. , .
- 2001. Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. Obstet Gynecol 98:1059–1066. , , , et al.
- 1980. Genes, chromosomes and reproductive failure. Fertil Steril 33:107–116. .
- 1994. Coteratogenic effects of caffeine. Regul Toxicol Pharmacol 19:1–13. .
- 2008. Maternal body mass index and lifestyle exposures and he risk of bilateral renal agenesis or hypoplasia: The National Birth Defects Prevention Study. Am J Epidemiol 168:1259–1267, Page 17. , , , et al.
- 1947. Effects of maternal under nutrition upon the newborn infant in Holland (1944–1945). J Pediatr 30:229. .
- 1987. Effects of administering caffeine to pregnant rats either as a single daily dose or as divided doses four times a day. Food Chem Toxicol 25:125–133. , , .
- 1984. Cholinergic mechanisms in affective disorders. N Engl J Med 311:254–255. .
- 1988. Methylxanthines: toxicity to humans. 2. Caffeine. Food Chem Toxicol 26:645–642. .
- 1992. An update on research with coffee/caffeine (1989–1990). Food Chem Toxicol 30:533–555. .
- 1975. Spontaneous abortion as a screening device. The effect of fetal survival on the incidence of birth defects. Am J Epidemiol 102:275–290. , , , et al.
- 1981. Physiological roles for adenosine and adenosine 5′-triphosphate in the nervous system. Neuroscience 6:523–555. .
- 1987. Interpretation of animal experiments as illustrated by studies on caffeine. In: NauH, ScottWJ, editor. Pharmacokinetics in teatogenesis. Vol 1. Boca Raton, FL: CRC Press, Inc. p 123–127. , , .
- 1983. Spontaneous abortion and induced abortion: an adjustment for the presence of induced abortion when estimating the rate of spontaneous abortion from cross-sectional studies. Am J Epidemiol 117:305–308. .
- 1958. Fractionation and characterization of a cyclic adenine ribonucleoide formed by tissue particles. J Biol Chem 232:1077–1091. , .
- 1983. Adverse effect of maternal caffeine ingestion on fetal cerebrum in rat. Brain Dev 5:397–406. , ,
- 2003. Buffalo and cattle hybrid embryo development is decreased by caffeine treatment during in vitro fertilization. Theriogenology 59:709–717. , , .
- 1999. The confirmation and control of metabolic caffeine in standard bred horses after administration of theophylline. J Vet Pharmacol Ther 22:333–342. , , , .
- 2003. Does caffeine and alcohol intake before pregnancy predict the occurrence of spontaneous abortion? Hum Reprod 18:2704–2710. , , , et al.
- 2007. Maternal caffeine administration and cerebral oxygenation in near-term fetal sheep. Reprod Sci 4:588–594. , , , et al.
- 2000. Effect of maternal smoking and coffee consumption on the risk of having a recognized Down syndrome pregnancy. Am J Epidemiol 152:1185–1191. , .
- 2006. Effect of coffee intake on blood flow and maternal stress during the third trimester of pregnancy. Int J Gyanaecol Obstet 92:19–22. , , , et al.
- 1979. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J Neurochem 33:999–1005. , , .
- 2003. High caffeine consumption in the third trimester of pregnancy: gender-specific effects on fetal growth. Paediatr Perinat Epidemiol 17:324–331. , , , et al.
- 1997. Effect of careine intake during pregnancy on birth weight. Am J Epidemiol 145:335–338. , , , et al.
- 1984. Caffeine and cardiovascular effects of physiological levels of adenosine. In: , editor. Caffeine—perspectives from recent research. Springer: Berlin. p 142–150. , .
- 2000. The pharmacokinetics, metabolism and urinary detection time of caffeine in camels. Res Vet Sci 69:69–74. , , , et al.
- 1989. Nausea and vomiting of early pregnancy and pregnancy outcome: a meta-analytical review. Br J Obstet Gynaecol 96:1312–1318. , .
- 2001. The association of maternal caffeine consumption and nausea with spontaneous abortion. Epidemioloogy 12:38–42. , , , et al.
- 2008. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am J Obstet Gynecol 198:279–286. , , .
- 1981. Are female sex hormones teratogenic? Am J Obstet Gynecol 141:567–580. , .
- 2004. Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study. Am J Hum Genet 74:1282–1285. , , , et al.
- World Health Organization. 1970. Spontaneous and induced abortion. World Health Organization Technical Report Series, Number 461, Geneva, World Health Organization.
- 2008. Parental characteristics as predictors of birthweight. Hum Reprod 23:168–177. Epub 2007 Oct 12. , , , et al.
- 2000. Polymorphisms in biotransformation enzymes and the risk of recurrent early pregnancy loss. Mol Hum Reprod 6:474–478. , , , et al.