Caffeine Metabolism, Genetics, And Perinatal Outcomes- A Review of Exposure Assessment Considerations During Pregnancy

8/2/2019 Caffeine Metabolism, Genetics, And Perinatal Outcomes- A Review of Exposure Assessment Considerations During Pregnancy

1/7

Caffeine Metabolism, Genetics, and Perinatal Outcomes: A Review of

Exposure Assessment Considerations during Pregnancy

LAURA M. GROSSO, PHD, AND MICHAEL B. BRACKEN, PHD

PURPOSE: To review the methodologic issues complicating caffeine exposure assessment duringpregnancy; to discuss maternal and fetal caffeine metabolism, including genetic polymorphisms affectingcaffeine metabolism; and to discuss the endogenous and exogenous risk factors known to influence caffeinemetabolism.METHODS: A review of the relevant literature.RESULTS: There is wide inter-individual variation in caffeine metabolism, primarily due to variations inCYP1A2 enzyme activity. Some variability in CYP1A2 activity is due to genetic polymorphisms in theCYP1A2 gene which can cause increased or decreased inducibility of the enzyme. Considerable evidenceexists that maternal caffeine metabolism is influenced by a variety of endogenous and exogenous factors and

studying the genetic polymorphisms may improve understanding of the potential effects of caffeine and itsmetabolites on perinatal outcomes. There is substantial evidence that measurement of maternal, fetal, andneonatal caffeine metabolites may allow for a more precise measure of fetal caffeine exposure.CONCLUSIONS: Research on the genetic polymorphisms affecting caffeine metabolism may furtherexplain the potential effects of caffeine and its metabolites on perinatal outcomes.Ann Epidemiol 2005;15:460466. 2005 Elsevier Inc. All rights reserved.

KEY WORDS: Caffeine, Cytochrome P450 1A2, CYP1A2, Genetic Polymorphisms, Pregnancy,Reproduction, Fetal Growth Retardation, Gestational Age, Spontaneous Abortion.

INTRODUCTION

Maternal caffeine consumption during pregnancy has been

studied for many years but convincing evidence for an asso-ciation with poor perinatal outcomes remains elusive. Caf-feine is an exposure of major public health interest because itis one of the most widely consumed drugs. Coffee makes upthe largest percentage of total caffeine intake (75%), fol-lowed by tea (15%), and caffeinated sodas (10%) (1). In theUnited States, per capita consumption of coffee is nearly3.5 kg of coffee per year, or more than 150 mg/day, andmore than 75% of pregnant women consume caffeinatedbeverages (2, 3).

Epidemiologic studies of caffeine and reproductive out-comes have produced conflicting results. Some epidemio-

logical studies have linked relatively high antenatal caffeineconsumption (typicallyO 300 mg/day) to poor reproduc-tive outcomes, including subfecundity (48); fetal growth

retardation (2, 912); and spontaneous abortion (1318).One study among smoking women who consumedO 400mg caffeine per day noted a significant reduction in birth-

weight (19) and a more recent study reported a small,detrimental effect on birthweight, although it is only likelyto be of clinical importance in women consuming largequantities of caffeine (20). Other studies suggest that ante-natal caffeine consumption is not a reproductive hazard(2125).

These equivocal findings are likely due to inconsistentdefinition and categorization of caffeine exposure amongstudies, selection and recall biases, and to varying studydesigns. The major limitations of the extant studies include:lack of control for confounding variables (4, 12), bias due tomisclassification of caffeine exposure (4, 9, 21), and im-

precise/inadequate measurement of caffeine intake (4, 21).Some studies were retrospective and the exposure informa-tion was collected long after the exposure occurred (9, 10,21). Three prospective cohort studies that found an increasein risk for intrauterine growth retardation (IUGR) withthird trimester caffeine consumption suffer from additionalmethodological problems including lack of a completelyunexposed referent group (4, 19) and residual confoundingdue to inadequate control for the effects of smoking (12).Two retrospective cohort studies, one finding no effect (21)and the other finding an effect in women consuming coffee(26), inadequately assessed caffeine intake. Linn et al. (21)

From the Yale Center for Perinatal, Pediatric, and EnvironmentalEpidemiology, Yale University School of Medicine, Department ofEpidemiology and Public Health, New Haven, CT.

Address correspondence to: Dr. Laura M. Grosso, Yale Center forPerinatal, Pediatric, and Environmental Epidemiology, Yale UniversitySchool of Medicine, Department of Epidemiology and Public Health, OneChurch Street, 6th Floor, New Haven, CT 06510. Tel.: (203) 764-9375;Fax: (203) 764-9378. E-mail: [email protected]

Received April 19, 2004; accepted December 15, 2004.

2005 Elsevier Inc. All rights reserved. 1047-2797/05/$see front matter360 Park Avenue South, New York, NY 10010 doi:10.1016/j.annepidem.2004.12.011
mailto:[email protected]:[email protected]


2/7

assessed caffeine consumption in the first trimester only andthe caffeine content per cup of coffee was not estimated andMcDonald et al. (26) only assessed coffee consumption.

Studies investigating the association between maternalcaffeine consumption and spontaneous abortion are alsofraught with methodological complexity. A comprehensivereview of this literature was conducted by Signorello et al.(27). Cross-sectional and case-control studies suffer from

a variety of methodologic issues including recall bias; in-accurate recall of caffeine exposure due to exposure assess-ment several years later; confounding due to cigarette andalcohol consumption (18, 28); and selection bias (27).Confounding due to pregnancy symptoms is anotherimportant issue complicating the relation between caffeineconsumption and spontaneous abortion. Nausea may in-fluence the amount of caffeine consumed in early pregnancyand it is also related to fetal viability. Women with non-viable pregnancies may have little or no nausea and there-fore do not decrease their caffeine intake, falsely suggestingthat their higher caffeine intake is related to the spon-

taneous abortion (29).Change in caffeine consumption over pregnancy isanother important factor complicating exposure assessment.Women frequently have an aversion to caffeinated bev-erages in the first trimester of pregnancy and thereforedecrease caffeine intake. They may also decrease caffeineintake upon confirmation of the pregnancy (30, 31). It istherefore crucial that caffeine exposure be assessed atmultiple time periods throughout pregnancy.

Measurement Heterogeneity of Caffeine Exposure

There is a considerable amount of heterogeneity in caffeine

exposure because caffeine content of caffeinated beveragesvaries widely and there are large differences in caffeinecontent per serving of coffee, tea, and soft drinks (7, 19, 32).Methodological issues related to retrospective ascertain-ment of exposure include inaccurate recall by the subjectdue to unawareness and/or forgetfulness of consumption andbiased recall. Caffeine content of caffeinated beveragesvaries considerably, depending on brewing method, servingsize, and portion of serving consumed. Estimates of caffeinecontent per serving for coffee, tea, and soft drinks range from

92 to 120 mg/serving, 34 to 65mg/serving, and 34to 47 mg/serving, respectively, and current ranges for soft drinks maybe considerably higher (7, 19, 32).

The caffeine content of coffee is quite variable anddepends on brand, whether it is a blend or a pure variety(33), quantity brewed, brewing method, and type of coffee

bean. Caffeine extraction efficiency varies from 75% to100%, depending on whether coffee is boiled, filtered,percolated, or prepared as espresso (34). Serving sizes rangefrom 5 to 32 ounces and the caffeine content per cup isreported to range as much as 19 to 160 mg depending onbrewing method and cup size (34). Considerable variation incaffeine content was found, even when the same studyparticipant brewed coffee or tea under the same conditionson the same day (35).

Variation in caffeine consumption categorization alsocontributes to exposure misclassification and decreasedcomparability among studies. Categorization for the lowest

levels of consumption (often used as the referent category)varies from no intake (21) to< 400 mg/day (32) and for thehighest categories of consumption fromO 300 mg/day (19)toO 800 mg/day (32). If caffeine consumption of approx-imately 300 mg/day or more is associated with poor perinataloutcomes, grouping such exposed individuals with the lesserexposed or unexposed would dilute any effect of caffeineexposure.

In most studies of caffeine consumption and perinataloutcomes, self-reported caffeine exposure is calculated usinga standard measure of caffeine per unit exposure that hasbeen obtained by laboratory analyses. In a recent study,samples of caffeinated and decaffeinated coffee and tea were

collected from the study participants and analyzed for actualcaffeine content (35). It was observed that for all cup sizes,the actual amounts of caffeine in both coffee and tea weremuch lower than the amounts predicted using widely usedlaboratory estimates. For example, a 10 oz. cup of dripbrewed coffee is estimated to contain 300 mg caffeine,according to Bunker and McWilliams (36), but Brackenet al. (35), found that a 10 oz. drip brewed cup of coffeetypically contained 100 mg caffeine. Similarly, a 10 oz. cupof tea brewed for more than 3 minutes was found to contain42 mg caffeine compared with the predicted 94 mg (35).

Use of Caffeine Biomarkers

Even among well designed studies with valid exposureassessment, nearly all of them relied on self-reportedcaffeine consumption to estimate exposure. This does notprovide an accurate measure of maternal or fetal dosebecause it does not necessarily indicate how much caffeineor caffeine metabolites enter maternal or fetal circulation. Avariety of endogenous and exogenous risk factors are knownto influence caffeine metabolism and it is possible that

Selected Abbreviations and Acronyms

AAMU Z 5-acetyl-6-amino-3-methyluracilAFMU Z 5-acetylamino-6-formylamino-3-methyluracilCYP1A2 Z cytochrome P450 1A2CYP450 Z cytochrome P450

NAT2 Z N-acetyltransferase 2SNP Z single nucleotide polymorphismXO Z xanthine oxidase

Note: Throughout the manuscript, when the abbreviation is in italics itrefers to the gene, otherwise it refers to the gene product.

AEP Vol. 15, No. 6 Grosso and BrackenJune 2005: 460466 CAFFEINE EXPOSURE ASSESSMENT IN PREGNANCY

461


3/7

caffeine metabolites, rather than caffeine itself, are re-sponsible for deleterious reproductive and perinatal effects.Serum and urinary biomarkers, used in conjunction withself-reported caffeine intake, may provide a more accurateand direct measure of maternal and fetal dose thaninformation obtained solely via questionnaire (37).

There are potential disadvantages in using a caffeinebiomarker. Timing of sample collection, relative to reportedintake, can greatly affect biomarker accuracy. For example,if a pregnant woman consumes all of her daily caffeine in themorning, but after urine or serum sample collection, thesample would substantially under-represent her caffeine in-take since most of the previous days caffeine would bemetabolized. A more appropriate time for sampling thisconsumption pattern is mid-to-late afternoon, since caffeinehalf-life, at this point in pregnancy, is approximately 10hours (38).

Cigarette smoking can affect accuracy of the biomarker

by accelerating caffeine metabolism (3840), resulting indecreased urinary caffeine and underestimation of caffeineconsumption. Similarly, concurrent drug use affecting caf-feine metabolism will alter how much caffeine is excretedin urine.

One study investigating the relation between maternalthird-trimester serum paraxanthine, the primary metaboliteof caffeine and fetal growth, found that maternal serumparaxanthine was only associated with growth retardationamong smokers (41). These samples had been stored for 30years and it is possible that some of the paraxanthine de-graded. This would result in a differential misclassificationbias because smoking and non-smoking women exposed to

moderate levels of caffeine may have been subsequentlycategorized into the lowest paraxanthine level used as areferent category, biasing any association toward unity (42,43).

Caffeine Metabolism in Humans

Caffeine is absorbed rapidly and completely from thegastrointestinal tract. Peak plasma concentrations arereached within 15 (33) to 60 (44) minutes after intake,but can take as long as 120 minutes after ingestion (33).Delayed gastric emptying is thought to account for this

variation in peak concentration (33). First pass metabolismoccurs as oral agents are absorbed through the smallintestine into the portal circulation where initial metabo-lism by CYP450 isoenzymes occurs in the bowel wall andliver before entering the systemic circulation. Since there isa minimal first-pass effect for caffeine (33), once it isabsorbed it readily enters all body tissues and freely crossesthe blood-brain, placental, and blood-testicular barriers(33, 45). Caffeine and its primary metabolites, para-xanthine, theobromine, and theophylline, are detectable

in all body fluids and in umbilical cord blood (33, 46).Caffeine is eliminated from the body overnight, but someprimary metabolites (theophylline and theobromine) havelonger half-lives (47).

In humans, the half-life of caffeine ranges from 2 to 4.5hours (45, 48), but can be as long as 12 hours (47). Caffeine

is metabolized in the liver by the hepatic microsomalenzyme systems to dimethylxanthines. The main enzymeinvolved in caffeine metabolism is cytochrome P450 1A2(CYP1A2), accounting for about 95% of caffeine clearance.The rate of caffeine metabolism is controlled by CYP1A2and to a lesser extent by xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) (49). Only 0.5% to 2% ofingested caffeine is excreted as such in the urine due to 98%tubular reabsorption (33) and paraxanthine accounts for72% to 80% of caffeine metabolism (33, 50).

Paraxanthine, the primary metabolite of caffeine, hasa molecular structure and half-life similar to caffeine (51)

and is easily measured in urine and serum. Approximately60% of orally administered paraxanthine is excretedunchanged (52). The rate of paraxanthine degradationapproximates its rate of formation and serum levels are morereliable and less variable throughout the day compared withcaffeine (53), although they reflect only recent intake (16).Plasma paraxanthine concentrations decrease less rapidlythan caffeine, even after accounting for inter-individualdifferences in metabolism, and paraxanthine concentrationsbecome higher than caffeine within 8 to 10 hours ofingestion (33). Paraxanthine is further metabolized viatwo parallel but independent reactions (40). One produces8-hydroxyparaxanthine and the other reaction is the

7-demethylation of paraxanthine which leads to threemetabolites: 1-methylxanthine, 1-methylurate, and 5-ace-tylamino-6-formylamino-3-methyluracil (AFMU) (40).AFMU accounts for 67% of paraxanthine metabolism (33).AFMU is converted to 5-acetyl-6-amino-3-methyluracil(AAMU) which can be easily and reliably measured in urine(40). These paraxanthine metabolites appear in the urinealmost as fast as they are formed due to active renal tubularsecretion (40).

Theobromine comprises the largest percentage of thebiologically active caffeine metabolites (54). It is rapidlyabsorbed and approximately 50% is excreted in urine within

8to12hours (55). Its pharmacologic effects include diuresis,stimulation of the cardiovascular system, relaxation ofsmooth muscle, and increased glandular secretion (56).Metabolic clearance of theobromine is mediated primarilyby the CYP1A2 enzyme which is estimated to account for86% of its demethylation, and to a lesser degree by CYP2E1(57). The half-life ranges from 7.2 (58) to 11.5 (55) hoursand plasma and renal clearance is reported as 46% and 67%,respectively (59). Plasma clearance is reported to be 33%higher in smokers than in nonsmokers (60).

Grosso and Bracken AEP Vol. 15, No. 6CAFFEINE EXPOSURE ASSESSMENT IN PREGNANCY June 2005: 460466

462


4/7

Theophylline is structurally similar to caffeine, lackingonly one additional N-methyl group. Its pharmacologicalproperties are very similar as well, but theophylline incursstronger toxicological effects than caffeine and theobro-mine. The half-life is longer than that of caffeine (3-9 hours)but is quite variable (61). Theophylline is cleared from the

body via renal and metabolic clearance. Metabolic clear-ance is mediated primarily by CYP1A2 with N-demethyla-tion to monomethylxanthines and 8-hydroxylation to1,3-dimethyl-uric acid. The urinary excretion rate is highlydependent on urinary flow and dose. Higher plasmaconcentrations of theophylline result in decreased metabol-ic clearance and increased renal clearance. Like caffeine,there is considerable inter-individual variation in theoph-ylline clearance, metabolism, and elimination (61). Severalexogenous factors influence metabolic and excretion ratesincluding cigarette smoking, viral infections, liver and heartdiseases, pregnancy, foods, and concomitant drug use.

Smoking increases clearance and drugs including cimeti-dine, ranitidine, erythromycin, rifamycin, and troleando-mycin slow metabolism. Pregnancy decreases clearance andexcretion and therefore theophylline (like caffeine) canaccumulate in the body (61). Fetuses and newborns lack theenzymes necessary to metabolize theophylline, so elimina-tion is almost entirely dependent on renal excretion.

Factors Affecting Caffeine Metabolism

Two of the most important endogenous and exogenousfactors influencing caffeine metabolism are pregnancy andcigarette smoking, respectively. Pregnancy slows caffeine

metabolism while cigarette smoking accelerates it (39, 40,62). During pregnancy, caffeine half-life remains the sameduring the first trimester but increases to 10 hours at 17weeks gestation (38). By the end of pregnancy the half-lifein non-smokers varies from 11.5 (63) to 18 (38) hours,leading to an accumulation of caffeine in the body. Thisgestational increase in caffeine half-life is likely related toa reduction in NAT2 enzyme activity in early pregnancy,and reduction in CYP1A2 activity throughout pregnancy(64). One study noted a 35%, 50%, and 52% reduction inCYP1A2 activity in early, middle, and late pregnancy,respectively, compared with 4 to 6 weeks after delivery (64).

Cook et al. (65) noted that serum caffeine concentrationsrosefrom a meanof 2.35mg/ml in early pregnancy to 4.12mg/ml by the third trimester, despite little change in reportedconsumption.

Cigarette smoking is an important exogenous factorinfluencing caffeine metabolism, nearly doubling themetabolism rate (38). Cigarette smoke contains polycyclicaromatic hydrocarbons known to increase liver enzymeactivity, thereby increasing caffeine metabolism (39, 40).Smoking may accelerate the first and second demethylation

steps of caffeine metabolism, via induction of hepaticmicrosomal oxidative enzymes (66). Smokers have beenobserved to have lower serum caffeine concentrations thannon-smokers within each category of reported consumption(65).

Other exogenous factors that slow caffeine metabolism

are liver disorders (33), oral contraceptive use (67, 68), andluteal phase of the menstrual cycle (69). Several drugs,including fluvoxamine (a serotonin reuptake inhibitor),mexiletine (an antiarrhythmic), clozapine (an antipsychot-ic), furafylline and theophylline (bronchodilators), andenoxacin (a quinolone) may slow caffeine metabolism (70).Consumption of apiaceous (Apiaceae or Umbelliferae)vegetables including dill weed, celery, parsley, parsnips andcarrots, has been shown to reduce CYP1A2 activity,subsequently slowing caffeine metabolism. Consumption ofbrassica (Cruciferae) vegetables, particularly radish sprouts,broccoli, cauliflower, and cabbage, accelerates CYP1A2

activity, thereby accelerating caffeine metabolism (71).

Genetic Variations Affecting Caffeine Metabolism

There is wide inter-individual variation in caffeine metab-olism, primarily due to variations in CYP1A2 enzymeactivity (7274) and there is recent interest in identifyingpolymorphisms which influence caffeine metabolism. Somevariability in CYP1A2 activity is due to genetic poly-morphisms in the CYP1A2 gene which can cause increasedor decreased inducibility of the enzyme. Urinary caffeinemetabolite ratios have been used extensively to phenotyp-ically assess acetylator status (72, 7578), but recently,

polymerase chain reaction (PCR) has been used to de-termine allelic variants ofCYP1A2, specifically whether anindividual is a slow (mutated allele) or fast (wild type)acetylator. To date, several recently discovered singlenucleotide polymorphisms (SNPs) may help explain someof the inter-individual variation in caffeine metabolism (73,74, 79). One SNP, CYP1A2 3858G/A (CYP1A2*1C) hasbeen observed to cause a significant decrease in CYP1A2inducibility in Japanese smokers (73). This SNP is rare inCaucasians. A common polymorphism in Caucasians,CYP1A2 164C/A (CYP1A2*1F) influences caffeinemetabolism, and is associated with increased inducibility

in smokers homozygous for the A allele (80). CYP1A21545T/C (CYP1A2*1B) is associated with three othermutationsd740T/G (CYP1A2*1G), 951A/C (CY-P1A2*1H), and 1042G/A (CYP1A2*3)dthat are alsofrequent in Caucasians. The frequency of this SNP is 35.0%(81) and 38.2% (82) in French and British populations,respectively, however the effects of this polymorphism onCYP1A2 activity remain unclear.

Further investigation of the effects of these maternalpolymorphisms on CYP1A2 enzyme activity (and


463


5/7

subsequently caffeine metabolism) is needed to predict fetalcaffeine exposure and more fully understand any effects ofmaternal caffeine consumption on perinatal outcomes.

Placental/Fetal MetabolismCaffeine readily crosses the placenta into the fetus andamniotic fluid and maternal serum concentrations arebelieved to be reliable indicators of fetal serum concentra-tion (83, 84). This equilibration occurs as early as week 7 ofgestation (83). Since neither fetus nor placenta canmetabolize caffeine, the fetus is exposed to caffeine and itsmetabolites for a prolonged period of intra-uterine life. Thehuman placenta cannot metabolize caffeine because itcontains only CYP1A1, not CYP1A2 (72). The fetus alsolacks liver enzymes necessary to metabolize caffeine, whichare not present until about the eighth month of age (23).

As a result of hepatic immaturity, the neonate hascompensatory pathways including renal elimination forcaffeine and theophylline (85). Since renal elimination isnot as efficient as CYP1A2 mediated clearance, overall fetalmetabolism is much less compared with adults. In neonates,80% to 90% of caffeine is excreted in urine, compared withless than 2% in adults (85). Excretion of theophylline is lesscomplete; nearly 50% is eliminated unchanged in neonates,compared with 10% in adults (85).

Caffeine concentrations in umbilical cord blood arehigher than expected based on maternal caffeine consump-tion (46). Other evidence suggests that transplacentallyacquired theophylline, an active alkaloid from tea, may

further increase fetal and early neonatal caffeine load.Human fetal liver can methylate theophylline to caffeine asearly as the 12th week of gestation (86). This reversebiotransformation of theophylline into caffeine was firstreported in preterm infants treated with theophylline forapnea (33). Back-methylation, where a methyl group isadded to theophylline, accounts for approximately 5% to10% of the overall urinary excretion of caffeine in neonates(85).

Cazeneuve et al. (87) noted that formation of dimethyl-xanthines was significantly less in fetuses, neonates, andinfants than in adults. In neonates and infants, production of

total dimethylxanthine, paraxanthine, and theophyllineincreased significantly with postnatal age. The half-life ofcaffeine in the newborn is estimated to range from 50 to 103hours, compared with 6 hours in the non-smoking adult (33,86). Caffeine half-life decreases to 14 hours and 3 hours in3 to 5 months and 5 to 6 months, respectively (33). Urinarycaffeine and theophylline from newborn urine mayaccurately estimate fetal exposure to caffeine during thelast month of pregnancy, since caffeine and theophyllineelimination in the newborn is so immature.

One effect of caffeine ingestion is to increase release ofcatecholamines, particularly epinephrine, into the maternalcirculation (84). The direct effects of caffeine on fetalcirculation remain unknown but Kirkinen et al. (84)documented a decrease in intervillous placental blood flowafter maternal caffeine ingestion of just 200 mg. Caffeine

also inhibits phosphodiesterase, an enzyme responsible forthe breakdown of cyclic AMP (88). An increase in cyclicAMP may interfere with cell division, or cause catechol-amine-mediated uterine vasoconstriction (89). If uterineblood flow is inadequate, extraction of oxygen and nutrientsincrease until a critical point during pregnancy at whichreductions in blood flow can profoundly affect fetaloxygenation and nutrition (90). The exact mechanisms bywhich caffeine may impair fetal growth remain unknownbutthe literature suggests that impairment of uteroplacentalblood flow,fetoplacental blood flow, or villous blood flow canlead to IUGR (88, 90). In a study of very low birth weight,

preterm infants with apnea who were given caffeine therapy,neonatal oxygen consumption increased and there wasa reduction in weight gain (91). Caffeine exposure duringthe third trimester may have a similar effect on fetal growth.

In summary, there is substantial evidence that measure-ment of maternal, fetal, and neonatal caffeine metabolitesmay allow for a more precise measure of fetal caffeineexposure. There is preliminary evidence that the metabolitesof caffeine may play an important role in the associationswith perinatal outcomes and there is also considerableevidence that maternal caffeine metabolism is influenced bya variety of endogenous and exogenous factors. Studying thegenetic polymorphisms influencing metabolism, in particu-

lar, mayimprove our understandingof thepotentialeffects ofcaffeine and its metabolites on perinatal outcomes.

REFERENCES

1. Lundsberg L. Caffeine consumption. In: Spiller GA, ed. Caffeine. BocaRaton, New York: CRC PRESS; 1998:200.

2. Eskenazi B, Stapleton A, Kharrazi M, Chee W. Associations betweenmaternal decaffeinated and caffeinated coffee consumption and fetalgrowth and gestational duration. Epidemiology. 1999;10:242249.

3. Eskenazi B, University of CA School of Public Health. Caffeine-filteringthe facts [editorial] New Engl J Med. 1999;341:16881689.

4. Olsen J. Cigarette smoking, tea and coffee drinking, and subfecundity.Am J Epidemiol. 1991;133:734739.

5. Grodstein F, Goldman M, Ryan L, Cramer D. Relation of femaleinfertility to consumption of caffeinated beverages. Am J Epidemiol.1993;137:13531360.

6. Hatch E, Bracken M. Association of delayed conception with caffeineconsumption. Am J Epidemiol. 1993;138:10821092.

7. Stanton C, Gray R. Effects of caffeine consumption on delayedconception. Am J Epidemiol. 1995;142:13221329.


464


6/7

8. Bolumar F, Olsen J, Rebagliato M, Bisanti L, The European Study Groupon Infertility and Subfecundity. Caffeine intake and delayed conception:A European multicenter study on infertility and subfecundity. Am JEpidemiol. 1997;145:324334.

9. Vlajinac H, Petrovic R, Marinkovic J, Sipetic S, Adanja B. Effects ofcaffeine intake during pregnancy on birth weight. Am J Epidemiol.1997;145:335338.

10. Fortier I, Marcoux S, Beaulac-Baillargeon L. Relation of caffeine intakeduring pregnancy to intrauterine growth retardation and preterm birth.Am J Epidemiol. 1993;137:931940.

11. Fenster L, Eskenazi B, Windham G, Swan S. Caffeine consumption duringpregnancy and fetal growth. Am J Public Health. 1991;81:458461.

12. Martin T, Bracken M. The association between low birth weight andcaffeine consumption during pregnancy. Am J Epidemiol. 1987;126:813821.

13. Infante-Rivard C, Fernandez A, Gauthier R, David M, Rivard G. Fetal lossassociated with caffeine intake before and during pregnancy. JAMA.1993;270:29402943.

14. Dlugosz L, Belanger K, Hellenbrand K, Holford T, Leaderer B, Bracken M.Maternal caffeine consumption and spontaneous abortion: A prospectivestudy. Epidemiology. 1996;7:250255.

15. Zhang H, Bracken M. Tree-based, two-stage risk factor analysis for

spontaneous abortion. Am J Epidemiol. 1996;144:989996.

16. Klebanoff M, Levine R, DerSimonian R, Clemens J, Wilkins D. Maternalserum paraxanthine, a caffeine metabolite, and the risk of spontaneousabortion. New Engl J Med. 1999;341:16391644.

17. Cnattingius S, Signorello L, Anneren G, Clausson B, Ekbom A, Ljunger E,et al. Caffeine intake and the risk of first-trimester spontaneous abortion.New Engl J Med. 2000;343:18391845.

18. Armstrong B, McDonald A, Sloan M. Cigarette, alcohol, and coffee con-sumption and spontaneous abortion. Am J Public Health. 1992;82:8587.

19. Peacock J, Bland J, Anderson H. Effects on birthweight of alcohol andcaffeine consumption in smoking women. J Epidemiol Community Health.1991;45:159163.

20. Bracken M, Triche E, Belanger K, Hellenbrand K, Leaderer B. Associationof maternal caffeine consumption with decrements in fetal growth. Am J

Epidemiol. 2003;157:111.21. Linn S, Schoenbaum S, Monson R, Rosner B, Stubblefield P, Ryan K. No

association between coffee consumption and adverse outcomes ofpregnancy. New Engl J Med. 1982;306:141145.

22. Curtis K, Savitz D, Arbuckle T. Effects of cigarette smoking, caffeineconsumption and alcohol intake on fecundability. Am J Epidemiol.1997;146:3241.

23. Santos I, Victora C, Huttly S, Carvalhal J. Caffeine intake and low birthweight: A population-based case-control study. Am J Epidemiol. 1998;147:620627.

24. Grosso L, Rosenberg K, Belanger K, Saftlas A, Leaderer B, BrackenM. Maternal caffeine intake and intrauterine growth retardation.Epidemiology. 2001;12:447455.

25. Clausson B, Granath F, Ekbom A, Lundgren S, Nordmark A, Signorello L,et al. Effect of caffeine exposure during pregnancy on birth weight and

gestational age. Am J Epidemiol. 2002;155:429436.

26. McDonald A, Armstrong B, Sloan M. Cigarette, alcohol, and coffeeconsumption and prematurity. Am J Public Health. 1992;82:8790.

27. Signorello L, McLaughlin J. Maternal caffeine consumption andspontaneous abortion: A review of the epidemiologic evidence. Epidemi-ology. 2004;15:229239.

28. Axelsson G, Rylander R, Molin I. Outcome of pregnancy in relation toirregular and inconvenient work schedules. Br J Ind Med. 1989;46:393398.

29. Stein Z, Susser M. Miscarriage, caffeine, and the epiphenomena ofpregnancy: The causal model. Epidemiology. 1991;2:163167.

30. Watkinson B, Fried P. Maternal caffeine use before, during, and afterpregnancy and effects upon offspring. Neurobehav Toxicol Teratol. 1985;7:917.

31. Fenster L, Swan S, Windham G, Neutra R. Assessment of reportingconsistency in a case-control study of spontaneous abortions. Am JEpidemiol. 1991;133:477488.

32. Larroque B, Kaminski M, Lelong N, Subtil D, Dehaene P. Effects on birth

weight of alcohol and caffeine consumption during pregnancy. Am JEpidemiol. 1993;137:941950.

33. Arnaud M. Metabolism of Caffeine and Other Components of Coffee.New York: Raven Press;1993:4396.

34. Nehlig A, Debry G. Potential teratogenic and neurodevelopmentalconsequences of coffee and caffeine exposure: A review on human andanimal data. Neurotoxicol Teratol. 1994;16:531543.

35. Bracken M, Triche E, Grosso L, Hellenbrand K, Belanger K, Leaderer B.Heterogeneity in assessing self-reports of caffeine exposure: Implicationsfor studies of health effects. Epidemiology. 2002;13:165171.

36. Bunker M, McWilliams M. Caffeine content of common beverages.Journal of the American Dietetic Association. 1979;74:2831.

37. Bracken M, Leaderer B, Belanger K. Role of biologic markers inepidemiologic studies of prenatal drug exposure: Issues in study design.NIDA Res Monogr Ser. 1992;117:4160.

38. Aldridge A, Bailey J, Neims A. The disposition of caffeine during and afterpregnancy. Seminars in Perinatology. 1981;5:310314.

39. Parsons W, Neims A. Effect of smoking on caffeine clearance. ClinPharmacol Ther. 1978;24:734739.

40. Kalow W, Tang B-K. Caffeine as a metabolic probe: Exploration of theenzyme-inducing effect of cigarette smoking. Clin Pharmacol Ther.1991;49:4448.

41. Klebanoff M, Levine R, Clemens J, Wilkins D. Maternal serum caffeinemetabolites and small-for-gestational age birth. Am J Epidemiol.2002;155:3237.

42. Grosso L, Triche E, Bracken MB. Letter to editor: Regarding Anunexpected distribution of sodium concentration in serum specimensstored for more than 30 years. Ann Epidemiology. 2004;14:7778.

43. Klebanoff M, Longnecker M. Response to letter by Grosso et al. Ann

Epidemiology. 2004;14:7980.44. Hinds T, West W, Knight E, Harland B. The effect of caffeine on

pregnancy outcome variables. Nutrition Reviews. 1996;54:203207.

45. Weathersbee P, Lodge J. Caffeine: Its direct and indirect influence onreproduction. J Reprod Med. 1977;19:5563.

46. Parsons W, Aranda J, Neims A. Elimination of transplacentally acquiredcaffeine in fullterm neonates. Pediatr Res. 1976;10:33.

47. Benowitz N. Clinical pharmacology of caffeine. Annu Rev Med. 1990;41:277278.

48. Daly J. Mechanism of action of caffeine. In: Garattini S, ed. Caffeine,Coffee, and Health. New York: Raven Press; 1993:97149.

49. Fenster L, Quale C, Hiatt R, Wilson M, Windham G, Benowitz N. Rate ofcaffeine metabolism and risk of spontaneous abortion. Am J Epidemiol.1998;147:503510.

50. Benowitz N, Jacob P, Mayan H, Denaro C. Sympathomimetic effectsof paraxanthine and caffeine in humans. Clin Pharmacol Ther. 1995;58:684691.

51. Lelo A, Miners J, Robson R, Birkett D. Assessment of caffeine exposure:Caffeine content of beverages, caffeine intake, and plasma concentrationsof methylxanthines. Clin Pharmacol Ther. 1986;36:5459.

52. Arnaud M, Welsch C. Caffeine metabolism in human subjects. NinthInternational Colloquium on Science and Technology of Coffee, London,1980. Association Scientifique Internationale du Cafe.

53. Klebanoff M, Levine R, DerSimonian R, Clemens J, Wilkins D. Serumcaffeine and paraxanthine as markers for reported caffeine intake inpregnancy. Ann Epidemiol. 1998;8:107111.


465


7/7

54. Eteng M, Eyong E, Akpanyung E, Agiang M, Aremu C. Recent advancesin caffeine and theobromine toxicities: A review. Plant Foods for HumanNutrition. 1997;51:231243.

55. Tarka S, Arnaud M, Dvorchik B, Vesell E. Theobromine kinetics andmetabolic disposition. Clin Pharmacol Ther. 1983;34:546555.

56. Shively C, Tarka S, Arnaud M, Dvorchik B, Passananti G, Vesell E. Highlevels of methylxanthines in chocolate do not alter theobromine

disposition. Clin Pharmacol Ther. 1985;37:415424.57. Rostami-Hodjegan A, Nurminen S, Jackson P, Tucker G. Caffeine urinary

metabolite ratios as markers of enzyme activity: A theoretical assessment.Pharmacogenetics. 1996;6:121149.

58. Lelo A, Birkett D, Robson R, Miners J. Comparative pharmacokinetics ofcaffeine and its primary demethylated metabolites: Paraxanthine, theo-bromine, and theophylline in man. Br J Clin Pharmac. 1986;22:177182.

59. Birkett D, Dahlquist R, Miners J, Lelo A, Billing B. Comparison oftheophylline and theobromine metabolism in man. Drug Metabolism andDisposition. 1985;13:725728.

60. Gates S, Miners J. Cytochrome P450 isoform selectivity in human hepatictheobromine metabolism. Br J Clin Paramacol. 1999;47:299305.

61. Stavric B. Methylxanthines: Toxicity to humans. 1. Theophylline. FoodChem Toxic. 1988;26:541565.

62. Bracken M, Leaderer B, Belanger K. Role of biologic markers in

epidemioloic studies of prenatal drug exposure: Issues in study design.NIDA Res Monogr Ser. 1992;117:4160.

63. Arnaud M, Murray C, Youssif A, Milon H, Devoe L. Caffeine consumptionand metabolism in pregnant women during the third-trimester pregnancy.Vol. II. Montpellier: International Scientific Colloquium on Coffee/International Scientific Association of Coffee. 1993:433441.

64. Tsutsumi K, Kotegawa T, Matsuki S, Tanaka Y, Ishii Y, Kodama Y, et al.The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, andN-acetyltransferase activities in humans. Clin Pharmacol Ther. 2001;70:121125.

65. Cook D, Peacock J, Feyerabend C, Carey I, Jarvis M, Anderson H, et al.Relation of caffeine intake and blood caffeine concentrations duringpregnancy to fetal growth: Prospective population based study. BMJ.1996;313:13581362.

66. Brown C, Jacob P, Wilson M, Benowitz N. Changes in rate and pattern of

caffeine metabolism after cigarette abstinence. Clin Pharmacol Ther.1988;43:488493.

67. Patwardhan R, Desmond P, Johnson R, Schenker S. Impaired eliminationof caffeine by oral contraceptive steroid. J Lab Clin Med. 1980;95:603608.

68. Abernethy D, Todd E. Impairment of caffeine clearance by chronic use oflow-dose estrogen-containing oral contraceptives. Eur J Clin Pharmacol.1985;28:425428.

69. Lane J, Steege J, Rupp S, Kuhn C. Menstrual cycle effects on caffeineelimination in the human female. Eur J Clin Pharmacol. 1992;43:543546.

70. Carrillo J, Benitez J. Clinically significant pharmacokinetic interactionsbetween dietary caffeine and medications. Clin Pharmacokinet. 2000;39:127153.

71. Lampe J, King I, Li S, Grate M, Barale K, Chen C, et al. Brassicavegetables increase and apiaceous vegetables decrease cytochrome P450

1A2 activity in humans: Changes in caffeine metabolic ratios in responseto controlled vegetable diets. Carcinogenesis. 2000;21:11571162.

72. Kalow W, Tang B-K. Use of caffeine metabolite ratios to explore CYPIA2and xanthine oxidase activities. Clin Pharmacol Ther. 1991;50:508519.

73. Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama M, KamatakiT. Genetic polymorphism in the 50-flanking region of human CYP1A2

gene: Effect on the CYP1A2 inducibility in humans. J Biochem. 1999;125:803808.

74. Han X, Ou-Yang D, Lu P, Jiang C, Shu Y, Chen X, et al. Plasma caffeinemetabolite ratio (17x/137x) in vivo associated with G-2964A and C734Apolymorphisms of human CYP1A2. Pharmacogenetics. 2001;11:429435.

75. Campbell M, Spielberg S, Kalow W. A urinary metabolite ratio that re-flects systemic caffeine clearance. Clin Pharmacol Ther. 1987;42:157165.

76. Hildebrand M, Seifert W. Determination of acetylator phenotype inCaucasians with caffeine. Eur J Clin Pharmacol. 1989;37:525526.

77. Denaro C, Wilson M, Jacob P, Benowitz N. Validation of urine caffeinemetabolite ratios with use of stable isotope-labeled caffeine clearance. ClinPharmacol Ther. 1996;59:284296.

78. Nyeki A, Buclin T, Biollaz J, Decosterd L. NAT2 and CYP1A2 pheno-typing with caffeine: Head-to-head comparison of AFMU vs. AAMU inthe urine metabolite ratios. Br J Clin Pharmacol. 2003;55:6267.

79. Signorello L, Nordmark A, Granath F, Blot W, McLaughlin J, Anneren G,et al. Caffeine metabolism and the risk of spontaneous abortion of normalkaryotype fetuses. Obstet Gynecol. 2001;98:10591066.

80. Sachse C, Brockmoller J, Bauer S, Roots I. Functional significance of a Cto A polymorphism in intron 1 of the cytochrome P450 1A2 (CYP1A2)gene tested with caffeine. Br J Clin Pharmacol. 1999;47:445449.

81. Chevalier D, Cauffiez C, Allorge D, Lo-Guidice J, Lhermitte M, Lafitte J,et al. Five novel natural allelic variantsd951A>C, 1042G>A (D348N),1156A>T (I386F), 1217G>A (C406Y) and 1291C>T (C431Y) dof thehuman CYP1A2 gene in a French Caucasian population. HumanMutation. 2001;17:355358.

82. Sachse C, Bhambra U, Smith G, Lightfoot T, Barrett J, Scollay J, et al.Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) incolorectal cancer patients and controls: Allele frequencies, linkagedisequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol.2003;55:6876.

83. Goldstein A, Warren R. Passage of caffeine into human gonadal and fetaltissue. Biochem Pharmacol. 1962;11:166168.

84. Kirkinen P, Jouppila P, Koivula A, Vuori J, Puukka M. The effect ofcaffeine on placental and fetal blood flow in human pregnancy. Am JObstet Gynecol. 1983;147:939942.

85. Ginsberg G, Hattis D, Russ A, Sonawane B. Physiologically basedpharmacokinetic (PBPK) modelling of caffeine and theophylline inneonates and adults: Implications for assessing childrens risks fromenvironmental agents. J Toxicol Environ Health A. 2004;67:297329.

86. Aranda J, Louridas A, Vitullo B, Thom P, Aldridge A, Haber R.Metabolism of theophylline to caffeine in human fetal liver. Science.1979;206:13191321.

87. Cazeneuve C, Pons G, Rey E, Treluyer J, Cresteil T, Thiroux G, et al.Biotransformation of caffeine in human liver microsomes from foetuses,neonates, infants, and adults. Br J Clin Pharmacol. 1994;37:405412.

88. Liu Y-A, Ostlund E, Fried G. Endothelin-induced contractions in humanplacental blood vessels are enhanced in intrauterine growth retardation,and modulated by agents that regulate levels of intracellular calcium. ActaPhysiol Scand. 1995;155:405414.

89. Soyka L. Effects of methylxanthines on the fetus. Clin Perinatol.

1979;6:3751.90. Ghidini A. Idiopathic fetal growth restriction: A pathophysiologic

approach. Obstet Gynecol Surv. 1996;51:376382.

91. Bauer J, Maier K, Linderkamp O, Hentschel R. Effect of caffeine on oxygenconsumption and metabolic rate in very low birth weight infants withidiopathic apnea. Pediatrics. 2001;107:660663.


466

Documents

Caffeine Metabolism, Genetics, And Perinatal Outcomes- A Review of Exposure Assessment Considerations During Pregnancy