COT statement on the reproductive effects of caffeine

A number of human epidemiological studies, reporting increased risks of adverse reproductive effects with caffeine consumption during pregnancy, have been published since this Committee last considered the safety of caffeine in 1984.

Several important studies have also been published since the most recent consideration by the European Scientific Committee on Food (SCF) in 1999. In the light of this increasing body of human data, the Committee was asked to review the evidence for possible reproductive effects of caffeine. We have considered a large number of both animal and human studies, including recent epidemiological data.

Background

Intake
Caffeine is present in a wide range of foods and beverages including coffee, tea, cocoa, chocolate, colas and energy drinks. It is also present in a number of prescription and over-the-counter medicines including cold and flu remedies, headache treatments, diet pills, diuretics and stimulants. While over-the-counter medications are labelled that they should not be taken during pregnancy without consulting a GP, most foods and beverages contain no such labelling (with the exception of some energy drinks). However, most pregnant women are likely to consume caffeine from one or more of these sources.

Table 1 indicates typical caffeine contents of a range of foods and beverages. Values for energy drinks, chocolate, drinking chocolate and cola are taken from a 1998 survey. Typical values for coffee and tea are quoted from the literature, as the caffeine contents of these beverages vary greatly, depending on brewing method, brand and preferred strength. The caffeine intake will also depend on the volume consumed at a single serving and the values cited in Table 1 assume a standard cup size of 190ml.

Table 1: Caffeine contents of some commonly consumed beverages and food
Source Typical caffeine content (mg) per serving
Instant coffee Approximately 75 mg per 190 ml cup1
Brewed coffee (filter or percolated) Approximately 100-115 mg per 190 ml cup1
Decaffeinated coffee (brewed or instant) Approximately 4 mg per 190 ml cup1
Tea Approximately 50 mg per 190 ml cup1
Drinking chocolate 1.1 - 8.2 mg when made up as per manufacturers' instructions in 200 ml water2
Energy drinks (containing either added caffeine or guarana) 28 - 87 mg per 250 ml serving2
Cola (regular and diet) 11 - 70 mg per 330 ml serving2
Chocolate 5.5 - 35.5 mg per 50 g bar2

The most recent data on caffeine consumption in the UK are provided by a 1988 survey of consumption of coffee, tea and colas. The mean caffeine intake from these sources was estimated to be 3.98 mg/kg body weight per day (i.e. 239 mg/day for a 60 kg person) for the general population and 3.43 mg/kg body weight per day (i.e. 206 mg/day for a 60 kg person) for pregnant women³. If an average content of 75 mg per 190 ml cup of instant coffee is assumed, these intakes correspond to approximately 3 cups per day.

Previous considerations
The Committee last considered the safety of caffeine (present as an additive and naturally occurring) in 1980-19844. At that time, we noted that renal excretion of intact caffeine was very slow, so the rate of elimination of caffeine was dependent on the rate at which it is metabolised. The rate of elimination of caffeine was markedly decreased during pregnancy, the half-life increasing from 4-6 hours in the non-pregnant adult to 18 hours in late pregnancy. As a result, serum caffeine levels may be much higher in pregnant women than in non-pregnant adults for an equal intake. We also noted that caffeine freely crosses the placenta and that plasma caffeine concentrations in the neonate are similar to maternal plasma concentrations. For these reasons particular attention was paid to the potential effects of caffeine in pregnancy and on the neonate.

In our previous discussions, we considered a number of animal studies on caffeine and effects on reproduction and several epidemiological studies. However, at that time human data on caffeine intake were limited and were considered inadequate to draw any clear conclusions. The studies had failed to take into account potential confounding factors such as alcohol intake and smoking, which are known to affect pregnancy outcome, and data on caffeine intake were often lacking. We were satisfied that the available human data did not suggest any increased risk of congenital malformations as a result of caffeine intake during pregnancy, but there remained some doubt about possible effects of coffee on human birth weight.

The SCF considered the safety of caffeine as part of its review on ingredients in so-called 'energy drinks' in January 19995. Regarding risk to pregnancy, it noted that contradictory results have been reported in human studies. It concluded that maternal caffeine consumption during pregnancy did not appear to have any measurable adverse consequences for the human fetus at intakes up to 300 mg/day, but that the question of possible effects on pregnancy and the offspring at regular intakes above this level remained open.

Consideration of possible adverse effects on reproduction

Toxicokinetics
We note that smoking approximately doubles the rate at which caffeine is metabolised6. We also note that there is evidence of a trend between cigarette smoking and caffeine consumption, with smokers consuming more caffeine on average than non-smokers. There is evidence to suggest that while it is assumed that enzyme activities in those who give up smoking quickly return to the levels of non-smokers, it takes up to 6 months for there to be a significant reduction in caffeine intake. As a result, serum caffeine levels may be increased by up to 2½ times previous levels for several months6. We also note that caffeine elimination is very slow in infants up to 3 months of age, due to lower rates of metabolism.

We note that the rate of caffeine elimination varies between individuals. Some of this variation may be due to polymorphisms in genes encoding enzymes involved in the metabolism of caffeine, in particular the cytochrome P450 enzymes, CYP1A1 and CYP1A2, that are involved in caffeine demethylation. However, although different rates of expression of these enzymes have been observed, the contribution of genetic polymorphisms is unclear. Lifestyle factors, such as smoking and regular taking of drugs that induce or inhibit the enzymes involved in caffeine metabolism may be more significant than genetic factors to inter-individual variability in caffeine elimination.

Animal studies
The potential reproductive effects of caffeine have been studied in a wide range of species and strains of animal. Studies in rats and mice have shown increased rates of fetal malformations, such as cleft palate and ectrodactyly (absence of digits) when single parenteral caffeine doses of 50 mg/kg body weight or higher have been given between the 9th and 14th days of gestation. No increased rates of malformation have been observed at single doses below 50 mg/kg body weight in either rats or mice.

Repeat doses of 12.5 mg/kg body weight caffeine per day and higher, given by oral gavage to rats throughout pregnancy, have been associated with significantly decreased birth weights.7 As effects have been observed at all dose levels studied it has not been possible to determine a No Observed Adverse Effect Level (NOAEL). It is not possible to determine whether these effects are secondary to decreased maternal body weight gain, which has also been seen in some studies.

Studies in the Cynomolgus monkey, Macaca fascicularis, have shown a high rate of stillbirths and miscarriage with maternal caffeine intakes of 10-15 mg/kg body weight per day given via the drinking water 8. This is equivalent to a 60 kg woman consuming 8 to 12 average cups of coffee per day (assuming 75 mg caffeine/cup). We note that the main serum metabolite of caffeine in monkeys is theophylline, whereas in humans it is paraxanthine and that information on the comparative toxicities of these metabolites is not available.

Human data
We have considered a number of epidemiological studies of maternal caffeine consumption and risk of spontaneous abortion or low birth weight. These cohort and case-control studies assessed caffeine intake at various stages of pregnancy by the use of dietary questionnaires. Caffeine intakes were assessed by multiplying the number of servings of a beverage or food by an estimated mean caffeine concentration. Different studies assume different caffeine contents of beverages and this accounts for some of the variation in the levels of caffeine intake associated with adverse effects on reproduction in different studies. One study used serum paraxanthine levels as a marker for caffeine intake9 after previously showing that serum paraxanthine levels were closely correlated to caffeine intakes reported by dietary questionnaire10.

A number of studies have reported significantly increased risks of spontaneous abortion with caffeine intakes greater than 300 mg/day11-16 and some studies have shown increased risks at lower intakes, ranging from about 150 mg/day and above14,16. In these studies, caffeine intakes were commonly estimated from assessments of coffee, tea and cola consumption. One study used coffee consumption only16. Other sources of caffeine, including chocolate, drinking chocolate, chocolate syrup, chocolate brownies and caffeine-containing medications were additionally used in other studies11,13. Several studies considered more than two levels of intake and demonstrated dose-response relationships, i.e. the greater the reported caffeine intake during pregnancy, the greater the odds ratio for spontaneous abortion11,15,16. The studies used different populations and different categories of caffeine intake and the dose-response curves do not superimpose. It is therefore not possible to identify a threshold above which the increased risk becomes significant. Not all studies of caffeine intakes up to about 300 mg/day have shown an association17,18. Where an association was found it is not possible to establish whether the association was causal or whether it could be due to an unknown factor or because confounding for social factors was only partially removed by adjustment.

It has been suggested that caffeine intake decreases more during pregnancy in women who have symptoms of nausea than in women who do not. There is evidence that women who have symptoms of nausea are less likely to miscarry than women who do not. If women without nausea were to consume more caffeine, then absence of nausea could be related to the underlying cause of their apparent risk, without the higher caffeine intake being necessarily causal. Several studies have attempted to take account of this theory and adjust the data accordingly, either by questioning study participants on their nausea status at various time-points throughout pregnancy or by assessing caffeine intake in the first month of pregnancy, before the onset of nausea11,13,19,20. A case-control study, investigating the relationship between maternal caffeine intake, nausea and spontaneous abortion, showed no association between caffeine consumption and risk of spontaneous abortion in women who did not report nausea. However, the study did show a significant association between caffeine consumption of 300 mg/day and above and spontaneous abortion in women who did report nausea (odds ratio = 5.4, 95% confidence interval 2.0-14.6)13. This would suggest that the associations between maternal caffeine intake and spontaneous abortion cannot be entirely accounted for by the relationship between nausea and the viability of the pregnancy, although an association was only shown at caffeine intakes of >300 mg/day.

Several studies have shown an association between maternal caffeine intakes greater than 300 mg/day during pregnancy and low birth weight21-24. Two of these studies also showed an association at lower intakes, ranging from estimated intakes of about 70 to 150 mg/day and above23,24. Assessments of coffee, tea and cola consumption were used to estimate caffeine intake21-24; one study also took caffeine-containing drugs into account23. Again, dose-response relationships were demonstrated21,22, although it is not possible to establish a level of intake above which the increase becomes significant as the levels of intake associated with low birth weight differ between studies. Not all studies have shown an association between caffeine intake and low birth weight at caffeine intakes above 300 mg/day26-28. Again, it is not possible to establish whether the associations shown in a number of the studies are causal or whether they could be due to other risk factors or because confounding for social factors was only partially removed.

We also considered a meta-analysis of studies of maternal caffeine intake during pregnancy and risk of spontaneous abortion or low birth weight, which compared maternal caffeine intakes during pregnancy of more than 150 mg/day with less than 150 mg/day25. Calculated odds ratios were significantly increased for spontaneous abortion (odds ratio = 1.36; 95% confidence interval, 1.29-1.45) and low birth weight (odds ratio = 1.51; 95% confidence interval, 1.39-1.63), defined as a birth weight of less than 2,500 g. However, although the odds ratios in the individual studies were adjusted for confounding factors, the meta-analysis used unadjusted data only. It was noted that adjustment of individual studies for confounding factors significantly decreased the odds ratios for spontaneous abortion and low birth weight calculated by these studies.

Coffee was the main source of caffeine in most studies and we cannot exclude the possibility that the effects seen in these studies are due to a component of coffee other than caffeine. Several studies have compared the results for various individual sources of caffeine or have re-analysed the data excluding coffee drinkers. These have not shown a significant difference between different sources of caffeine. However, these analyses had low statistical power, as acknowledged by the authors11,14,20.

Several studies have investigated maternal caffeine consumption during pregnancy and risk of pre-term birth and have not shown an association29,30. However, one study showed an association between consumption of more than 3 cups of coffee per day and pre-term birth as a result of premature membrane rupture31.

We considered a number of studies that investigated potential effects on fertility. Studies in animals have indicated no adverse effects on male fertility at levels in excess of normal or likely human intakes. The evidence for effects on female fertility is contradictory, but human studies have not shown any effect on time to conception at caffeine intakes less than 300 mg/day32,33.

Maternal caffeine intake appears to have pharmacological effects on the fetus. High maternal caffeine intakes (greater than 500 mg/day) have been shown to increase the time the fetus spends in a state of arousal during the third trimester34. Cardiac arrhythmias have been shown in newborn infants born to mothers with high caffeine intakes (>500 mg/day) during pregnancy35. These resolved within one week. An association between heart rate in newborn infants and maternal caffeine intake during pregnancy has been shown in one study36.

We considered two studies investigating incidence of sudden infant death syndrome (SIDS) and maternal caffeine intake during pregnancy. One of the studies showed an association, but did not adequately measure cigarette consumption. Smoking is a known risk factor for SIDS37. The other study did not show an association38. Overall we concluded that there was no reliable evidence of an association between maternal caffeine intake during pregnancy and SIDS.

Conclusions

We note that the risk of low birth weight and spontaneous abortion increases with increasing maternal caffeine intake during pregnancy. However, a threshold level of caffeine intake, above which maternal caffeine intake presents a risk to pregnancy, cannot be determined. Different studies assume different caffeine contents of beverages and this leads to some variation in the levels of caffeine intake associated with adverse effects on reproduction in different studies. We consider it prudent to assume that caffeine intakes above 300 mg/day show a plausible association with low birth weight and spontaneous abortion, given the available evidence from studies in experimental animals and epidemiological studies. However, on the basis of the available evidence, it is not possible to define this association as causal. We note that 300 mg/day caffeine is equivalent to four cups of instant coffee or about six cups of tea, assuming average caffeine contents.

We note that for caffeine intakes of 150 to 300 mg/day there is less evidence for an association, with greater inconsistency in the results of epidemiological studies than for intakes above 300 mg/day.

We note that data on maternal caffeine consumption during pregnancy and associations with adverse effects on reproduction other than low birth weight and spontaneous abortion, such as pre-term birth and adverse effects on the fetus are inconclusive. We do not consider there to be reliable evidence for associations with these parameters at moderate consumption levels (below 300 mg/day).

There do not appear to be effects of caffeine consumption on male fertility. Evidence for adverse effects on female fertility is inconclusive.

We note that the studies used to establish this association focused on caffeine intake from coffee, and that a possible influence of other constituents of coffee cannot be excluded. We also recognise that coffee and tea are just two sources of caffeine and do not necessarily represent the main sources of caffeine intake for all people.

Further studies are required to establish whether the observed association is causal. These might include the use of biomarkers of caffeine intake.

October 2001
COT Statement 2001/06

References

1. Gray J (1998). Caffeine, coffee and health. Nutrition and Food Science 6: 314-319

2. Ministry of Agriculture, Fisheries and Food (MAFF) (1998). Survey of caffeine and other methylxanthines in energy drinks and other caffeine-containing products (updated). Food Surveillance Information Sheet No. 144 (No. 103 revised). London.

3. Barone J J and Roberts H R (1996). Caffeine consumption. Fd Chem Toxic 34: 119-129

4. Department of Health (1984). Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. Statement on the review of caffeine. October 1984

5. Scientific Committee on Food (1999). Opinion on caffeine, taurine and D-glucurono-γ-lactone as constituents of so-called 'energy' drinks (expressed on 21 January, 1999).

6. Benowitz N L, Hall S M and Modin G (1989). Persistent increase in caffeine concentrations in people who stop smoking. Br Med J 298: 1075-1076

7. National Institutes of Health. Final Report on the reproductive toxicity of caffeine (CAS #58-08-2) administered by gavage to Sprague-Dawley rats. National Toxicology Program. National Institute of Environmental Health Services. July 1996

8. Gilbert S G, Rice D C, Reuhl K R, Stavric B (1988). Adverse pregnancy outcome in the monkey (Macaca fascicularis) after chronic caffeine exposure. J Pharmacol Exp Ther 245: 1048-1053

9. Klebanoff M A, Levine R J, DerSimonian R, Clemens J D, Wilkins D G (1999). Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N Engl J Med 341: 1639-44

10. Klebanoff M A, Levine R J, DerSimonian R, Clemens J D, Wilkins D G (1998). Serum caffeine and paraxanthine as markers for reported caffeine intake in pregnancy. Ann Epidemiol 8: 107-111

11. Cnattingius S, Signorello L B, Anneren G, Clausson B, Ekbom A, Ljunger E, Blot W J, McLaughlin J K, Petersson G, Rane A, Granath F (2000). Caffeine intake and the risk of first-trimester spontaneous abortion. N Eng J Med 343: 1839-45

12. Fenster L, Eskanazi B, Windham G C, Swan S H (1991). Caffeine consumption during pregnancy and spontaneous abortion. Epidemiology 2: 168-174

13. Wen W, Shu X O, Jacobs D R, Brown J E (2001). The associations of maternal caffeine consumption and nausea with spontaneous abortion. Epidemiology 12: 38-42

14. Srisuphan W and Bracken M B (1986). Caffeine consumption during pregnancy and association with late spontaneous abortion. Am J Obstet Gynecol 154: 14-20

15. Infante-Rivard C, Fernandez A, Gauthier R, David M, Rivard G-E (1993). Fetal loss associated with caffeine intake before and during pregnancy. JAMA 270: 2940-2943

16. Dom¿nguez-Rojas V, de Juanes-Pardo J R, Astasio-Arbiza P, Ortega-Molina P, Gordillo-Florencio E (1994). Spontaneous abortion in a hospital population: are tobacco and coffee intake risk factors? Eur J Epidemiol 10: 665-668

17. Wilcox A J, Weinberg C R, Baird D D (1990). Risk factors for early pregnancy loss. Epidemiology 1: 382-385

18. Mills J L, Holmes L B, Aarons J H, Simpson J L, Brown Z A, Jovanovic-Peterson L G, Conley M R, Graubard B I, Knopp R H, Metzger B E (1993). Moderate caffeine use and the risk of spontaneous abortion and intrauterine growth retardation. JAMA 269: 593-597

19. Dlugosz L, Belanger K, Hellenbrand K, Holford T R, Leaderer B and Bracken M B (1996). Maternal caffeine consumption and spontaneous abortion: a prospective cohort study. Epidemiology 7: 250-255

20. Fenster L, Hubbard A E, Swan S H, Windham G C, Waller K, Hiatt R A and Benowitz N (1997). Caffeinated beverages, decaffeinated coffee, and spontaneous abortion. Epidemiology 8: 515-523

21. Caan B J and Goldhaber M K (1989). Caffeinated beverages and low birthweight: a case-control study. Am J Public Health 79: 1299-1300

22. Fenster L, Eskenazi B, Windham G C, Swan S H (1991). Caffeine consumption during pregnancy and fetal growth. Am J Public Health 81: 458-461

23. Martin T R and Bracken M B (1987). The association between low birth weight and caffeine consumption during pregnancy. Am J Epidemiol 126: 813-821

24. Vlajinac H D, Petrovic R R, Marinkovic J M, Sipetic S B, Adanja B J (1997). Effect of caffeine intake during pregnancy on birth weight. Am J Epidemiol 145: 335-338

25. Fernandes O, Sabharwal M, Smiley T, Pastuszak A, Koren G, Einarson T (1998). Moderate to heavy caffeine consumption during pregnancy and relationship to spontaneous abortion and abnormal fetal growth: a meta-analysis. Reprod Toxicol 12: 435-444

26. Santos I S, Victora C G, Huttly S, Carvalhal J B (1998). Caffeine intake and low birth weight: a population-based case-control study. Am J Epidemiol 147: 620-626

27. Godel J C, Pabst H F, Hodges P E, Johnson K E, Froese G J, Joffres M R (1992). Smoking and caffeine and alcohol intake during pregnancy in a northern population: effect on fetal growth. Can Med Assoc J 147:181-188

28. Grosso L M, Rosenberg K D, Belanger K, Saftlas A F, Leaderer B, Bracken M B (2001). Maternal caffeine intake and intrauterine growth retardation. Epidemiology 11: 447-455

29. Fortier I, Marcoux S, Beaulac-Baillargeon L (1993). Relation of caffeine intake during pregnancy to intrauterine growth retardation and preterm birth. Am J Epidemiol 137: 931-940

30. Pastore L M and Savitz D A (1995). Case-control study of caffeinated beverages and preterm delivery. Am J Epidemiol 141: 61-69

31. Williams M, Mittendorf R, Stubblefield P, Lieberman E, Schoenbaum S and Monson R (1992). Cigarettes, coffee and preterm premature rupture of the membranes. Clin Infect Dis 14: 927-932

32. Jensen T K, Henriksen T B, Hjollund N H I, Scheike T, Kolstad H, Giwercman A, Ernst E, Bonde J P, Skakkebæk and Olsen J (1998). Caffeine intake and fecundability: a follow-up study among 430 Danish couples planning their first pregnancy. Reprod Toxicol 12: 289-295

33. Stanton C K and Gray R H (1995). Effects of caffeine consumption on delayed conception. Am J Epidemiol 142: 1322-1329

34. Devoe L D, Murray C, Youssif A and Arnaud M (1993). Maternal caffeine consumption and fetal behavior in normal third-trimester pregnancy. Am J Obstet Gynecol 168: 1105-1112

35. Hadeed A and Siegel S (1993). Newborn cardiac arrythmias associated with maternal caffeine use during pregnancy. Clinical Pediatrics 32: 45-47

36. Schuetze P and Zeskind P S (1997). Relation between reported maternal caffeine consumption during pregnancy and neonatal state and heart rate. Infant behavior and development 20: 559-562

37. Ford R P K, Schluter P J, Mitchell E A, Taylor B J, Scragg R, Stewart A W. Heavy caffeine intake in pregnancy and sudden infant death syndrome. Arch Dis Child 78: 9-13

38. Alm B, Wennergren G, Norvenius G, Skjærven R, Øyen N, Helweg-Larsen K, Lagerkrantz H, Irgens L M (1999). Caffeine and alcohol as risk factors for sudden infant death syndrome Arch Dis Child 81: 107-111