Caffeine versus Aminophylline for Apnea of Prematurity: A Randomized Clinical Trial

Document Type : Original Article


1 Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

2 Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran


Background: Apnea of prematurity is often found in preterm neonates with gestational age less than 34-37 weeks or birth weight (BW) less than 1000 grams. The American Academy of Pediatrics defines apnea as a respiratory halt lasting at least 20 seconds, with bradycardia or cyanosis. Methylxanthines reduce the incidence of apnea. The purpose of this study was to compare the effect of caffeine and aminophylline on the incidence of the apnea in premature infants.
Methods: This randomized clinical trial study was conducted on 80 premature neonates at Shahid Sadoughi hospital in Yazd. The first group received the initial dose of 5 mg/kg aminophylline diluted in 5% dextrose with a maintenance dose of 2 mg/kg every 8 hours, while the second group received 30 mg/kg of caffeine diluted in 5% dextrose with a 24-hour maintenance dose of 10 mg/kg.
Results: There was no significant difference infrequency of apnea between the two groups (P = 0.121). However there was a significant difference in respiratory status between the two groups so that in caffeine group, oxyhood was less necessary for neonates (P = 0.012) and using continuous positive airway pressure (CPAP) was significantly less in aminophylline group (P = 0.012).
Conclusion: Our study showed that the frequency of apnea was less in the caffeine group, but there was no significant difference between the two groups. Aminophylline treatment in comparison with caffeine can reduce the need for CPAP in neonates with apnea.


  1. Cramer SJE, Dekker J, Dankelman J, Pauws SC, Hooper SB, Te Pas AB. Effect of tactile stimulation on termination and prevention of apnea of prematurity: a systematic review. Front Pediatr2018; 6: 45.
  2. Committee on Fetus and Newborn. American Academy of Pediatrics. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics2003; 111(4 Pt 1): 914-7.
  3. Eichenwald EC. Apnea of prematurity. Pediatrics2016; 137(1).
  4. Henderson-Smart DJ, de Paoli AG. Prophylactic methylxanthine for prevention of apnoea in preterm infants. Cochrane Database Syst Rev2010; 2010(12): Cd000432.
  5. Dobson NR, Patel RM, Smith PB, Kuehn DR, Clark J, Vyas-Read S, et al. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr2014; 164(5): 992-8.e3.
  6. Abu Jawdeh EG, O'Riordan M, Limrungsikul A, Bandyopadhyay A, Argus BM, Nakad PE, et al. Methylxanthine use for apnea of prematurity among an international cohort of neonatologists. J Neonatal Perinatal Med2013; 6(3): 251-6.
  7. Wilson CG, Martin RJ, Jaber M, Abu-Shaweesh J, Jafri A, Haxhiu MA, et al. Adenosine A2A receptors interact with GABAergic pathways to modulate respiration in neonatal piglets. Respir Physiol Neurobiol2004; 141(2): 201-11.
  8. Bhatia J. Current options in the management of apnea of prematurity. Clin pediatr 2000; 39(6): 327-36.
  9. Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, et al. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr2015; 169(1): 33-8.
  10. Dobson NR, Hunt CE. Pharmacology review: caffeine use in neonates: indications, pharmacokinetics, clinical effects, outcomes. NeoReviews2013; 14(11): e540-e550.
  11. Abdel-Hady H, Nasef N, Shabaan AE, Nour I. Caffeine therapy in preterm infants. World J Clin Pediatr 2015; 4(4): 81-93.
  12. Chandrasekharan P, Rawat M, Reynolds AM, Phillips K, Lakshminrusimha S. Apnea, bradycardia and desaturation spells in premature infants: impact of a protocol for the duration of 'spell-free' observation on interprovider variability and readmission rates. J Perinatol2018; 38(1): 86-91.
  13. Philip RK, Ismail A, Murphy B, Mirza A, Quinn C, Dunworth M. Caffeine treatment for apnea of prematurity and the influence on dose-dependent postnatal weight gain observed over 15 years. J Caffeine Adenosine Res 2018; 8(3): 99-106.
  14. Poets CF. Apnea of prematurity: What can observational studies tell us about pathophysiology? Sleep Med2010; 11(7): 701-7.
  15. Leonardis RL, Robison JG, Otteson TD. Evaluating the management of obstructive sleep apnea in neonates and infants.JAMA otolaryngol Head Neck Surg2013; 139(2): 139-46.
  16. Boison D. Methylxanthines, seizures, and excitotoxicity. Handb Exp Pharmacol 2011; (200): 251-66.
  17. Shivakumar M, Jayashree P, Najih M, Simon Lewis LE, Bhat Y R, Kamath A. Comparative Efficacy and Safety of Caffeine and Aminophylline for Apnea of Prematurity in Preterm (≤34 weeks) Neonates: A Randomized Controlled Trial. Indian Pediatr 2017; 54(4): 279-83.
  18. Kua KP, Lee SWH. Systematic review and meta‐analysis of clinical outcomes of early caffeine therapy in preterm neonates. British journal of clinical pharmacology. 2017; 83(1): 180-191.
  19. Atik A, Harding R, De Matteo R, Kondos-Devcic D, Cheong J, Doyle LW, et al. Caffeine for apnea of prematurity: Effects on the developing brain. NeuroToxicology 2017; 58: 94-102.
  20. Armanian AM, Iranpour R, Faghihian E, Salehimehr N. Caffeine administration to prevent apnea in very premature infants. Pediatrics and neonatology. Pediatr Neonat 2016; 57: 408-12.
  21. Scanlon JE, Chin KC, Morgan ME, Durbin GM, Hale KA, Brown SS. Caffeine or theophylline for neonatal apnoea? Arch Dis Child 1992; 67(4 Spec No): 425-8.
  22. Henderson-Smart DJ, Steer PA. Caffeine versus theophylline for apnea in preterm infants. The Cochrane Database Syst Rev 2010; 20(1): Cd000273.
  23. Schellack N, Gous AGS, Mawela PB. Caffeine versus aminophylline for the prevention of apnoea of prematurity in a teaching hospital in South Africa. South African Family Practice2015; 57(3): 140-5.
  24. Korvadiya M, Masand R, Purohit A. Study of comparative efficacy and adverse effects of caffeine and aminophylline in the management of apnea of prematurity: a randomized control trial. J Evol MedDent Sci 2014; 3(23):
  25. Habibi M, Mahyar A, Nikdehghan S. Effect of Caffeine and Aminophylline on Apnea of Prematurity. Iranian Journal of Neonatology2019; 10(2): 37-41.