Methylxanthines During Pregnancy and Early Postnatal Life

  • Ulrika Ådén
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 200)


World-wide, many fetuses and infants are exposed to methylxanthines via maternal consumption of coffee and other beverages containing these substances. Methylxanthines (caffeine, theophylline and aminophylline) are also commonly used as a medication for apnea of prematurity.

The metabolism of methylxanthines is impaired in pregnant women, fetuses and neonates, leading to accumulating levels thereof. Methylxanthines readily passes the placenta barrier and enters all tissues and thus may affect the fetus/newborn at any time during pregnancy or postnatal life, given that the effector systems are mature.

At clinically relevant doses, the major effector system for methylxanthines is adenosine receptors. Animal studies suggest that adenosine receptors in the cardiovascular, respiratory and immune system are developed at birth, but that cerebral adenosine receptors are not fully functional. Furthermore animal studies have shown protective positive effects of methylxanthines in situations of hypoxia/ischemia in neonates. Similarly, a positive long-term effect on lung function and CNS development was found in human preterm infants treated with high doses of caffeine for apneas. There is now evidence that the overall benefits from methylxanthine therapy for apnea of prematurity outweigh potential short-term risks.

On the other hand it is important to note that experimental studies have indicated that long-term effects of caffeine during pregnancy and postnatally may include altered behavior and altered respiratory control in the offspring, although there is currently no human data to support this.

Some epidemiology studies have reported negative effects on pregnancy and perinatal outcomes related to maternal ingestion of high doses of caffeine, but the results are inconclusive. The evidence base for adverse effects of caffeine in first third of pregnancy are stronger than for later parts of pregnancy and there is currently insufficient evidence to advise women to restrict caffeine intake after the first trimester.


Caffeine Fetus Methylxanthines Neonatal Newborn Pregnancy Theophylline 


  1. Abbracchio MP, Camurri A, Ceruti S, Cattabeni F, Falzano L, Giammarioli AM, Jacobson KA, Trincavelli L, Martini C, Malorni W, Fiorentini C (2001) The A3 adenosine receptor induces cytoskeleton rearrangement in human astrocytoma cells via a specific action on rho proteins. Ann N Y Acad Sci 939:63–73PubMedCrossRefGoogle Scholar
  2. Aden U, Herlenius E, Tang LQ, Fredholm BB (2000) Maternal caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain. Pediatr Res 48:177–183PubMedCrossRefGoogle Scholar
  3. Aden U, Leverin AL, Hagberg H, Fredholm BB (2001) Adenosine A(1) receptor agonism in the immature rat brain and heart. Eur J Pharmacol 426:185–192PubMedCrossRefGoogle Scholar
  4. Aldridge A, Bailey J, Neims AH (1981) The disposition of caffeine during and after pregnancy. Semin Perinatol 5:310–314PubMedGoogle Scholar
  5. Andersen SL (2005) Stimulants and the developing brain. Trends Pharmacol Sci 26:237–243PubMedCrossRefGoogle Scholar
  6. Aranda JV, Sitar DS, Parsons WD, Loughnan PM, Neims AH (1976) Pharmacokinetic aspects of theophylline in premature newborns. N Engl J Med 295:413–416PubMedCrossRefGoogle Scholar
  7. Aranda JV, Gorman W, Bergsteinsson H, Gunn T (1977) Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr 90:467–472PubMedCrossRefGoogle Scholar
  8. Aranda JV, Collinge JM, Zinman R, Watters G (1979) Maturation of caffeine elimination in infancy. Arch Dis Child 54:946–949PubMedCrossRefGoogle Scholar
  9. Arnaud MJ (1987) The pharmacology of caffeine. Prog Drug Res 31:273–313PubMedGoogle Scholar
  10. Back SA, Craig A, Luo NL, Ren J, Akundi RS, Ribeiro I, Rivkees SA (2006) Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol 60:696–705PubMedCrossRefGoogle Scholar
  11. Barr HM, Streissguth AP (1991) Caffeine use during pregnancy and child outcome: a 7-year prospective study. Neurotoxicol Teratol 13:441–448PubMedCrossRefGoogle Scholar
  12. Bauer J, Maier K, Linderkamp O, Hentschel R (2001) Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea. Pediatrics 107:660–663PubMedCrossRefGoogle Scholar
  13. Bech BH, Obel C, Henriksen TB, Olsen J (2007) Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial. BMJ 334:409PubMedCrossRefGoogle Scholar
  14. Bjorklund O, Halldner-Henriksson L, Yang J, Eriksson TM, Jacobson MA, Dare E, Fredholm BB (2008a) Decreased behavioral activation following caffeine, amphetamine and darkness in A3 adenosine receptor knock-out mice. Physiol Behav 95:668–676PubMedCrossRefGoogle Scholar
  15. Bjorklund O, Kahlstrom J, Salmi P, Fredholm BB (2008b) Perinatal caffeine, acting on maternal adenosine A(1) receptors, causes long-lasting behavioral changes in mouse offspring. PLoS ONE 3:e3977PubMedCrossRefGoogle Scholar
  16. Bodineau L, Saadani-Makki F, Jullien H, Frugiere A (2006) Caffeine in the milk prevents respiratory disorders caused by in utero caffeine exposure in rats. Respir Physiol Neurobiol 150:94–98PubMedCrossRefGoogle Scholar
  17. Bona E, Aden U, Fredholm BB, Hagberg H (1995) The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate. Pediatr Res 38:312–318PubMedCrossRefGoogle Scholar
  18. Bona E, Aden U, Gilland E, Fredholm BB, Hagberg H (1997) Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists. Neuropharmacology 36:1327–1338PubMedCrossRefGoogle Scholar
  19. Bracken MB, Triche EW, Belanger K, Hellenbrand K, Leaderer BP (2003a) Association of maternal caffeine consumption with decrements in fetal growth. Am J Epidemiol 157:456–466PubMedCrossRefGoogle Scholar
  20. Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP (2003b) Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol 102:739–752PubMedCrossRefGoogle Scholar
  21. Browne ML (2006) Maternal exposure to caffeine and risk of congenital anomalies: a systematic review. Epidemiology 17:324–331PubMedCrossRefGoogle Scholar
  22. CARE Study Group (2008) Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ 337:a2332CrossRefGoogle Scholar
  23. Carnielli VP, Verlato G, Benini F, Rossi K, Cavedagni M, Filippone M, Baraldi E, Zacchello F (2000) Metabolic and respiratory effects of theophylline in the preterm infant. Arch Dis Child Fetal Neonatal Ed 83:F39–F43PubMedCrossRefGoogle Scholar
  24. Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC (2009) Caffeinated and alcoholic beverage intake in relation to ovulatory disorder infertility. Epidemiology 20:374–381PubMedCrossRefGoogle Scholar
  25. Chavez-Valdez R, Wills-Karp M, Ahlawat R, Cristofalo EA, Nathan A, Gauda EB (2009) Caffeine modulates tnf-alpha production by cord blood monocytes: the role of adenosine receptors. Pediatr Res 65:203–208PubMedCrossRefGoogle Scholar
  26. Cnattingius S, Signorello LB, Anneren G, Clausson B, Ekbom A, Ljunger E, Blot WJ, McLaughlin JK, Petersson G, Rane A, Granath F (2000) Caffeine intake and the risk of first-trimester spontaneous abortion. N Engl J Med 343:1839–1845PubMedCrossRefGoogle Scholar
  27. Conde SV, Obeso A, Vicario I, Rigual R, Rocher A, Gonzalez C (2006) Caffeine inhibition of rat carotid body chemoreceptors is mediated by A2A and A2B adenosine receptors. J Neurochem 98:616–628PubMedCrossRefGoogle Scholar
  28. Cook DG, Peacock JL, Feyerabend C, Carey IM, Jarvis MJ, Anderson HR, Bland JM (1996) Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study. BMJ 313:1358–1362PubMedCrossRefGoogle Scholar
  29. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ (2004) Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 200:689–695PubMedCrossRefGoogle Scholar
  30. Dani C, Bertini G, Reali MF, Tronchin M, Wiechmann L, Martelli E, Rubaltelli FF (2000) Brain hemodynamic changes in preterm infants after maintenance dose caffeine and aminophylline treatment. Biol Neonate 78:27–32PubMedCrossRefGoogle Scholar
  31. Davi MJ, Sankaran K, Simons KJ, Simons FE, Seshia MM, Rigatto H (1978) Physiologic changes induced by theophylline in the treatment of apnea in preterm infants. J Pediatr 92:91–95PubMedCrossRefGoogle Scholar
  32. Eldridge FL, Millhorn DE, Kiley JP (1985) Antagonism by theophylline of respiratory inhibition induced by adenosine. J Appl Physiol 59:1428–1433PubMedGoogle Scholar
  33. Eskenazi B (1999) Caffeine–filtering the facts. N Engl J Med 341:1688–1689PubMedCrossRefGoogle Scholar
  34. Fenster L, Quale C, Hiatt RA, Wilson M, Windham GC, Benowitz NL (1998) Rate of caffeine metabolism and risk of spontaneous abortion. Am J Epidemiol 147:503–510PubMedCrossRefGoogle Scholar
  35. Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133Google Scholar
  36. Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14:1315–1323PubMedCrossRefGoogle Scholar
  37. Godel JC, Pabst HF, Hodges PE, Johnson KE, Froese GJ, Joffres MR (1992) Smoking and caffeine and alcohol intake during pregnancy in a northern population: effect on fetal growth. CMAJ 147:181–188PubMedGoogle Scholar
  38. Grosso LM, Bracken MB (2005) Caffeine metabolism, genetics, and perinatal outcomes: a review of exposure assessment considerations during pregnancy. Ann Epidemiol 15:460–466PubMedCrossRefGoogle Scholar
  39. Hammarberg C, Schulte G, Fredholm BB (2003) Evidence for functional adenosine A3 receptors in microglia cells. J Neurochem 86:1051–1054PubMedCrossRefGoogle Scholar
  40. Hart AD, Grimble RF (1990) The effect of methylxanthines on milk volume and composition, and growth of rat pups. Br J Nutr 64:339–350PubMedCrossRefGoogle Scholar
  41. Haskó G, Cronstein B (2010) Methylxanthines and inflammatory cells. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  42. Henderson MG, McConnaughey MM, McMillen BA (1991) Long-term consequences of prenatal exposure to cocaine or related drugs: effects on rat brain monoaminergic receptors. Brain Res Bull 26:941–945PubMedCrossRefGoogle Scholar
  43. Herlenius E, Aden U, Tang LQ, Lagercrantz H (2002) Perinatal respiratory control and its modulation by adenosine and caffeine in the rat. Pediatr Res 51:4–12PubMedCrossRefGoogle Scholar
  44. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002) A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 99:8921–8926PubMedCrossRefGoogle Scholar
  45. Johansson B, Halldner L, Dunwiddie TV, Masino SA, Poelchen W, Gimenez-Llort L, Escorihuela RM, Fernandez-Teruel A, Wiesenfeld-Hallin Z, Xu XJ, Hardemark A, Betsholtz C, Herlenius E, Fredholm BB (2001) Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor. Proc Natl Acad Sci USA 98:9407–9412PubMedCrossRefGoogle Scholar
  46. Kalow W, Tang BK (1991) Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 50:508–519PubMedCrossRefGoogle Scholar
  47. Khanna NN, Somani SM (1984) Maternal coffee drinking and unusually high concentrations of caffeine in the newborn. J Toxicol Clin Toxicol 22:473–483PubMedCrossRefGoogle Scholar
  48. Kirkinen P, Jouppila P, Koivula A, Vuori J, Puukka M (1983) The effect of caffeine on placental and fetal blood flow in human pregnancy. Am J Obstet Gynecol 147:939–942PubMedGoogle Scholar
  49. Klebanoff MA, Levine RJ, DerSimonian R, Clemens JD, Wilkins DG (1999) Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N Engl J Med 341:1639–1644PubMedCrossRefGoogle Scholar
  50. Klebanoff MA, Levine RJ, Clemens JD, Wilkins DG (2002) Maternal serum caffeine metabolites and small-for-gestational age birth. Am J Epidemiol 155:32–37PubMedCrossRefGoogle Scholar
  51. Kuzemko JA (1973) Aminophylline in apnoeic attacks of newborn. Lancet 1:1509PubMedCrossRefGoogle Scholar
  52. Lagercrantz H, Yamamoto Y, Fredholm BB, Prabhakar NR, von Euler C (1984) Adenosine analogues depress ventilation in rabbit neonates. Theophylline stimulation of respiration via adenosine receptors? Pediatr Res 18:387–390PubMedCrossRefGoogle Scholar
  53. Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK, Vassart G, Parmentier M (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2A receptor. Nature 388:674–678PubMedCrossRefGoogle Scholar
  54. Leinekugel X, Medina I, Khalilov I, Ben-Ari Y, Khazipov R (1997) Ca2+ oscillations mediated by the synergistic excitatory actions of GABA(A) and NMDA receptors in the neonatal hippocampus. Neuron 18:243–255PubMedCrossRefGoogle Scholar
  55. Linnet KM, Wisborg K, Secher NJ, Thomsen PH, Obel C, Dalsgaard S, Henriksen TB (2009) Coffee consumption during pregnancy and the risk of hyperkinetic disorder and ADHD: a prospective cohort study. Acta Paediatr 98:173–179PubMedCrossRefGoogle Scholar
  56. Marie-Soleil B, Graham TE (2010) Methylxanthines and human health. Epidemiological and experimental evidence. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  57. McGowan JD, Altman RE, Kanto WP Jr (1988) Neonatal withdrawal symptoms after chronic maternal ingestion of caffeine. South Med J 81:1092–1094PubMedCrossRefGoogle Scholar
  58. McPhee MD, Whiting SJ (1989) The effect of adenosine and adenosine analogues on methylxanthine-induced hypercalciuria in the rat. Can J Physiol Pharmacol 67:1278–1282PubMedCrossRefGoogle Scholar
  59. Millar D, Schmidt B (2004) Controversies surrounding xanthine therapy. Semin Neonatol 9:239–244PubMedCrossRefGoogle Scholar
  60. Milsap RL, Krauss AN, Auld PA (1980) Oxygen consumption in apneic premature infants after low-dose theophylline. Clin Pharmacol Ther 28:536–540PubMedCrossRefGoogle Scholar
  61. Momoi N, Tinney JP, Liu LJ, Elshershari H, Hoffmann PJ, Ralphe JC, Keller BB, Tobita K (2008) Modest maternal caffeine exposure affects developing embryonic cardiovascular function and growth. Am J Physiol Heart Circ Physiol 294:H2248–H2256PubMedCrossRefGoogle Scholar
  62. Montandon G, Kinkead R, Bairam A (2008) Adenosinergic modulation of respiratory activity: developmental plasticity induced by perinatal caffeine administration. Respir Physiol Neurobiol 164:87–95PubMedCrossRefGoogle Scholar
  63. Müller C, Jacobson KA (2010) Xanthines as adenosine receptor antagonists. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  64. Nakamoto T, Roy G, Gottschalk SB, Yazdani M, Rossowska M (1991) Lasting effects of early chronic caffeine feeding on rats’ behavior and brain in later life. Physiol Behav 49:721–727PubMedCrossRefGoogle Scholar
  65. Nehlig A, Debry G (1994) Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data. Neurotoxicol Teratol 16:531–543PubMedCrossRefGoogle Scholar
  66. Neims AH, von Borstel RW (1983) Caffeine: Metabolism and biochemical mechanisms of action. In: Wurtman RJ, Wurtman JJ (Eds) Nutrition and the Brain, Vol. 6. Raven Press, New York, pp 1–30Google Scholar
  67. Ogilvie RI (1978) Clinical pharmacokinetics of theophylline. Clin Pharmacokinet 3:267–293PubMedCrossRefGoogle Scholar
  68. Ohta A, Sitkovsky M (2001) Role of g-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916–920PubMedCrossRefGoogle Scholar
  69. Ohta A, Sitkovsky M (2010) Methylxanthines, inflammation and cancer: fundamental mechanisms. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  70. Rieg T, Steigele H, Schnermann J, Richter K, Osswald H, Vallon V (2005) Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine. J Pharmacol Exp Ther 313:403–409PubMedCrossRefGoogle Scholar
  71. Riksen NP, Smits P, Rongen GA (2010) The cardiovascular effects of methylxanthines. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  72. Rivkees SA (1995) The ontogeny of cardiac and neural A1 adenosine receptor expression in rats. Brain Res Dev Brain Res 89:202–213PubMedCrossRefGoogle Scholar
  73. Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, Newman RB, Hauth JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Paul RH, Varner MW, O’Sullivan MJ, Thurnau GR, Conway DL (2004) The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol 113:1040–1045PubMedCrossRefGoogle Scholar
  74. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W (2007) Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 357:1893–1902PubMedCrossRefGoogle Scholar
  75. Stenius-Aarniala B, Riikonen S, Teramo K (1995) Slow-release theophylline in pregnant asthmatics. Chest 107:642–647PubMedCrossRefGoogle Scholar
  76. Tilley SL (2010) Methylxanthines in asthma. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  77. Tsutsumi K, Kotegawa T, Matsuki S, Tanaka Y, Ishii Y, Kodama Y, Kuranari M, Miyakawa I, Nakano S (2001) The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans. Clin Pharmacol Ther 70:121–125PubMedCrossRefGoogle Scholar
  78. Turner CP, Seli M, Ment L, Stewart W, Yan H, Johansson B, Fredholm BB, Blackburn M, Rivkees SA (2003) A1 adenosine receptors mediate hypoxia-induced ventriculomegaly. Proc Natl Acad Sci USA 100:11718–11722PubMedCrossRefGoogle Scholar
  79. Varani K, Portaluppi F, Gessi S, Merighi S, Vincenzi F, Cattabriga E, Dalpiaz A, Bortolotti F, Belardinelli L, Borea PA (2005) Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. Cell Mol Life Sci 62:2350–2358PubMedCrossRefGoogle Scholar
  80. Vlajinac HD, Petrovic RR, Marinkovic JM, Sipetic SB, Adanja BJ (1997) Effect of caffeine intake during pregnancy on birth weight. Am J Epidemiol 145:335–338PubMedCrossRefGoogle Scholar
  81. Walther FJ, Erickson R, Sims ME (1990) Cardiovascular effects of caffeine therapy in preterm infants. Am J Dis Child 144:1164–1166PubMedGoogle Scholar
  82. Wen W, Shu XO, Jacobs DR Jr, Brown JE (2001) The associations of maternal caffeine consumption and nausea with spontaneous abortion. Epidemiology 12:38–42PubMedCrossRefGoogle Scholar
  83. Wisborg K, Kesmodel U, Bech BH, Hedegaard M, Henriksen TB (2003) Maternal consumption of coffee during pregnancy and stillbirth and infant death in first year of life: prospective study. BMJ 326:420PubMedCrossRefGoogle Scholar
  84. Yang JN, Tiselius C, Dare E, Johansson B, Valen G, Fredholm BB (2007) Sex differences in mouse heart rate and body temperature and in their regulation by adenosine A1 receptors. Acta Physiol (Oxf) 190:63–75CrossRefGoogle Scholar
  85. Yurchak AM, Jusko WJ (1976) Theophylline secretion into breast milk. Pediatrics 57:518–520PubMedGoogle Scholar

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© Springer Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Department of Woman and Child HealthKarolinska InstituteStockholmSweden

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