Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose–response meta-analysis

Abstract

Caffeine is commonly consumed during pregnancy, crosses the placenta, with fetal serum concentrations similar to the mother’s, but studies of birth outcome show conflicting findings. We systematically searched Medline and Embase for relevant publications. We conducted meta-analysis of dose–response curves for associations between caffeine intake and spontaneous abortion, stillbirth, preterm delivery, low birth weight and small for gestational age (SGA) infants. Meta-analyses included 60 unique publications from 53 cohort and case–control studies. An increment of 100 g caffeine was associated with a 14 % (95 % CI 10–19 %) increase in risk of spontaneous abortion, 19 % (5–35 %) stillbirth, 2 % (−2 to 6 %) preterm delivery, 7 % (1–12 %) low birth weight, and 10 % (95 % CI 6–14 %) SGA. There was substantial heterogeneity in all models, partly explained by adjustment for smoking and previous obstetric history, but not by prospective assessment of caffeine intake. There was evidence of small-study effects such as publication bias. Greater caffeine intake is associated with an increase in spontaneous abortion, stillbirth, low birth weight, and SGA, but not preterm delivery. There is no identifiable threshold below which the associations are not apparent, but the size of the associations are generally modest within the range of usual intake and are potentially explained by bias in study design or publication. There is therefore insufficient evidence to support further reductions in the maximum recommended intake of caffeine, but maintenance of current recommendations is a wise precaution.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Ministry of Agriculture Fisheries and Food. Survey of caffeine and other methylxanthines in energy drinks and other caffeine-containing products (updated). London: Ministry of Agriculture, Fisheries and Food. 1998. Report No.: 144.

  2. 2.

    Committee on Toxicity of Chemicals in Food Consumer Products and the Environment. Statement on the reproductive effects of caffeine. Food Standards Agency. 2001.

  3. 3.

    Wilcox A, Weinberg C, Baird D. Caffeinated beverages and decreased fertility. The Lancet. 1988;332:1453–6.

    Article  Google Scholar 

  4. 4.

    Santos IS, Victora CG, Huttly S, Morris S. Caffeine intake and pregnancy outcomes: a meta-analytic review. Cad Saude Publica. 1998;14:523–30.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Fernandes O, Sabharwal M, Smiley T, Pastuszak A, Koren G, Einarson T. Moderate to heavy caffeine consumption during pregnancy and relationship to spontaneous abortion and abnormal fetal growth: a meta-analysis. Reprod Toxicol. 1998;12:435–44.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Boylan SM, Cade JE, Kirk SFL, Greenwood DC, White KLM, Shires S, et al. Assessing caffeine exposure in pregnant women. Br J Nutr. 2008;100:875–82.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Bech BH, Obel C, Henriksen TB, Olsen J. Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial. BMJ. 2007;334:409.

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Committee on Toxicity of Chemicals in Food Consumer Products and the Environment. Statement on the review of caffeine. Department of Health. 1984.

  9. 9.

    Committee on Toxicity of Chemicals in Food Consumer Products and the Environment. Statement on the reproductive effects of caffeine. Food Standards Agency. 2008.

  10. 10.

    Organisation of Teratology Information Specialists. Caffeine and pregnancy. 2006. http://www.otispregnancy.org/pdf/caffeine. Accessed 13 June 2014.

  11. 11.

    NHS Choices. Caffeine and pregnancy. http://www.nhs.uk/news/2008/11November/Pages/Newcaffeineadviceinpregnancy.aspx. Accessed 13 June 2014.

  12. 12.

    American College of Obstetricians and Gynecologists. Education pamphlet AP001—Nutrition during pregnancy. Washington DC: American College of Obstetricians and Gynecologists; 2008.

    Google Scholar 

  13. 13.

    Yu WW, Schmid CH, Lichtenstein AH, Lau J, Trikalinos TA. Empirical evaluation of meta-analytic approaches for nutrient and health outcome dose–response data. Res Syn Meth. 2013;4:256–68.

    Google Scholar 

  14. 14.

    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. J Am Med Assoc. 2000;283:2008–12.

    Article  CAS  Google Scholar 

  15. 15.

    NHS Choices. Should I limit caffeine during pregnancy? http://www.nhs.uk/chq/Pages/limit-caffeine-during-pregnancy.aspx. Accessed 13 June 2014.

  16. 16.

    Wells GA, Shea B, O’Connell D, Peterson J, Losos M, Tugwell P. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 13 June 2014.

  17. 17.

    Greenland S, Longnecker MP. Methods for trend estimation from summarized dose–response data, with applications to meta-analysis. Am J Epidemiol. 1992;135:1301–9.

    PubMed  CAS  Google Scholar 

  18. 18.

    Chiaffarino F, Parazzini F, Chatenoud L, Ricci E, Tozzi L, Chiantera V, et al. Coffee drinking and risk of preterm birth. Eur J Clin Nutr. 2006;60:610–3.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Williams MA, Mittendorf R, Stubblefield PG, Lieberman E, Schoenbaum SC, Monson RR. Cigarettes, coffee, and preterm premature rupture of the membranes. Am J Epidemiol. 1992;135:895–903.

    PubMed  CAS  Google Scholar 

  20. 20.

    Hamling J, Lee P, Weitkunat R, Ambuhl M. Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med. 2008;27:954–70.

    PubMed  Article  Google Scholar 

  21. 21.

    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Harrell FE Jr, Lee KL, Pollock BG. Regression models in clinical studies: determining relationships between predictors and response. J Natl Cancer Inst. 1988;80:1198–202.

    PubMed  Article  Google Scholar 

  23. 23.

    White IR. Multivariate random-effects meta-analysis. Stata J. 2009;9:40–56.

    Google Scholar 

  24. 24.

    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    PubMed  Article  Google Scholar 

  25. 25.

    Boylan SM, Greenwood DC, Alwan N, Cooke MS, Dolby VA, Hay AW, et al. Does nausea and vomiting of pregnancy play a role in the association found between maternal caffeine intake and fetal growth restriction? Matern Child Health J. 2013;17:601–8.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    StataCorp. Stata statistical software: Release 13.1. College Station, TX: Stata Corporation; 2013.

    Google Scholar 

  27. 27.

    Infante-Rivard C, Fernandez A, Gauthier R, David M, Rivard GE. Fetal loss associated with caffeine intake before and during pregnancy. JAMA. 1993;270:2940–3.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Caan BJ, Goldhaber MK. Caffeinated beverages and low birthweight: a case–control study. Am J Public Health. 1989;79:1299–300.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  29. 29.

    Boylan S, Cade JE, Dolby VA, Greenwood DC, Hay AWM, Kirk SFL, et al. Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ. 2008;337:a2332.

    Article  Google Scholar 

  30. 30.

    Khoury JC, Miodovnik M, Buncher CR, Kalkwarf H, McElvy S, Khoury PR, et al. Consequences of smoking and caffeine consumption during pregnancy in women with type 1 diabetes. J Matern Fetal Neonatal Med. 2004;15:44–50.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Sengpiel V, Elind E, Bacelis J, Nilsson S, Grove J, Myhre R, et al. Maternal caffeine intake during pregnancy is associated with birth weight but not with gestational length: results from a large prospective observational cohort study. BMC Med. 2013;11:42.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  32. 32.

    Spinillo A, Capuzzo E, Nicola SE, Colonna L, Egbe TO, Zara C. Factors potentiating the smoking-related risk of fetal growth retardation. Br J Obstet Gynaecol. 1994;101:954–8.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Al-Ansary LA, Babay ZA. Risk factors for spontaneous abortion: a preliminary study on Saudi women. J R Soc Health. 1994;114:188–93.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Axelsson G, Rylander R, Molin I. Outcome of pregnancy in relation to irregular and inconvenient work schedules. Br J Ind Med. 1989;46:393–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  35. 35.

    Furuhashi N, Sata S, Suzuki M, Hiruta M, Tanaka M, Takahashi T. Effects of caffeine ingestion during pregnancy. Gynecol Obstet Invest. 1985;19:187–91.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Parazzini F, Bocciolone L, Fedele L, Negri E, La VC, Acaia B. Risk factors for spontaneous abortion. Int J Epidemiol. 1991;20:157–61.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Windham GC, Von BJ, Waller K, Fenster L. Exposure to environmental and mainstream tobacco smoke and risk of spontaneous abortion. Am J Epidemiol. 1999;149:243–7.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Pollack AZ, Buck Louis GM, Sundaram R, Lum KJ. Caffeine consumption and miscarriage: a prospective cohort study. Fertil Steril. 2010;93:304–6.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  39. 39.

    Dominguez-Rojas V, De Juanes-Pardo JR, Astasio-Arbiza P, Ortega-Molina P, Gordillo-Florencio E. Spontaneous abortion in a hospital population: are tobacco and coffee intake risk factors? Eur J Epidemiol. 1994;10:665–8.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Eskenazi B, Stapleton AL, Kharrazi M, Chee WY. Associations between maternal decaffeinated and caffeinated coffee consumption and fetal growth and gestational duration. Epidemiology. 1999;10:242–9.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Tough SC, Newburn-Cook CV, White DE, Fraser-Lee NJ, Faber AJ, Frick C, et al. Do maternal characteristics and past pregnancy experiences predict preterm delivery among women aged 20 to 34? J Obstet Gynaecol Can. 2003;25:656–66.

    PubMed  Google Scholar 

  42. 42.

    Kesmodel U, Olsen SF, Secher NJ. Does alcohol increase the risk of preterm delivery? Epidemiology. 2000;11:512–8.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Mikkelsen TB, Osterdal ML, Knudsen VK, Haugen M, Meltzer HM, Bakketeig L, et al. Association between a Mediterranean-type diet and risk of preterm birth among Danish women: a prospective cohort study. Acta Obstet Gynecol Scand. 2008;87:325–30.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Jarosz M, Wierzejska R, Siuba M. Maternal caffeine intake and its effect on pregnancy outcomes. Eur J Obstet Gynecol Reprod Biol. 2012;160:156–60.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Stusser R, Paz G, Ortega M, Pineda S, Infante O, Martin P, et al. Risk of low birth weight in the Plaza de la Habana region. Bol Oficina Sanit Panam. 1993;114:229–41.

    PubMed  CAS  Google Scholar 

  46. 46.

    Jadsri S, Jadsri C. Parental smoking habits and infant birth weight. Asia Pac J Public Health. 1995;8:134–7.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Alonso J, Sosa C, Verde ME, Balsamo A, Moraes M, Zolessi M, et al. Risk factors for term small for gestational age. A case-control study in an uruguayan population. Int J Gynecol Obstet. 2012;119:S276.

    Article  Google Scholar 

  48. 48.

    Infante-Rivard C. Caffeine intake and small-for-gestational-age birth: modifying effects of xenobiotic-metabolising genes and smoking. Paediatr Perinat Epidemiol. 2007;21:300–9.

    PubMed  Article  Google Scholar 

  49. 49.

    Leonardi-Bee J, Britton J, Venn A. Secondhand smoke and adverse fetal outcomes in nonsmoking pregnant women: a meta-analysis. Pediatrics. 2011;127:734–41.

    PubMed  Article  Google Scholar 

  50. 50.

    Barker DJ. Childhood causes of adult diseases. Arch Dis Child. 1988;63:867–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  51. 51.

    Nathanielsz PW. Fetal programming: how the quality of fetal life alters biology for a lifetime. NeoReviews. 2000;1:e126–31.

    Article  Google Scholar 

  52. 52.

    Eriksson M, Wallander MA, Krakau I, Wedel H, Svardsudd K. The impact of birth weight on coronary heart disease morbidity and mortality in a birth cohort followed up for 85 years: a population-based study of men born in 1913. J Intern Med. 2004;256:472–81.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Ong KK, Dunger DB. Birth weight, infant growth and insulin resistance. Eur J Endocrinol. 2004;151(Suppl 3):U131–9.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Levy-Marchal C, Jaquet D. Long-term metabolic consequences of being born small for gestational age. Pediatr Diabetes. 2004;5:147–53.

    PubMed  Article  Google Scholar 

  55. 55.

    Grosso LM, Triche EW, Belanger K, Benowitz NL, Holford TR, Bracken MB. Caffeine metabolites in umbilical cord blood, cytochrome P-450 1A2 activity, and intrauterine growth restriction. Am J Epidemiol. 2006;163:1035–41.

    PubMed  Article  Google Scholar 

  56. 56.

    Cook DG, Peacock JL, Feyerabend C, Carey IM, Jarvis MJ, Anderson HR, et al. Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study. BMJ. 1996;313:1358–62.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  57. 57.

    Maslova E, Bhattacharya S, Lin SW, Michels KB. Caffeine consumption during pregnancy and risk of preterm birth: a meta-analysis. Am J Clin Nutr. 2010;92:1120–32.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. 58.

    Leviton A, Cowan L. A review of the literature relating caffeine consumption by women to their risk of reproductive hazards. Food Chem Toxicol. 2002;40:1271–310.

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Peck JD, Leviton A, Cowan LD. A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: a 2000–2009 update. Food Chem Toxicol. 2010;48:2549–76.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Landi MT, Sinha R, Lang NP, Kadlubar FF. Human cytochrome P4501A2. IARC scientific publications 1999. Issue 148.

  61. 61.

    Klebanoff MA, Levine RJ, DerSimonian R, Clemens JD, Wilkins DG. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N Engl J Med. 1999;341:1639–44.

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Klebanoff MA, Levine RJ, Clemens JD, Wilkins DG. Maternal serum caffeine metabolites and small-for-gestational age birth. Am J Epidemiol. 2002;155:32–7.

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

This review was funded by the Food Standards Agency (Contract T01033). We would like to acknowledge the contribution of Alastair Hay, Kay White and Nigel Simpson from the University of Leeds for comments on preliminary analyses and Gary Welsh from the Food Standards Agency Information Services and the University of Leeds Health Sciences Library for assistance with the literature searches.

Conflict of interests

The authors have no competing interests.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Darren C. Greenwood.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 128 kb)

Supplementary material 2 (DOCX 25 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Greenwood, D.C., Thatcher, N.J., Ye, J. et al. Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose–response meta-analysis. Eur J Epidemiol 29, 725–734 (2014). https://doi.org/10.1007/s10654-014-9944-x

Download citation

Keywords

  • Caffeine
  • Pregnancy
  • Miscarriage
  • Stillbirth
  • Preterm birth
  • Birth weight
  • Small for gestational age infant
  • Meta-analysis