Efficacy of aminophylline vs. caffeine for preventing apnea of prematurity

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Hendy Hendy
Setya Wandita
I Made Kardana


Background Apnea of prematurity (AOP) usually occurs
in neonates with a gestational age < 34 weeks. The World
Health Organization has recommended the administration of
caffeine or aminophylline to prevent AOP, but the efficacy of
aminophylline remains unclear, and caffeine citrate is not available
in Indonesia.
Objective To compare the efficacy of aminophylline to that of
caffeine for preventing AOP.
Methods This single-blind, clinical trial was conducted on
neonates (gestational age 28-34 weeks) who were able to breathe
spontaneously within the first 24 hours of life and admitted to
Sanglah Hospital from December 2012 to April 2013. Subjects
were randomly allocated into two groups, namely groups of
aminophyllin and caffeine. The aminophylline group received
aminophylline dihydrate at an initial dose of 10 mg/kg body weight,
then continued with a maintenance dose of 2.5 mg/kg body weight
every 12 hours. The caffeine group received anhydrous caffeine
at an initial dose of 10 mg/kg body weight, then continued with
a maintenance dose of 1.25 mg/kg body weight every 12 hours.
We followed subjects up until they were 10 days old. Subjects
received per oral therapy for seven days. The efficacy comparison
between the two groups was assessed by Chi-square test with 95%
confidence interval (CI) and a statistical significance value of P
< 0.05. We used multivariate test to analyze the confounding
Results Ninety-six subjects participated in this study; 48 subjects
received aminophylline therapy and the other 48 subjects received
caffeine therapy. Twenty-eight subjects experienced apnea: 13
subjects from the aminophylline group (27.1%), and 15 subjects
from the caffeine group (31.3%). It appeared that aminophylline
was slightly better compared to caffeine, but the difference was
not statistically significant, with a relative risk of 0.9 (95% CI
0.5 to 1.3; P=0.8). We found vomiting to be a side effect of both
therapies, and not significantly different between groups. Sepsis
From the Department of Child Health, Udayana University Medical
School/Sanglah Hospital, Denpasar1 and Gadjah Mada University Medical
School/Sardjito Hospital, Yogyakarta2.
Reprint requests to: Hendy, Department of Child Health, Udayana
University Medical School, Sanglah Hospital, Jl. Pulau Nias, Denpasar,
Bali 80114. Tel./Fax: +62-361-244038. E-mail: hendyhalim.md@gmail.
Infant prematurity is defined as a gestational
age of < 37 weeks. Africa has the highest birth
rate of premature infants of 11.9%, while that
of Southeast Asia is approximately 11.1%.1
The main issue that premature infants face is apnea.
Apnea is caused by incomplete development of
the respiratory center, and is known as apnea of
prematurity (AOP). Several factors underlie the
necessity of AOP prevention: an 85% incidence of
AOP in infants with gestational age <34 weeks,2
difficulty in diagnosing AOP, unpredictable onset,
short- and long-term effects, long treatment length
and requirement of intensive care. The World Health
and hyaline membrane disease were found to be confounding
factors in this study.
Conclusion Aminophylline and caffeine have similar efficacy
with regards to preventing AOP.

Article Details

How to Cite
Hendy H, Wandita S, Kardana IM. Efficacy of aminophylline vs. caffeine for preventing apnea of prematurity. PI [Internet]. 30Dec.2014 [cited 16Sep.2019];54(6):365-1. Available from: https://paediatricaindonesiana.org/index.php/paediatrica-indonesiana/article/view/1240
Received 2017-02-01
Accepted 2017-02-01
Published 2014-12-30


1. Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88:31-8.
2. Barrington K, Finer N. The natural history of the appearance of apnea of prematurity. Pediatr Res. 1991;29:372-5.
3. Ashworth A, Bickler S, Deen J, Duke T, Hussey G, English M, et al. Problems of the neonate and young infant. In: Campbell H, editor. Pocket book of hospital care for children. Geneva: World Health Organiztion; 2005. p. 55.
4. Martin RJ, Abu-Shaweesh JM, Baird TM. Pathophysiologic mechanisms underlying apnea of prematurity. Neoreviews. 2002;3:e59-65.
5. Skouroliakou M, Bacopoulou F, Markantonis SL. Caffeine versus theophylline for apnea of prematurity: a randomised controlled trial. J Paediatr Child Health. 2009;45:587-92.
6. Lagercrantz H, Rane A, Tunell R. Plasma concentrationeffect relationship of theophylline in treatment of apnea in preterm infants. Eur J Clin Pharmacol. 1980;18:65-8.
7. Fleiss JL, Tytun A, Ury HK. A simple approximation for calculating sample size for comparing independent proportions. Biometrics. 1980;36:343-6.
8. Larsen PB, Brendstrup L, Skov L, Flachs H. Aminophylline versus caffeine citrate for apnea and bradycardia prophylaxis in premature neonates. Acta Paediatr. 1995;84:360-4.
9. Aden U. Methylxanthines during pregnancy and early postnatal life. In: Fredholm BB, editor. Methylxanthines: Handbook of experimental pharmacology, volume 200. New York: Springer Verlag Berlin Heidelberg; 2011. p. 373-89.
10. Ruby CL, Adams CA, Mrazek DA, Choi DS. Adenosine signaling in anxiety, [cited 2013 April 20]. Available from: http//www.intechopen.com
11. FDA professional drug information. Aminophylline injection. [cited 2012 October 20]. Available from: http://www.drugs.com/pro/aminophylline-injection.html.
12. FDA professional drug information. Caffeine citrate. [cited 2012 October 20]. Available from: http://www.drugs.com/pro/caffeine-citrate.html.
13. Merchant RH, Sakhalkar VS, Ashavaid TF. Prophylactic theophylline infusion for prevention of apnea of prematurity. Indian Pediatr. 1992;29:1359-63.
14. Pena EM, Parks VN, Peng J, Fernandez SA, Di Lorenzo C, Shaker R, et al. Lower esophageal sphincter relaxation reflex kinetics: effects of peristaltic reflexes and maturation in human premature neonates. Am J Physiol Gastrointest Liver Physiol. 2010;299:G1386-95.
15. Golski CA, Rome ES, Martin RJ, Frank SH, Worley S, Sun Z, et al. Pediatric specialists’ beliefs about gastroesophageal reflux disease in premature infants. Pediatrics. 2010;125:96-104.
16. Thompson MW, Hunt CE. Control of breathing: development, apnea of prematurity, apparent life-threatening events, sudden infant death syndrome. In: MacDonald MG, Seshia MMK, Mullett MD, editors. Avery’s neonatology. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 536-53.