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CAFFEINE

Fetal Risk Summary

Caffeine is one of the most popular drugs in the world (1). It is frequently used in combination products containing aspirin, phenacetin, and codeine, and is present in a number of commonly consumed beverages such as coffee, teas, and colas, as well as many food items. The mean caffeine content in the usual servings of some common beverages was reported as caffeinated coffee (66–146 mg), nonherbal tea (20–46 mg), and caffeinated soft drinks (47 mg) (2), but these amounts may vary widely. (For example, see also Reference 26 in which it is reported that the average caffeine content in two cups of regular coffee totaled 454 mg, and the average content in a similar amount of decaffeinated coffee totaled 12 mg.) Caffeine crosses the placenta, and fetal blood and tissue levels similar to maternal concentrations are achieved (1,3, 4 and 5). Cord blood levels of 1–1.6 mg/mL have been measured (3). Caffeine has also been found in newborns exposed to theophylline in utero (6).

The mutagenicity and carcinogenicity of caffeine have been evaluated in more than 50 studies involving laboratory animals, human and animal cell tissue cultures, and human lymphocytes in vivo (1,3). The significance of mutagenic and carcinogenic effects found in nonmammalian systems has not been established in man. The drug is an animal teratogen only when doses high enough to cause toxicity in the mother have been given (1).

The Collaborative Perinatal Project (CPP) monitored 50,282 mother-child pairs, 5,378 of whom had 1st trimester exposure to caffeine (7, pp. 366–370). No evidence of a relationship to congenital defects was found. For use anytime during pregnancy, 12,696 exposures were recorded (7, pp. 493–494). In this group, slightly increased relative risks were found for musculoskeletal defects, hydronephrosis, adrenal anomalies, and hemangiomas or granulomas, but the results are uninterpretable without independent confirmation (7, pp. 493–494). A follow-up analysis by the CPP on 2,030 malformed infants and maternal use of caffeine-containing beverages did not support caffeine as a teratogen (8). Other reports have also found no association between the use of caffeine during pregnancy and congenital malformations (9,10,11 and 12).

Several authors have associated high caffeine consumption (6–8 cups of coffee/day) with decreased fertility, increased incidence of spontaneous abortion, and low birth weights (3,13,14,15,16 and 17). Unfortunately, few of these studies have isolated the effects of caffeine from cigarette or alcohol use, both of which are positively associated with caffeine consumption (3). One German study has observed that high coffee use alone is associated with low birth weights (18). In an American study of more than 12,400 women, low birth weights and short gestations occurred more often among offspring of women who drank four or more cups of coffee/day and who also smoked (12). No relationship between low birth weights or short gestation and caffeine was found after controlling for smoking, alcohol intake, and demographic characteristics. However, other investigators have questioned whether this study accurately assessed the total caffeine intake of the women (19,20). A Canadian study retrospectively investigated 913 newborn infants for the effects of caffeine and cigarette smoking on birth weight and placental weight (21). Significant caffeine-cigarette interactions were found when daily consumption of caffeine was 300 mg or more. Compared to nonsmokers, cigarette smoking significantly lowered mean birth weight. When caffeine use was considered, daily consumption of 300 mg or more combined with smoking 15 cigarettes or more caused an additional significant reduction in weight. Head circumference and body length were not affected by any level of caffeine consumption. Placental weight, which normally increases with cigarette smoking, an effect hypothesized to be due to compensatory hypertrophy induced by chronic fetal hypoxia, was found to decrease significantly in women smoking 15 cigarettes or more/day and ingesting 300 mg or more of caffeine/day (21).

A prospective cohort study examined the relationship between caffeine intake and the incidence of late spontaneous abortion in 3,135 predominantly white, educated, professional women (22). A total of 2,483 (79%) of this population used caffeine during pregnancy. Caffeine consumption was calculated based on the intake of coffee (107 mg/serving), tea (34 mg/serving), colas (47 mg/serving), and drugs. Moderate to heavy consumption, defined as 151 mg or more of caffeine intake/day, occurred in 28% (879) and was associated with a 2-fold increased risk of late 1st and 2nd trimester spontaneous abortion (relative risk 1.95, p=0.07). Consumption of greater than 200 mg/day did not increase this risk. In women who had a spontaneous abortion in their last pregnancy, light use of caffeine (0–150 mg/day) was associated with a 4-fold increase in late pregnancy loss (relative risk 4.18, p=0.04). The data were adjusted for such factors as demographic characteristics, obstetric and medical histories, contraceptive use, smoking, and alcohol exposure. The investigators cautioned, however, that other independent epidemiologic studies were required to confirm their findings because spontaneous abortion is of multifactorial etiology (22,23).

No increased risk for spontaneous abortion, intrauterine growth retardation, or microcephaly was found in a study that was able to identify all abortions that occurred 21 or more days after conception (24). The mean 1st-trimester caffeine consumption was statistically similar in those who aborted compared to those who delivered liveborn infants, 125.9 ± 123.1 mg vs. 111.6 ± 107.0 mg. After adjustment for other risk factors, notably smoking, the adjusted odds ratios for growth retardation and microcephaly were 1.11 (95% confidence interval [CI] 0.88–1.40) and 1.09 (95% CI 0.86–1.37), respectively (24).

A publication evaluating studies published between 1981 and 1986 reviewed the effects of caffeine consumption on human pregnancies in terms of congenital malformations, low birth weight, preterm birth, spontaneous abortions, and behavior in in utero exposed children (25). Based on this evaluation of the literature, the author concluded that moderate intake of caffeine was not related to any adverse pregnancy outcome. A second article (120 References) reviewed the effect of caffeine on pregnancy outcome in both animals and humans (26). This author also concluded that modest amounts of caffeine present no proven risk to the fetus, but that limitation of daily amounts to less than 300 mg/day may lessen the possibility of growth retardation.

Research on the effects of caffeine consumption on human fecundability (i.e., the probability of becoming clinically pregnant in a given menstrual cycle) was reported in 1988 (27). Drawing from women they had enrolled in a study of very early pregnancy loss, the investigators chose 104 women who had not become pregnant in the first 3 months. Data were recorded daily by the women on menstrual bleeding, intercourse, and caffeine and other substance exposures. Caffeine consumption was calculated by assuming brewed coffee contained 100 mg, instant coffee 65 mg, tea 50 mg, and soft drinks 40 mg. The subjects were primarily white, college educated, and in their late 20s or early 30s. Caffeinated beverages were consumed by 93% (97 of 104) of the women. The women were divided into lower caffeine consumers (less than 3150 mg/month, or about one cup of brewed coffee/day) and higher consumers (using more than 3150 mg/month). Based on this division, the higher consumers were consistently less likely to become pregnant than the lower consumers, with a weighted mean of fecundability ratios across 13 menstrual cycles of 0.59. (The fecundability ratio was determined in each cycle by dividing the number of women who became pregnant by the total number of woman-cycles at risk and then by dividing the fraction obtained in the higher caffeine consumption group by the fraction obtained for the lower consumption group.) The ratio was less than 1.0 in every cycle. For cycles occurring after 6 months, the ratio was 0.53, indicating a slightly stronger association between higher caffeine consumption and the inability to become pregnant (27). Statistical adjustment of the data for age, frequency of intercourse, age at menarche, cigarette smoking, vitamin and analgesic intake, alcohol and marijuana use, and the mother's weight and height did not significantly change these findings. Moreover, when caffeine consumption was further subdivided, a partial dose-response relationship was observed with a ratio of 0.26 for women consuming more than 7000 mg/month (i.e., more than 70 cups of coffee/month). Unadjusted data on infertility (defined as women who failed to achieve pregnancy after 1 year) indicated that only 6% of the lower consumption group met this definition compared with 28% of the higher consumption group, an estimated relative risk of 4.7 (p<0.005) (27). Evidence was also found to suggest that the effects of caffeine on fertility were short-acting because recent consumption was far more important than previous consumption. Although the study attempted to include all related factors, the investigators did caution that they could not exclude the possibility that some unknown factor or condition might have accounted for these results and that independent confirmation was required (27,28). Partial confirmation of this study was reported in 1989 (29). In a retrospective analysis of data collected from 1959 to 1967 on 6,303 pregnancies, a dose-response relationship was found between caffeine consumption and difficulty in becoming pregnant. Using data adjusted for ethnicity (white, black), parity (0, 1), and smoking, the relative risk of decreased fertility for less than 1 cup of coffee/day was 1.00, 1–3 cups/day 1.20, 4–6 cups/day 1.88, and more than 7 cups/day 1.96 (29).

Some investigators have expressed concern over the altering of catecholamine levels in the fetus by caffeine (30). Two cups of regular coffee containing a total of 454 mg of caffeine have been shown to increase maternal epinephrine levels significantly, but not norepinephrine or dopamine concentrations (31). Decaffeinated coffee (12 mg of caffeine in two cups) did not affect these catecholamine levels.

A 1989 single-blind, crossover study of eight women at 32–36 weeks of gestation investigated the effects of 2 cups of caffeinated (regular) or decaffeinated coffee on fetal breathing movements and heart rate (31). Administration of the test beverages, containing a total of 454 mg and 12 mg of caffeine, respectively, were separated by 1 week, and in each case, were consumed over a 15-minute period. Fetal breathing movements increased significantly during the 3rd hour after regular coffee, rising from 144 breaths/hour to 614 breaths/hour (p<0.01). Fetal heart rate fell 9% (p<0.05) at 1–1.5 hours after the regular coffee and then slowly rose toward control levels at 2 and 4 hours. However, the mean number, amplitude, and duration of fetal heart rate accelerations did not differ statistically from the control period. Decaffeinated coffee also caused a significant increase in fetal breathing movements, rising to 505 breaths/hour during the 2nd hour, but this beverage caused only a slight, nonsignificant lowering of the fetal heart rate. In an earlier study using 200-mg tablets of caffeine, no increase in fetal breathing rates was observed (32). The differences between the two studies may have been related to the lower dose and/or the dosage form of caffeine.

Cardiac arrhythmias and other symptoms in newborn infants were associated with maternal caffeine use of more than 500 mg/day (N=16) in comparison to the offspring of women who used less than 250 mg/day (N=56) of caffeine (33). The percentages of observed symptoms in the infants of the high and low caffeine groups were tachyarrhythmias (supraventricular tachycardia and atrial flutter) 25% vs. 1.7% (p<0.01), premature atrial contraction 12.5% vs. 0 (p<0.01), fine tremors 100% vs. 10.7% (p<0.001), and tachypnea (resting respiratory rate >60 respirations/minute) 25% vs. 3.5% (p<0.01), respectively. The authors attributed the symptoms to caffeine withdrawal after birth (33).

Two reports have described adverse fetal outcomes, including teratogenic effects, in the offspring of two mothers taking migraine preparations consisting of ergotamine and caffeine (34,35). Complete details of these cases are provided under Ergotamine.

A 1993 Reference compared the effects of maternal caffeine greater than 500 mg/day with those of less than 200 mg/day on fetal behavior in the 3rd trimester (36). Long-term consumption of high amounts of caffeine apparently modulated fetal behavior in terms of quiet sleep (infrequent body movements, regular breathing patterns, and little variability in fetal heart rate [FHR]), active sleep (rapid eye movements, increased body activity, irregular breathing, and increased FHR variability), and arousal (rapid eye movements, frequent body movements, highly irregular FHR baseline, and breathing activity). Fetuses of mothers in the high caffeine group spent less mean time in active sleep, similar mean time in quiet sleep, and much greater mean time in arousal than did low caffeine-exposed fetuses (36). It could not be determined if the modulation of behavior had any clinical significance to the newborn or in later life.

In summary, although the amount of caffeine in commonly used beverages varies widely, caffeine consumption in pregnancy in moderate amounts apparently does not pose a measurable risk to the fetus. When used in moderation, no association with congenital malformations, spontaneous abortions, preterm birth, and low birth weight has been proven. Use of high doses may be associated with spontaneous abortions, difficulty in becoming pregnant, and infertility. A dose-response relationship may exist for the latter two problems. However, confirmation of these findings is needed before any firm conclusions can be drawn. The consumption of high caffeine doses with cigarette smoking may increase the risk for delivery of infants with lower birth weight than that induced by smoking alone.

Breast Feeding Summary

Caffeine is excreted into breast milk (37,38,39,40,41,42,43 and 44). Milk:plasma ratios of 0.5 and 0.76 have been reported (38,39). Following ingestion of coffee or tea containing known amounts of caffeine (36–335 mg), peak milk levels of 2.09–7.17 mg/mL occurred within 1 hour (40). An infant consuming 90 mL of milk every 3 hours would ingest 0.01–1.64 mg of caffeine over 24 hours after the mother drank a single cup of caffeinated beverage (40). In another study, peak milk levels after a 100-mg dose were 3.0 mg/mL at 1 hour (39). In this and an earlier study, the authors estimated a nursing infant would receive 1.5–3.1 mg of caffeine after a single cup of coffee (38,39).

Nine breast-feeding mothers consumed a measured amount of caffeine (750 mg/day) added to decaffeinated coffee for 5 days, then abstained from all caffeine ingestion for the next 4 days (43). In six women, 24-hour pooled aliquots of milk samples from each feeding were collected on days 5 and 9. In another mother, pooled aliquots were collected daily for 9 days. The average milk caffeine concentrations from these seven mothers on day 5 were 4.3 mg/mL (range <0.25–15.7 mg/mL). Caffeine was not detected (i.e., <0.25 mg/mL) in any of the seven samples on day 9. Serum levels in the infants of these seven mothers on day 5 averaged 1.4 mg/mL (range 0.8-2.8 mg/mL in five infants, not detectable in two). On day 9, caffeine was only detectable in the sera of two infants, decreasing from 0.8 mg/mL on day 5 to 0.6 mg/mL on day 9 in one, and decreasing from 2.8 to 2.4 mg/mL in the other. The remaining two mothers collected milk samples with each feeding for the entire 9 days of the study but did not pool the samples. These mothers were breast feeding infants aged 79 and 127 days, and their mean daily milk caffeine levels on days 1–5 ranged from 4.0 to 28.6 mg/mL. Caffeine could not be detected in any of the milk samples after 5 days. The two infant's sera contained <0.25 mg/mL (mother's milk 13.4 mg/mL) and 3.2 mg/mL (mother's milk 28.6 mg/mL) on day 5, and both were <0.25 mg/mL on day 9. The wide variance in milk concentrations of caffeine was attributed to the mother's ability to metabolize caffeine (43). Based on the average level of 4.3 mg/ml, and assuming an infant consumed 150–180 mL/kg/day, the author calculated the infant would receive 0.6–0.8 mg/kg/day of caffeine (43).

In an extension of the above study, the effect of 500 mg of caffeine consumption/day on infant heart rate and sleep time was evaluated in 11 mother-infant pairs (44). Mothers consumed decaffeinated coffee daily for 5 days and then decaffeinated coffee with added caffeine for another 5-day period. Milk caffeine levels on the last day of the caffeine period ranged from 1.6 to 6.2 mg/mL, providing an estimated 0.3–1.0 mg/kg/day of caffeine to the infants. No significant difference in 24-hour heart rate or sleep time was observed between the two phases of the study.

The elimination half-life of caffeine is approximately 80 hours in term newborns and 97.5 hours in premature babies (41). A 1987 study investigated the metabolism of caffeine in breast-fed and formula-fed infants given oral doses of caffeine citrate (45). The serum half-lives of caffeine were greater than three times as long in the breast-fed infants as compared with the formula-fed infants (76 vs. 21 hours at 47–50 weeks postconceptional age; 54 vs. 16 hours at 51–54 weeks postconceptional age). The investigators attributed the findings to inhibition or suppression of caffeine metabolism by the hepatic cytochrome P-450 system by some element of breast milk (45).

The amounts of caffeine in breast milk after maternal ingestion of caffeinated beverages are probably too low to be clinically significant. However, accumulation may occur in infants when mothers use moderate to heavy amounts of caffeinated beverages. Irritability and poor sleeping patterns have been observed in nursing infants during periods of heavy maternal use of caffeine (42). The American Academy of Pediatrics considers usual amounts of caffeinated beverages to be compatible with breast feeding (46).

References

1. Soyka LF. Effects of methylxanthines on the fetus. Clin Perinatol 1979;6:37–51.
2. Bunker ML, McWilliams M. Caffeine content of common beverages. J Am Diet Assoc 1979;74:28–32.
3. Soyka LF. Caffeine ingestion during pregnancy: in utero exposure and possible effects. Semin Perinatol 1981;5:305–9.
4. Goldstein A, Warren R. Passage of caffeine into human gonadal and fetal tissue. Biochem Pharmacol 1962;17:166–8.
5. Parsons WD, Aranda JV, Neims AH. Elimination of transplacentally acquired caffeine in fullterm neonates. Pediatr Res 1976;10:333.
6. Brazier JL, Salle B. Conversion of theophylline to caffeine by the human fetus. Semin Perinatol 1981;5:315–20.
7. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
8. Rosenberg L, Mitchell AA, Shapiro S, Slone D. Selected birth defects in relation to caffeine–containing beverages. JAMA 1982;247:1429–32.
9. Van't Hoff W. Caffeine in pregnancy. Lancet 1982;1:1020.
10. Kurppa K, Holmberg PC, Kuosma E, Saxen L. Coffee consumption during pregnancy. N Engl J Med 1982;306:1548.
11. Curatolo PW, Robertson D. The health consequences of caffeine. Ann Intern Med 1983;98(Part 1):641–53.
12. Linn S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ. No association between coffee consumption and adverse outcomes of pregnancy. N Engl J Med 1982;306:141–5.
13. Weathersbee PS, Olsen LK, Lodge JR. Caffeine and pregnancy. Postgrad Med 1977;62:64–9.
14. Anonymous. Caffeine and birth defects-another negative study. Pediatr Alert 1982;7:23–4.
15. Hogue CJ. Coffee in pregnancy. Lancet 1981;2:554.
16. Weathersbee PS, Lodge JR, Caffeine: its direct and indirect influence on reproduction. J Reprod Med 1977;19:55–63.
17. Lechat MF, Borlee I, Bouckaert A, Misson C. Caffeine study. Science 1980;207:1296–7.
18. Mau G, Netter P. Kaffee- und alkoholkonsum-riskofaktoren in der schwangerschaft? Geburtshilfe Frauenheilkd 1974;34:1018–22.
19. Bracken MB, Bryce-Buchanan C, Silten R, Srisuphan W. Coffee consumption during pregnancy. N Engl J Med 1982;306:1548–9.
20. Luke B. Coffee consumption during pregnancy. N Engl J Med 1982;306:1549.
21. Beaulac-Baillargeon L, Desrosiers C. Caffeine-cigarette interaction on fetal growth. Am J Obstet Gynecol 1987;157:1236–40.
22. Srisuphan W, Bracken MB. Caffeine consumption during pregnancy and association with late spontaneous abortion. Am J Obstet Gynecol 1986;154:14–20.
23. Bracken MB. Caffeine consumption during pregnancy and association with late spontaneous abortion: reply. Am J Obstet Gynecol 1986;155:1147.
24. Mills JL, Holmes LB, Aarons JH, Simpson JL, Brown ZA, Jovanovic-Peterson LG, Conley MR, Graubard BI, Knopp RH, Metzger BE. Moderate caffeine use and the risk of spontaneous abortion and intrauterine growth retardation. JAMA 1993;269:593–7.
25. Leviton A. Caffeine consumption and the risk of reproductive hazards. J Reprod Med 1988;33:175–8.
26. Berger A. Effects of caffeine consumption on pregnancy outcome: a review. J Reprod Med 1988;33:945–56.
27. Wilcox A, Weinberg C, Baird D. Caffeinated beverages and decreased fertility. Lancet 1988;2:1453–6.
28. Wilcox AJ. Caffeinated beverages and decreased fertility. Lancet 1989;1:840
29. Christianson RE, Oechsli FW, van den Berg BJ. Caffeinated beverages and decreased fertility. Lancet 1989;1:378.
30. Bellet S, Roman L, DeCastro O, Kim KE, Kershbaum A. Effect of coffee ingestion on catecholamine release. Metabolism 1969;18:288–91.
31. Salvador HS, Koos BJ. Effects of regular and decaffeinated coffee on fetal breathing and heart rate. Am J Obstet Gynecol 1989;160:1043–7.
32. McGowan J, Devoe LD, Searle N, Altman R. The effects of long- and short-term maternal caffeine ingestion on human fetal breathing and body movements in term gestations. Am J Obstet Gynecol 1987;157:726–9.
33. Hadeed A, Siegel S. Newborn cardiac arrhythmias associated with maternal caffeine use during pregnancy. Clin Pediatr 1993;32:45–7.
34. Graham JM Jr, Marin-Padilla M, Hoefnagel D. Jejunal atresia associated with CafergotÒ ingestion during pregnancy. Clin Pediatr 1983;22:226–8.
35. Hughes HE, Goldstein DA. Birth defects following maternal exposure to ergotamine, beta blockers, and caffeine. J Med Genet 1988;25:396–9.
36. Devoe LD, Murray C, Youssif A, Arnaud M. Maternal caffeine consumption and fetal behavior in normal third-trimester pregnancy. Am J Obstet Gynecol 1993;168:1105–12.
37. Jobe PC. Psychoactive substances and antiepileptic drugs. In Wilson JT, ed. Drugs in Breast Milk. Balgowlah, Australia:ADIS Press, 1981:40.
38. Tyrala EE, Dodson WE. Caffeine secretion into breast milk. Arch Dis Child 1979;54:787–800.
39. Sargraves R, Bradley JM, Delgado MJM, Wagner D, Sharpe GL, Stavchansky S. Pharmacokinetics of caffeine in human breast milk after a single oral dose of caffeine (abstract). Drug Intell Clin Pharm 1984;18:507.
40. Berlin CM Jr, Denson HM, Daniel CH, Ward RM. Disposition of dietary caffeine in milk, saliva, and plasma of lactating women. Pediatrics 1984;73:59–63.
41. Berlin CM Jr. Excretion of the methylxanthines in human milk. Semin Perinatol 1981;5:389–94.
42. Hill RM, Craig JP, Chaney MD, Tennyson LM, McCulley LB. Utilization of over-the-counter drugs during pregnancy. Clin Obstet Gynecol 1977;20:381–94.
43. Ryu JE. Caffeine in human milk and in serum of breast-fed infants. Dev Pharmacol Ther 1985;8:329–37.
44. Ryu JE. Effect of maternal caffeine consumption on heart rate and sleep time of breast-fed infants. Dev Pharmacol Ther 1985;8:355–63.
45. Le Guennec J-C, Billon B. Delay in caffeine elimination in breast-fed infants. Pediatrics 1987;79:264–8.
46. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
    
    

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