Caffeine, Neurodevelopmental Outcomes in Premature Infants, and Bronchopulmonary Dysplasia
DOI:
https://doi.org/10.17140/pnnoj.2025.v11.i01.pp01-08.2227Keywords:
Caffeine, Premature infants, Bronchopulmonary dysplasia, Neurodevelopmental outcomes, Adenosine receptorAbstract
Caffeine, a stimulant is the most widely used drug in the world in adults with increasing usage in children. It is commonly used in the treatment of apnea of prematurity in premature infants. Caffeine in a randomized trial has been shown to reduce the incidence of bronchopulmonary dysplasia in infants <1250 grams birth weight when used to treat apnea of prematurity in these infants. In the same cohort of infants, caffeine improved neurodevelopmental outcomes and survival at 18 months of age and was found to be safe without any adverse events up to 11 years of age. Caffeine is an adenosine receptor antagonist and inhibits adenosine receptors at physiologic concentrations with important effects on behavior and cognitive functions. However, higher doses of caffeine may inhibit the enzyme phosphodiesterase and affect vascular smooth muscle function. Anti-oxidant, anti-inflammatory and antiapoptotic properties of caffeine and its ability to scavenge reactive oxygen species may contribute to its lung and neuro protective effects in premature infants. Animal studies on whether caffeine is protective to the lung are not conclusive at this time. Similarly, caffeine is demonstrated to have adverse effects on brain development in animal studies. Despite the beneficial effects of caffeine in premature infants when administered in the neonatal period, the long-term effects on adult-oriented disease such as cardio-metabolic disease and neurobehavioral states in children and adults needs further study.
References
Temple JL. Caffeine use in children: What we know, what we have left to learn, and why we should worry. Neurosci Biobehav Rev. 2009; 33(6): 793-806. doi: 10.1016/j.neubiorev.2009.01.001
Malinauskas BM, Aeby VG, Overton RF, Carpenter-Aeby T, Barber-Heidal K. A survey of energy drink consumption patterns among college students. Nutr J. 2007; 6: 35. doi: 10.1186/1475- 2891-6-35
Richards G, Smith A. Caffeine consumption and self-as-sessed stress, anxiety, and depression in secondary school children. J Psychopharmacol. 2015; 29(12): 1236-1247. doi: 10.1177/0269881115612404
Kristjansson AL, Sigfusdottir ID, Frost SS, James JE. Adoles-cent caffeine consumption and self-reported violence and conduct disorder. J Youth Adolesc. 2013; 42(7): 1053-1062. doi: 10.1007/ s10964-013-9917-5
Fredholm BB, Abbracchio MP, Burnstock G, et al. Nomencla-ture and classification of purinoceptors. Pharmacol Rev. 1994; 46(2): 143-156.
Bonati M, Latini R, Galletti F, Young JF, Tognoni G, Garattini S. Caffeine disposition after oral doses. Clin Pharmacol Ther. 1982; 32(1): 98-106. doi: 10.1038/clpt.1982.132
Arnaud MJ. The pharmacology of caffeine. Prog Drug Res. 1987; 31: 273-313. doi: 10.1007/978-3-0348-9289-6_9
Lee TC, Charles B, Steer P, Flenady V, Shearman A. Popula-tion pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther. 1997; 61(6): 628-40. doi: 10.1016/S0009-9236(97)90097-7
Begas E, Kouvaras E, Tsakalof A, Papakosta S, Asprodini EK. In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios. Biomed Chromatogr. 2007; 21(2): 190-200. doi: 10.1002/bmc.736
Aranda JV, Collinge JM, Zinman R, Watters G. Maturation of caffeine elimination in infancy. Arch Dis Child. 1979; 54(12): 946- 949. doi: 10.1136/adc.54.12.946
Thorn CF, Aklillu E, McDonagh EM, Klein TE, Altman RB. PharmGKB summary: Caffeine pathway. Pharmacogenet Genomics. 2012; 22(5): 389-395. doi: 10.1097/FPC.0b013e3283505d5e
Al-Alaiyan S, Al-Rawithi S, Raines D, et al. Caffeine metabolism in premature infants. J Clin Pharmacol. 2001; 41(6): 620-627. doi: 10.1177/00912700122010500
Brachtel D, Richter E. Absolute bioavailability of caffeine from a tablet formulation. J Hepatol. 1992; 16(3): 385. doi: doi: 10.1016/ S0168-8278(05)80676-2
Le Guennec JC, Billon B, Pare C. Maturational changes of caf-feine concentrations and disposition in infancy during maintenance therapy for apnea of prematurity: influence of gestational age, he-patic disease, and breast-feeding. Pediatrics. 1985; 76(5): 834-840.
Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006; 354(20): 2112-2121. doi: 10.1056/NEJMoa054065
Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007; 357(19): 1893-1902. doi: 10.1056/NEJMoa073679
Schmidt B, Anderson PJ, Doyle LW, et al. Survival without disability to age 5 years after neonatal caffeine therapy for ap-nea of prematurity. JAMA. 2012; 307(3): 275-282. doi: 10.1001/ jama.2011.2024
Schmidt B, Roberts RS, Anderson PJ, et al. Academic per-formance, motor function, and behavior 11 years after neonatal caffeine citrate therapy for apnea of prematurity: An 11-year fol-low-up of the CAP randomized clinical trial. JAMA pediatr. 2017; 171(6): 564-572. doi: 10.1001/jamapediatrics.2017.0238
Marcus CL, Meltzer LJ, Roberts RS, et al. Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age. Am J Respir Crit Care Med. 2014; 190(7): 791-799. doi: 10.1164/ rccm.201406-1092OC
Doyle LW, Ranganathan S, Cheong JLY. Neonatal caffeine treatment and respiratory function at 11 years in children under 1,251 g at birth. Am J Respir Crit Care Med. 2017; 196(10): 1318- 1324. doi: 10.1164/rccm.201704-0767OC
Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev. 2010(12): CD000139. doi: 10.1002/14651858.CD000139
Steer P, Flenady V, Shearman A, et al. High dose caffeine ci-trate for extubation of preterm infants: A randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2004; 89(6): F499-F503. doi: 10.1136/adc.2002.023432
McPherson C, Neil JJ, Tjoeng TH, Pineda R, Inder TE. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. 2015; 78(2): 198-204. doi: 10.1038/pr.2015.72
Patel RM, Leong T, Carlton DP, Vyas-Read S. Early caffeine therapy and clinical outcomes in extremely preterm infants. J Peri-natol. 2013; 33(2): 134-140. doi: 10.1038/jp.2012.52
Taha D, Kirkby S, Nawab U, et al. Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm in-fants. J Matern Fetal Neonatal Med. 2014; 27(16): 1698-1702. doi: 10.3109/14767058.2014.885941
Nagatomo T, Jimenez J, Richter J, et al. Caffeine prevents hy-peroxia-induced functional and structural lung damage in preterm rabbits. Neonatology. 2016; 109(4): 274-281. doi: 10.1159/000442937
Weichelt U, Cay R, Schmitz T, et al. Prevention of hyperoxia-mediated pulmonary inflammation in neonatal rats by caffeine. Eur Respir J. 2013; 41(4): 966-973. doi: 10.1183/09031936.00012412
Teng RJ, Jing X, Michalkiewicz T, Afolayan AJ, Wu TJ, Konduri GG. Attenuation of endoplasmic reticulum stress by caffeine ame-liorates hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2017; 312(5): L586-L98. doi: 10.1152/ajplung.00405.2016
Dayanim S, Lopez B, Maisonet TM, Grewal S, Londhe VA. Caf-feine induces alveolar apoptosis in the hyperoxia-exposed develop-ing mouse lung. Pediatr Res. 2014; 75(3): 395-402. doi: 10.1038/ pr.2013.233
Rath P, Nardiello C, Surate Solaligue DE, et al. Caffeine ad-ministration modulates TGF-beta signaling but does not attenu-ate blunted alveolarization in a hyperoxia-based mouse model of bronchopulmonary dysplasia. Pediatr Res. 2017; 81(5): 795-805. doi: 10.1038/pr.2017.21
Dumpa V NL, Wang H, Kumar VH. Neonatal caffeine im-proves alveolization in the presence of hyperoxia in adult mice. Paper presented at: Pediatric Academic Societies Meeting. 2016; Baltimore, Maryland, USA.
Dumpa V WH, Nielsen L, Kumar VH. Caffeine modulates hyperoxia induced angiogenesis in newborn mice. Paper presented at: Pediatric Academic Societies Meeting. 2015; San Diego, Cali-fornia, USA.
Jobe AH. Caffeine: A lung drug for all very low birth weight preterm infants?. Am J Respir Crit Care Med. 2017; 196(10): 1241- 1243. doi: 10.1164/rccm.201707-1402ED
Li J, Li G, Hu JL, et al. Chronic or high dose acute caffeine treatment protects mice against oleic acid-induced acute lung in-jury via an adenosine A2A receptor-independent mechanism. Eur J Pharmacol. 2011; 654(3) :295-303. doi: 10.1016/j.ejphar.2010.12.040
Walsh MC, Morris BH, Wrage LA, et al. Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. J Pediatr. 2005; 146(6): 798-804. doi: 10.1016/j.jpeds.2005.01.047
Lodha A ER, Synnes A, Creighton D, et al. Early caffeine ad-ministration and neurodevelopmental outcomes in preterm in-fants. Pediatrics. 2019; 143(1): e20181348.
Poets CF, Roberts RS, Schmidt B, et al. Association between intermittent hypoxemia or bradycardia and late death or disability in extremely preterm infants. JAMA. 2015; 314(6): 595-603. doi: 10.1001/jama.2015.8841
Rhein LM, Dobson NR, Darnall RA, et al. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA pediatr. 2014; 168(3): 250-257. doi: 10.1001/ jamapediatrics.2013.4371
Bhatt-Mehta V, Schumacher RE. Treatment of apnea of prema-turity. Paediatr Drugs. 2003; 5(3): 195-210. doi: 10.2165/00128072- 200305030-00006
Dekker J, Hooper SB, van Vonderen JJ, Witlox R, Lopriore E, Te Pas AB. Caffeine to improve breathing effort of preterm infants at birth: a randomized controlled trial. Pediatr Res. 2017; 82(2): 290- 296. doi: 10.1038/pr.2017.45 Kumar VHS
Hatzakis G, G. Davis MG, Newth C, Jouvet P, Lands L. Effects of caffeine in lung mechanics of extremely low birth weight in-fants. Journal of Clinical Anesthesia and Pain Medicine. 2017; 1(2): 1-8.
Atik A, Cheong J, Harding R, Rees S, De Matteo R, Tolcos M. Impact of daily high-dose caffeine exposure on developing white matter of the immature ovine brain. Pediatr Res. 2014; 76(1): 54-63. doi: 10.1038/pr.2014.55
Fuller GN, Divakaran P, Wiggins RC. The effect of postna-tal caffeine administration on brain myelination. Brain Res. 1982; 249(1): 189-191. doi: 10.1016/0006-8993(82)90187-1
Black AM, Pandya S, Clark D, Armstrong EA, Yager JY. Ef-fect of caffeine and morphine on the developing pre-mature brain. Brain Res. 2008; 1219: 136-142. doi: 10.1016/j.brainres.2008.04.066
Wentz CT, Magavi SS. Caffeine alters proliferation of neuro-nal precursors in the adult hippocampus. Neuropharmacology. 2009; 56(6-7): 994-1000. doi: 10.1016/j.neuropharm.2009.02.002
Desfrere L, Olivier P, Schwendimann L, Verney C, Gressens P. Transient inhibition of astrocytogenesis in developing mouse brain following postnatal caffeine exposure. Pediatr Res. 2007; 62(5): 604- 609. doi: 10.1203/PDR.0b013e318156e425
Silva CG, Metin C, Fazeli W, et al. Adenosine receptor an-tagonists including caffeine alter fetal brain development in mice. Sci Transl Med. 2013; 5(197): 197ra04. doi: 10.1126/scitrans-lmed.3006258
Kabir ZD, McCarthy DM, Bhide PG, Kosofsky BE. Cup of Joe: A brain development "no"?. Sci Transl Med. 2013; 5(197): 197fs30. doi: 10.1126/scitranslmed.3006994
van Koert RR, Bauer PR, Schuitema I, Sander JW, Visser GH. Caffeine and seizures: A systematic review and quantitative analysis. Epilepsy Behav. 2018; 80: 37-47. doi: 10.1016/j.yebeh.2017.11.003
Banner W, Czajka PA. Acute caffeine overdose in the neo-nate. Am J Dis Child. 1980; 134(5): 495-498. doi: 10.1001/archpe-di.1980.02130170045015
Vesoulis ZA, McPherson C, Neil JJ, Mathur AM, Inder TE. Early high-dose caffeine increases seizure burden in extremely pre-term neonates: A preliminary study. J Caffeine Res. 2016; 6(3): 101- 107. doi: 10.1089/jcr.2016.0012
Kolahdouzan M, Hamadeh MJ. The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neurosci Ther. 2017; 23(4): 272-290. doi: 10.1111/cns.12684
Yadav S, Gupta SP, Srivastava G, Srivastava PK, Singh MP. Role of secondary mediators in caffeine-mediated neuroprotection in maneb- and paraquat-induced Parkinson's disease phenotype in the mouse. Neurochem Res. 2012; 37(4): 875-884. doi: 10.1007/ s11064-011-0682-0
Shi X, Dalal NS, Jain AC. Antioxidant behaviour of caffeine: efficient scavenging of hydroxyl radicals. Food Chem Toxicol. 1991; 29(1): 1-6. doi: 10.1016/0278-6915(91)90056-D
Devasagayam TP, Kamat JP, Mohan H, Kesavan PC. Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reac-tive oxygen species. Biochim Biophys Acta. 1996; 1282(1): 63-70. doi: 10.1016/0005-2736(96)00040-5
Barcelos RP, Souza MA, Amaral GP, et al. Caffeine supplemen-tation modulates oxidative stress markers in the liver of trained rats. Life Sci. 2014; 96(1-2): 40-45. doi: 10.1016/j.lfs.2013.12.002
Endesfelder S, Weichelt U, Strauss E, et al. Neuroprotection by caffeine in hyperoxia-induced neonatal brain injury. Int J Mol Sci. 2017; 18(1). 187. doi: 10.3390/ijms18010187
Chavez-Valdez R, Wills-Karp M, Ahlawat R, Cristofalo EA, Nathan A, Gauda EB. Caffeine modulates TNF-alpha production by cord blood monocytes: The role of adenosine receptors. Pediatr Res. 2009; 65(2): 203-208. doi: 10.1203/PDR.0b013e31818d66b1
Tsutsui S, Schnermann J, Noorbakhsh F, et al. A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci. 2004; 24(6): 1521-1529. doi: 10.1523/JNEUROSCI.4271-03.2004
Barker DJ. The fetal and infant origins of adult disease. BMJ. 1990; 301(6761): 1111. doi: 10.1136/bmj.301.6761.1111
Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placen-tal size and risk of hypertension in adult life. BMJ. 1990; 301(6746): 259-262. doi: 10.1136/bmj.301.6749.441
Papadopoulou E, Botton J, Brantsaeter AL, et al. Maternal caffeine intake during pregnancy and childhood growth and over-weight: results from a large Norwegian prospective observational cohort study. BMJ Open. 2018; 8(3): e018895. doi: 10.1136/bmjo-pen-2017-018895
Li DK, Ferber JR, Odouli R. Maternal caffeine intake dur-ing pregnancy and risk of obesity in offspring: A prospective co-Submit your article to this journal | https://openventio.org/submit-manuscript/ hort study. Int J Obes (Lond). 2015; 39(4): 658-664. doi: 10.1038/ ijo.2014.196
Sengpiel V, Elind E, Bacelis J, et al. Maternal caffeine intake during pregnancy is associated with birth weight but not with ges-tational length: results from a large prospective observational co-hort study. BMC Med. 2013; 11: 42. doi: 10.1186/1741-7015-11-42
Li J, Luo H, Wu Y, et al. Gender-specific increase in susceptibil-ity to metabolic syndrome of offspring rats after prenatal caffeine exposure with post- weaning high-fat diet. Toxicol Appl Pharmacol. 2015; 284(3): 345-353. doi: 10.1016/j.taap.2015.03.002
Xu D, Zhang B, Liang G, et al. Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypo-thalamic-pituitary-adrenal axis inhibition in fetal rats. PloS One. 2012;7(9):e44497. doi: 10.1371/journal.pone.0044497
Buscariollo DL, Fang X, Greenwood V, Xue H, Rivkees SA, Wendler CC. Embryonic caffeine exposure acts via A1 adenos-ine receptors to alter adult cardiac function and DNA methyla-tion in mice. PLoS One. 2014; 9(1): e87547. doi: 10.1371/journal. pone.0087547
Rivkees SA, Wendler CC. Adverse and protective influences of adenosine on the newborn and embryo: implications for preterm white matter injury and embryo protection. Pediatr Res. 2011; 69(4): 271-278. doi: 10.1203/PDR.0b013e31820efbcf
Wu YM, Luo HW, Kou H, et al. Prenatal caffeine exposure induced a lower level of fetal blood leptin mainly via placental mechanism. Toxicol Appl Pharmacol. 2015; 289(1): 109-116. doi: 10.1016/j.taap.2015.09.007
Singh AP LS, Nielsen L, Wang H, Gugino S, Kumar VH. Ef-fects of neonatal caffeine on blood pressure, vessel reactivity & systemic stress in adult mice. Paper presented at: Pediatric Aca-demic Societies Meeting. 2017; San Francisco, California, USA.
Fredholm BB, AP IJ, Jacobson KA, Klotz KN, Linden J. Inter-national union of pharmacology. XXV. nomenclature and classifi-cation of adenosine receptors. Pharmacol Rev. 2001; 53(4): 527-552.
Downloads
Published
How to Cite
Issue
Section
License

This work is licensed under a Creative Commons Attribution 4.0 International License.
All content published in Pediatrics and Neonatal Nursing (PNN) is licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license allows anyone to copy, distribute, transmit, and adapt the work — including for commercial purposes — provided appropriate credit is given to the original author(s) and source.