- Email: [email protected]
Caffeine and the fetus: Is trouble brewing?
American Journal of
Obstetrics and Gynecology Founded in 1920 volume 140 number 6
CLINICAL
This section reports opinion diagnosis and management eight to twenty typed pages, ify the author’s management. Frederick P. Zuspan, M.D.,
JULY
15, 1981
OPINION
on the handling of clinical situations, i.e., the clinical of certain disease entities. Papers should range from including illustrations, tables, and figures which clarReferences are limited to sixteen citations. Mail to Editor.
Caffeine and the fetus: Is trouble brewing? MERRI
B. MORRIS,
LOUIS
WEINSTEIN,
Tucson,
B.S. M.D.
Arizona
The developing fetus is often subjected to the influence of various drugs ingested by the mother during gestation. Currently, caffeine is one of the more common drugs used by the pregnant patient. It is important that the patient be made aware that caffeine is a drug and that it may cause potential harm to the fetus. Until more scientific data are available, it is our recommendation that moderate to excessive use of caffeine during pregnancy be curtailed and that mild use be decided on an individual basis. (AM. J. OBSTET. GYNECOL. 140:607, 1981.)
CONSUMERISM has been a major impetus for the improvement of health care in the United States. Patients are increasingly questioning the health care provider regarding treatment being initiated and medications being dispensed. This increased awareness has benefited the developing fetus, as many women now actively avoid the use of any drugs during pregnancy. Unfor-
From the Department University of Arizona,
of Obstetrics and Gynecology, Health Sciences Center.
Reprint requests: Dr. Louis Weinstein, Department Obstetrics and Gynecology, University of Arizona, Sciences Center, Tucson, Arizona 85724. 0002-9378/81/140607+04$00.40/0
@ 1981
The
C. V. Mosby
of Health
Co.
tunately, some women do not realize what constitutes a drug. Patient education regarding smoking (nicotine) and alcohol is helping to decrease the use of these substances in pregnancy. Currently, one of the most common drugs to be consumed during pregnancy is caffeine. The Food and Drug Administration has recently removed caffeine from the list of drugs “generally regarded as safe” and has issued a warning regarding the consumption of caffeine during pregnancy. The public needs to be informed about the potential harm from caffeine to the developing fetus. Current data are presented on the possible effects of caffeine intake on human pregnancy outcome.
607
608
Morris
and Weinstein
Characteristics
of caffeine
Caffeine ( 1,3,7-trimethylxanthine) is a methylated xanthine structurally related to uric acid. Caffeine is present in coffee, tea, cola and other carbonated beverages, and cocoa. Caffeine constitutes a substantial portion of many over-the-counter medications, such as cold and allergy tablets, headache tablets, diuretics, and stimulants. Certain prescription drugs also contain caffeine. Eight ounces of coffee contains from 85 to 233 mg of caffeine. The same amount of tea has a caffeine content of 50 to 79 tng. Cola beverages contain 12 to 36 mg per 8 ounces.‘, ’ In these studies, brand, type, and brewing methods varied as did analyses. Over-thecounter medications with caffeine often contain 100 to 200 mg per tablet, the approximate amount in 8 ounces of coffee. Caffeine is ubiquitous in the American diet and has been previously recognized as safe. The GRAS Survey Committee of the National Academy of Sciences estimated the mean daily intake of caffeine per person for 1977.’ By age group, the mean intakes were: 6-l 1 months, 4.2 mg/day; 12-23 months, 15 mg/day; 2-5 years, 29 mglday; 6-17 years, 43 mglday: 18+ years, 186 mgiday. Pregnant women have an average intake of 144 mg/day. To be of potential harm to the fetus, a drug must be able to enter the fetal circulation. The physicochemical characteristics of caffeine allow this to occur without difficulty. Its low molecular weight facilitates transport across the placenta. 3. ’ It is highly lipid soluble and unionized at a physiologic pH, factors which aid in placental transfer. Caffeine is 75% to 85% unbound at therapeutic levels. It has also been shown to diffuse easily into breast milk with milk to serum concentration ratios ranging from 0.52 to 0.9.j. 6 Any substance that might decrease uterine blood flow should be avoided during pregnancy. Ingestion of 220 mg of caffeine results in significant increases in the urinary excretion of total catecholamines. These catecholamines may have a vasoconstrictive effect on the uterine vasculature. One study of 23 maternal-infant pairs6 found the average maternal plasma caffeine concentration to be 0.8 pg/ml, with a range of 0.02 to 3.5 pg/ml.6 The average daily coffee intake was 1.5 cups with a range of 0 to 8. Seven banked blood samples from another study’ found caffeine concentrations in the range of 0.1 to 7.4 pglml. Therefore, measurable amounts of caffeine are demonstrable in maternal blood. Caffeine has been detected in the umbilical cord plasman and urine3 of newborn infants. The mothers of these infants received only dietary caffeine. Caffeine
and its metabolites were detected in !#Ci of the newborn urine samples studied.” The transfer of Inetaholites would be expected to be less than that of the parent compound because of the increased polarity of the metabolites. Caffeine has an elimination half litr 01’ approximately 3.5 hours in the adult. “’ It is metabolized b) N-demethylation and oxidation to monomethvl and dimethyl xanthines and uric acids, which are excreted in the urine. No studies specific for caffeine metabolism by the placenta have been published. Studies in newborn infants reflect a relative lack of the enzyme activity necessary to metabolize caffeine. Caffeine was excreted in newborn urine as up to 85% of the parent compoundY, IL compared to 26% or less in maternal urine.g In the infant, ratios of urine caffeine to metabolites decreased to near-adult values by 7 to !) months of age.12 The elimination half life of caffeine was found to be approximately 4 days for newborn infants and 4 hours at 8 months of age.” Certain drugs may act as inducers or inhibitors of caffeine metabolism. M’hile maternal smoking had no effect on caffeine elimination in infants,X the ability of‘ other known inducers such as 3-methytcholanthrenel” and inhibitors such as other methyl xanthinesla to exert their effects on fetal caffeine metabolism has not been studied.
Pharmacologic effects of caffeine Minimal data are available concerning the effect of caffeine on pregnancy outcome in humans, although the literature is replete with animal studies regarding the mutagenic and teratogenic properties of the drug. When applied to mammalian cells in vitro, caffeine decreases DNA polymerase activity and shortens the DNA-replicating units. ‘j It has also been demonstrated to increase cyclic nucleotide levels (cyclic adenosine monophosphate [CAMP] and cyciic guanosine monophosphate [cGMP]).” Since CAMP levels are usually low during early gestation,16 a marked increase in CAMP might influence fetal development. The ability of caffeine to increase circulating catecholamineslj. I6 could cause vasoconstriction of uterine and placental blood vessels. Decreased placental weights have been found in caffeine-treated rats.‘” Caffeine has also been shown to decrease normal oogenesis in female rats’” and its effects on spermatozoa are currently under investigation. An unusual study with the use of caffeine-fed female houseflies revealed ovarian growth to be retarded. This resulted in abnormal ovaries with malformed eggs, as well as a significant reduction in the hatchability of the e&w I7 Obviously these findings cannot be extrapolated
Volume Number
140 6
to the human female patient with an infertility problem but do allow for some interesting speculation. Palm and associatesI performed an experiment in rats with the use of dosages of caffeine comparable to those of human consumption. The only significant finding was a reduction in bone calcium deposition. The investigators were not able to demonstrate any dose-related teratogenic effects. The multitude of animal studies have been reviewed by Thayer and Palm. I9 The conclusion of the authors was that data exist to support the teratogenic potential of caffeine in animals but documentation was lacking concerning human malformations attributable to caffeine in amounts normally consumed by man. One retrospective human studyzO on caffeine and pregnancy showed increased fetal loss in families where caffeine intake was deemed to be excessive. Sixteen women were identified who had a daily caffeine consumption of 2600 mg per day. Pregnancy outcome was eight spontaneous abortions, five stillbirths, two premature deliveries with survival, and one uncomplicated term delivery. Thirteen pregnancies were identified where the father’s caffeine intake was 2600 mg per day while the mother’s intake was 5400 mg per day. This group experienced four spontaneous abortions, two stillbirths, two premature deliveries, and five uncomplicated term births. The data, as presented by the authors, do not establish a cause-and-effect relationship between high levels of caffeine consumption and poor pregnancy outcome. What these data do is establish the need for large, well-controlled epidemiologic studies regarding the effects of caffeine on the developing fetus.
Caffeine
and the fetus
609
Recent studies have shown increased blood glucose levels in caffeine-treated premature newborn infants with apnea. Z’s 22 One group has found a 0.98 concentration ratio of mean cerebrospinal fluid to plasma in caffeine-treated neonates, which indicates that the drug is free to exert its central nervous system effects.23 The implications of these effects for the fetus through caffeine use by the mother is unknown. One group of investigators has observed caffeinetreated infants of low birth weight with apnea for 18 to 40 months; no apparent long-term effects of caffeine on growth and development have been shown.24 The treatment regimen was not uniform, acute effects were not reported, and other disease states were poorly controlled.
Comment The significance of in vitro and poorly controlled in vivo studies is questionable with no adequate long-term studies having been done. With the scientific data available, it is our recommendation that minimal use of caffeine by the pregnant patient be decided on an individual basis with moderate to excessive use of the drug being curtailed during pregnancy until further scientific data are presented. Soyka and Neese’s’ summary of the literature in 1978 remains true today: “Caffeine may alter intrauterine growth and the duration of gestation; the present data do not establish useful or harmful effects of methylxanthines but serve to emphasize the common and multiple source exposure of the perinate to concentrations which may be pharmacologically active.”
REFERENCES 1. Bunker, M. L., and McWilliams, M.: Caffeine content of common beverages, J. Am. Diet. Assoc. 74:28, 1979. 2. Graham, D. M.: Caffeine-its identity, dietary sources, intake, and biological effects, Nutr. Rev. 36:97, 1978. 3. Mirkin, B. L.: Drug distribution in pregnancy, in Boreus, L., editor: Fetal Pharmacology, New York, 1973, Raven Press, pp. l-27. transfer of phar4. Mirkin, B. L., and Singh, S.: Placental macologically active molecules, in Mirkin, B. L., editor: Perinatal Pharmacology and Therapeutics, New York, 1976, Academic Press, Inc., pp. l-69. 5. Tyrala, E. E., and Dodson, W. E.: Caffeine secretion into breast milk, Arch. Dis. Child. 54~787, 1979. 6. Aranda, J. V., Costum, B., Turmen, T., Louridas, T., and Collinge, J.: Caffeine burden in young infants, Pediatr. Res. 14:464, 1980. 7. Soyka, L. F., and Neese, A. L.: Perinatal exposure to methylxanthines: possible effects on pregnancy outcome, Clin. Pharmacol. Ther. 23:130, 1978. 8. Parsons, W. D., Aranda, J. V., and Neims, A. H.: Elimination of transplacentally acquired caffeine in fullterm neonates, Pediatr. Res. 10:333, 1976.
9. Horning, M. G., Stratton, C., Nowlin, J., Wilson, A., Hornine. E. C.. and Hill. R.: Placental transfer of drugs, in Bon&, L.,‘editor: Fetal Pharmacology, New Yolk, 1973, Raven Press, pp. 355-373. 10. Sant’Ambrogio, G., Mognoni, P., and Ventrella, L.: Plasma levels of caffeine after oral, intramuscular, and intravenous administration, Arch. Int. Pharmacodyn. 150:259, 1964. 11. Aldridge, A., Aranda, J. V., and Neims, A. H.: Caffeine metabolism in the developing human infant, Pharmacologist 20~263, 1978. A., Aranda, J. V., and Neims, A. H.: Caffeine 12. Aldridge, metabolism in the newborn, Clin. Pharmacol. Ther. 25: 447, 1979. 13. Aldridge, A., Parsons, W. D., and Neims, A. H.: Stimulation of caffeine metabolism in the rat by 3-methylcholanthrene, Life Sci. 21:967. 1977. ’ 14. Caldwell, I., Lancaster. R.. Monks, T. I., and Smith. R. L.: The influ&e of dietary methylxanth:nes on the metabolism and pharmacokinetics of intravenously administered theophylline, Br. J. Clin. Pharmacol. 4~637, 1977. 15. Weathersbee, P. S., and Lodge, J. R.: Caffeine: Its direct
610
16.
17.
18.
19.
Morris and Weinstein
and indirect influence on reproduction, J. Reprod. Med. 19:55, 1977. Weathersbee, P. S., and Lodge, J, R.: Alcohol, caffeine, and nicotine as factors in pregnancy, Postgrad. Med. 66:165, 1979. Srinivasan, A., and Kesavan, P. C.: Reproductive toxicity of caffeine in Musca Domestica, J. Toxicol. Environ. Health 5:765, 1979. Palm, P. E.. Arnold, E. P., Rachwall, P. C., Leyczek, J. C., Teague, K. W., and Kensler, C. J.: Evaluation of the teratogenic potential of fresh brewed coffee and caffeine in the rat, Toxicol. Appl. Pharmacol. 44: 1, 1978. Thayer, P. S., and Palm, P. E.: A current assessment of the mutagenic and teratogenic effects of caffeine, CRC Crit. Rev. Toxicol. 3:345, 1975.
20.
21.
22.
23.
24.
Weathersbee. P. S., Olsen, L. K., and Lodge, J, R.: Catfeine and pregnancy-a retrospectike study, Postgrad. Med. 62:64. 1977. Lazaro-Lopez, F., Colle, E.. DuPont, C.. and Aranda. J. V.: Metabolic effects of caffeine in the preterm neonate, Pediatr. Res. 14:468, 1980. Rothberg. A. D.. Marks, K. H., Ward, R. M., and Maisels, M. J.: Effects of caffeine on glucose homeostasis, Pediatr. Res. 14:471, 1980. Turmen, T., Louridas, ‘1.. A., and Aranda, J. V.: Relationship of plasma and CSF concentrations of caffeine in neonates with apnea. J. Pediatr. 95:644. 1979. Gunn, T. R., Metrakos, K.. Riley, P., Willis, D., and Aranda, J. V.: Sequelae of caffeine treatment in preterm infants with apnea, J. Pediatr. 94106, 1979.
Obstetrics and Gynecology Founded in 1920 volume 140 number 6
CLINICAL
This section reports opinion diagnosis and management eight to twenty typed pages, ify the author’s management. Frederick P. Zuspan, M.D.,
JULY
15, 1981
OPINION
on the handling of clinical situations, i.e., the clinical of certain disease entities. Papers should range from including illustrations, tables, and figures which clarReferences are limited to sixteen citations. Mail to Editor.
Caffeine and the fetus: Is trouble brewing? MERRI
B. MORRIS,
LOUIS
WEINSTEIN,
Tucson,
B.S. M.D.
Arizona
The developing fetus is often subjected to the influence of various drugs ingested by the mother during gestation. Currently, caffeine is one of the more common drugs used by the pregnant patient. It is important that the patient be made aware that caffeine is a drug and that it may cause potential harm to the fetus. Until more scientific data are available, it is our recommendation that moderate to excessive use of caffeine during pregnancy be curtailed and that mild use be decided on an individual basis. (AM. J. OBSTET. GYNECOL. 140:607, 1981.)
CONSUMERISM has been a major impetus for the improvement of health care in the United States. Patients are increasingly questioning the health care provider regarding treatment being initiated and medications being dispensed. This increased awareness has benefited the developing fetus, as many women now actively avoid the use of any drugs during pregnancy. Unfor-
From the Department University of Arizona,
of Obstetrics and Gynecology, Health Sciences Center.
Reprint requests: Dr. Louis Weinstein, Department Obstetrics and Gynecology, University of Arizona, Sciences Center, Tucson, Arizona 85724. 0002-9378/81/140607+04$00.40/0
@ 1981
The
C. V. Mosby
of Health
Co.
tunately, some women do not realize what constitutes a drug. Patient education regarding smoking (nicotine) and alcohol is helping to decrease the use of these substances in pregnancy. Currently, one of the most common drugs to be consumed during pregnancy is caffeine. The Food and Drug Administration has recently removed caffeine from the list of drugs “generally regarded as safe” and has issued a warning regarding the consumption of caffeine during pregnancy. The public needs to be informed about the potential harm from caffeine to the developing fetus. Current data are presented on the possible effects of caffeine intake on human pregnancy outcome.
607
608
Morris
and Weinstein
Characteristics
of caffeine
Caffeine ( 1,3,7-trimethylxanthine) is a methylated xanthine structurally related to uric acid. Caffeine is present in coffee, tea, cola and other carbonated beverages, and cocoa. Caffeine constitutes a substantial portion of many over-the-counter medications, such as cold and allergy tablets, headache tablets, diuretics, and stimulants. Certain prescription drugs also contain caffeine. Eight ounces of coffee contains from 85 to 233 mg of caffeine. The same amount of tea has a caffeine content of 50 to 79 tng. Cola beverages contain 12 to 36 mg per 8 ounces.‘, ’ In these studies, brand, type, and brewing methods varied as did analyses. Over-thecounter medications with caffeine often contain 100 to 200 mg per tablet, the approximate amount in 8 ounces of coffee. Caffeine is ubiquitous in the American diet and has been previously recognized as safe. The GRAS Survey Committee of the National Academy of Sciences estimated the mean daily intake of caffeine per person for 1977.’ By age group, the mean intakes were: 6-l 1 months, 4.2 mg/day; 12-23 months, 15 mg/day; 2-5 years, 29 mglday; 6-17 years, 43 mglday: 18+ years, 186 mgiday. Pregnant women have an average intake of 144 mg/day. To be of potential harm to the fetus, a drug must be able to enter the fetal circulation. The physicochemical characteristics of caffeine allow this to occur without difficulty. Its low molecular weight facilitates transport across the placenta. 3. ’ It is highly lipid soluble and unionized at a physiologic pH, factors which aid in placental transfer. Caffeine is 75% to 85% unbound at therapeutic levels. It has also been shown to diffuse easily into breast milk with milk to serum concentration ratios ranging from 0.52 to 0.9.j. 6 Any substance that might decrease uterine blood flow should be avoided during pregnancy. Ingestion of 220 mg of caffeine results in significant increases in the urinary excretion of total catecholamines. These catecholamines may have a vasoconstrictive effect on the uterine vasculature. One study of 23 maternal-infant pairs6 found the average maternal plasma caffeine concentration to be 0.8 pg/ml, with a range of 0.02 to 3.5 pg/ml.6 The average daily coffee intake was 1.5 cups with a range of 0 to 8. Seven banked blood samples from another study’ found caffeine concentrations in the range of 0.1 to 7.4 pglml. Therefore, measurable amounts of caffeine are demonstrable in maternal blood. Caffeine has been detected in the umbilical cord plasman and urine3 of newborn infants. The mothers of these infants received only dietary caffeine. Caffeine
and its metabolites were detected in !#Ci of the newborn urine samples studied.” The transfer of Inetaholites would be expected to be less than that of the parent compound because of the increased polarity of the metabolites. Caffeine has an elimination half litr 01’ approximately 3.5 hours in the adult. “’ It is metabolized b) N-demethylation and oxidation to monomethvl and dimethyl xanthines and uric acids, which are excreted in the urine. No studies specific for caffeine metabolism by the placenta have been published. Studies in newborn infants reflect a relative lack of the enzyme activity necessary to metabolize caffeine. Caffeine was excreted in newborn urine as up to 85% of the parent compoundY, IL compared to 26% or less in maternal urine.g In the infant, ratios of urine caffeine to metabolites decreased to near-adult values by 7 to !) months of age.12 The elimination half life of caffeine was found to be approximately 4 days for newborn infants and 4 hours at 8 months of age.” Certain drugs may act as inducers or inhibitors of caffeine metabolism. M’hile maternal smoking had no effect on caffeine elimination in infants,X the ability of‘ other known inducers such as 3-methytcholanthrenel” and inhibitors such as other methyl xanthinesla to exert their effects on fetal caffeine metabolism has not been studied.
Pharmacologic effects of caffeine Minimal data are available concerning the effect of caffeine on pregnancy outcome in humans, although the literature is replete with animal studies regarding the mutagenic and teratogenic properties of the drug. When applied to mammalian cells in vitro, caffeine decreases DNA polymerase activity and shortens the DNA-replicating units. ‘j It has also been demonstrated to increase cyclic nucleotide levels (cyclic adenosine monophosphate [CAMP] and cyciic guanosine monophosphate [cGMP]).” Since CAMP levels are usually low during early gestation,16 a marked increase in CAMP might influence fetal development. The ability of caffeine to increase circulating catecholamineslj. I6 could cause vasoconstriction of uterine and placental blood vessels. Decreased placental weights have been found in caffeine-treated rats.‘” Caffeine has also been shown to decrease normal oogenesis in female rats’” and its effects on spermatozoa are currently under investigation. An unusual study with the use of caffeine-fed female houseflies revealed ovarian growth to be retarded. This resulted in abnormal ovaries with malformed eggs, as well as a significant reduction in the hatchability of the e&w I7 Obviously these findings cannot be extrapolated
Volume Number
140 6
to the human female patient with an infertility problem but do allow for some interesting speculation. Palm and associatesI performed an experiment in rats with the use of dosages of caffeine comparable to those of human consumption. The only significant finding was a reduction in bone calcium deposition. The investigators were not able to demonstrate any dose-related teratogenic effects. The multitude of animal studies have been reviewed by Thayer and Palm. I9 The conclusion of the authors was that data exist to support the teratogenic potential of caffeine in animals but documentation was lacking concerning human malformations attributable to caffeine in amounts normally consumed by man. One retrospective human studyzO on caffeine and pregnancy showed increased fetal loss in families where caffeine intake was deemed to be excessive. Sixteen women were identified who had a daily caffeine consumption of 2600 mg per day. Pregnancy outcome was eight spontaneous abortions, five stillbirths, two premature deliveries with survival, and one uncomplicated term delivery. Thirteen pregnancies were identified where the father’s caffeine intake was 2600 mg per day while the mother’s intake was 5400 mg per day. This group experienced four spontaneous abortions, two stillbirths, two premature deliveries, and five uncomplicated term births. The data, as presented by the authors, do not establish a cause-and-effect relationship between high levels of caffeine consumption and poor pregnancy outcome. What these data do is establish the need for large, well-controlled epidemiologic studies regarding the effects of caffeine on the developing fetus.
Caffeine
and the fetus
609
Recent studies have shown increased blood glucose levels in caffeine-treated premature newborn infants with apnea. Z’s 22 One group has found a 0.98 concentration ratio of mean cerebrospinal fluid to plasma in caffeine-treated neonates, which indicates that the drug is free to exert its central nervous system effects.23 The implications of these effects for the fetus through caffeine use by the mother is unknown. One group of investigators has observed caffeinetreated infants of low birth weight with apnea for 18 to 40 months; no apparent long-term effects of caffeine on growth and development have been shown.24 The treatment regimen was not uniform, acute effects were not reported, and other disease states were poorly controlled.
Comment The significance of in vitro and poorly controlled in vivo studies is questionable with no adequate long-term studies having been done. With the scientific data available, it is our recommendation that minimal use of caffeine by the pregnant patient be decided on an individual basis with moderate to excessive use of the drug being curtailed during pregnancy until further scientific data are presented. Soyka and Neese’s’ summary of the literature in 1978 remains true today: “Caffeine may alter intrauterine growth and the duration of gestation; the present data do not establish useful or harmful effects of methylxanthines but serve to emphasize the common and multiple source exposure of the perinate to concentrations which may be pharmacologically active.”
REFERENCES 1. Bunker, M. L., and McWilliams, M.: Caffeine content of common beverages, J. Am. Diet. Assoc. 74:28, 1979. 2. Graham, D. M.: Caffeine-its identity, dietary sources, intake, and biological effects, Nutr. Rev. 36:97, 1978. 3. Mirkin, B. L.: Drug distribution in pregnancy, in Boreus, L., editor: Fetal Pharmacology, New York, 1973, Raven Press, pp. l-27. transfer of phar4. Mirkin, B. L., and Singh, S.: Placental macologically active molecules, in Mirkin, B. L., editor: Perinatal Pharmacology and Therapeutics, New York, 1976, Academic Press, Inc., pp. l-69. 5. Tyrala, E. E., and Dodson, W. E.: Caffeine secretion into breast milk, Arch. Dis. Child. 54~787, 1979. 6. Aranda, J. V., Costum, B., Turmen, T., Louridas, T., and Collinge, J.: Caffeine burden in young infants, Pediatr. Res. 14:464, 1980. 7. Soyka, L. F., and Neese, A. L.: Perinatal exposure to methylxanthines: possible effects on pregnancy outcome, Clin. Pharmacol. Ther. 23:130, 1978. 8. Parsons, W. D., Aranda, J. V., and Neims, A. H.: Elimination of transplacentally acquired caffeine in fullterm neonates, Pediatr. Res. 10:333, 1976.
9. Horning, M. G., Stratton, C., Nowlin, J., Wilson, A., Hornine. E. C.. and Hill. R.: Placental transfer of drugs, in Bon&, L.,‘editor: Fetal Pharmacology, New Yolk, 1973, Raven Press, pp. 355-373. 10. Sant’Ambrogio, G., Mognoni, P., and Ventrella, L.: Plasma levels of caffeine after oral, intramuscular, and intravenous administration, Arch. Int. Pharmacodyn. 150:259, 1964. 11. Aldridge, A., Aranda, J. V., and Neims, A. H.: Caffeine metabolism in the developing human infant, Pharmacologist 20~263, 1978. A., Aranda, J. V., and Neims, A. H.: Caffeine 12. Aldridge, metabolism in the newborn, Clin. Pharmacol. Ther. 25: 447, 1979. 13. Aldridge, A., Parsons, W. D., and Neims, A. H.: Stimulation of caffeine metabolism in the rat by 3-methylcholanthrene, Life Sci. 21:967. 1977. ’ 14. Caldwell, I., Lancaster. R.. Monks, T. I., and Smith. R. L.: The influ&e of dietary methylxanth:nes on the metabolism and pharmacokinetics of intravenously administered theophylline, Br. J. Clin. Pharmacol. 4~637, 1977. 15. Weathersbee, P. S., and Lodge, J. R.: Caffeine: Its direct
610
16.
17.
18.
19.
Morris and Weinstein
and indirect influence on reproduction, J. Reprod. Med. 19:55, 1977. Weathersbee, P. S., and Lodge, J, R.: Alcohol, caffeine, and nicotine as factors in pregnancy, Postgrad. Med. 66:165, 1979. Srinivasan, A., and Kesavan, P. C.: Reproductive toxicity of caffeine in Musca Domestica, J. Toxicol. Environ. Health 5:765, 1979. Palm, P. E.. Arnold, E. P., Rachwall, P. C., Leyczek, J. C., Teague, K. W., and Kensler, C. J.: Evaluation of the teratogenic potential of fresh brewed coffee and caffeine in the rat, Toxicol. Appl. Pharmacol. 44: 1, 1978. Thayer, P. S., and Palm, P. E.: A current assessment of the mutagenic and teratogenic effects of caffeine, CRC Crit. Rev. Toxicol. 3:345, 1975.
20.
21.
22.
23.
24.
Weathersbee. P. S., Olsen, L. K., and Lodge, J, R.: Catfeine and pregnancy-a retrospectike study, Postgrad. Med. 62:64. 1977. Lazaro-Lopez, F., Colle, E.. DuPont, C.. and Aranda. J. V.: Metabolic effects of caffeine in the preterm neonate, Pediatr. Res. 14:468, 1980. Rothberg. A. D.. Marks, K. H., Ward, R. M., and Maisels, M. J.: Effects of caffeine on glucose homeostasis, Pediatr. Res. 14:471, 1980. Turmen, T., Louridas, ‘1.. A., and Aranda, J. V.: Relationship of plasma and CSF concentrations of caffeine in neonates with apnea. J. Pediatr. 95:644. 1979. Gunn, T. R., Metrakos, K.. Riley, P., Willis, D., and Aranda, J. V.: Sequelae of caffeine treatment in preterm infants with apnea, J. Pediatr. 94106, 1979.