Methylxanthines During Pregnancy and Early Postnatal Life
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.
KeywordsCaffeine Fetus Methylxanthines Neonatal Newborn Pregnancy Theophylline
- 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
- 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
- Haskó G, Cronstein B (2010) Methylxanthines and inflammatory cells. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
- 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
- Marie-Soleil B, Graham TE (2010) Methylxanthines and human health. Epidemiological and experimental evidence. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
- Müller C, Jacobson KA (2010) Xanthines as adenosine receptor antagonists. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
- 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
- Ohta A, Sitkovsky M (2010) Methylxanthines, inflammation and cancer: fundamental mechanisms. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
- Riksen NP, Smits P, Rongen GA (2010) The cardiovascular effects of methylxanthines. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
- 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
- Tilley SL (2010) Methylxanthines in asthma. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar