Title: Insights into Aminophylline and Neurodevelopmental Outcome in Premature Infants
Abstract: Apnea of prematurity is a common occurrence in infants born under the gestational age (GA) of 34 weeks. Frequent apneic episodes may lead to decreased cerebral oxygen delivery, thus possibly having a serious detrimental impact on the developing brain. Treatment for apnea includes mechanical support such as continuous positive airway pressure and/or administration of methylxanthines. Thus, methylxanthines (caffeine, theophylline, aminophylline) are among the most commonly used drugs in premature infants. However, reports on the short- and long-term safety of methylxanthine therapy in premature infants have been surprisingly limited. To date, few clinical trials reported on the long-term effect of methylxanthines, and most of these studies focused on the effect of caffeine therapy. Compared to aminophylline, caffeine was shown to have better long-term outcomes with lower toxicity and no association with neurodevelopmental disability.1Henderson-Smart D.J. Steer P.A. Caffeine versus theophylline for apnea in preterm infants.Cochrane Database Syst Rev. 2010; : CD000273PubMed Google Scholar In addition, in a study of 33 preterm infants that compared the effect of aminophylline and caffeine on cerebral blood flow, it was shown that as soon as 2 hours after administration of aminophylline, global cerebral blood flow was significantly decreased in the aminophylline group.2Lundstrøm K.E. Larsen P.B. Brendstrup L. Skov L. Greisen G. Cerebral blood flow and left ventricular output in spontaneously breathing, newborn preterm infants treated with caffeine or aminophylline.Acta Paediatr. 1995; 84: 6-9Crossref PubMed Scopus (19) Google Scholar While more investigations on the long-term effect of caffeine therapy for apnea of prematurity have been published during the past decade, reports on the effects of aminophylline/theophylline on clinically important outcomes such as drug safety and long-term effects on neurodevelopmental outcome are still sparse. This is of substantial concern to many neonatologists in Taiwan and many other countries where aminophylline/theophylline is used extensively due to lack of caffeine. The report of Davis et al3Davis P.G. Doyle L.W. Rickards A.L. Kelly E.A. Ford G.W. Davis N.M. et al.Methylxanthines and sensorineural outcome at 14 years in children < 1501 g birthweight.J Paediatr Child Health. 2000; 36: 47-50Crossref PubMed Scopus (23) Google Scholar was the first human clinical observational study to show a possible association between the administration of theophylline and cerebral palsy at 14 years of age in a cohort study of 130 premature children of birth body weight of < 1501 g. The mechanisms by which methylxanthines might induce inadvertent cerebral damage have been disputed over past years. Several reports suggested caution in the use of aminophylline, because it was shown to increase cerebral metabolic rate and decrease the rate of anoxic survival in neonatal mice.4Thurston J.H. Hauhard R.E. Dirgo J.A. Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice.Science. 1978; 201: 649-651Crossref PubMed Scopus (58) Google Scholar It has been demonstrated that after 24–48 hours of aminophylline administration, there was an increased oxygen consumption by 20–25% in preterm infants.5Milsap R.L. Krauss A.N. Auld P.A. Oxygen consumption in apneic premature infants after low-dose theophylline.Clin Pharmacol Ther. 1980; 28: 536-540Crossref PubMed Scopus (28) Google Scholar Another reason that raised the concern about aminophylline use in preterm infants is that methylxanthines are antagonists of adenosine receptors. Adenosine has neuroprotective ability and plays an important role in the mediation of local vascular regulation, and serves to maintain a consistent oxygen uptake. Inhibition of such regulatory ability (e.g., by aminophylline) may result in perturbations of vascular circulation. It is therefore speculated that as an adenosine inhibitor, aminophylline may impair the regulation of neonatal cerebral oxygenation, resulting in potentially harmful neurological outcomes. However, not all reports showed a detrimental effect of aminophylline administration. Bona et al6Bona E. Adén U. Gilland E. Fredholm B.B. Hagberg H. Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists.Neuropharmacology. 1997; 36: 1327-1338Crossref PubMed Scopus (109) Google Scholar found that, compared to controls, pretreatment with theophylline in 7-day-old premature rats markedly reduced brain injury after hypoxia-ischemia insult. As mentioned earlier, although Davis et al3Davis P.G. Doyle L.W. Rickards A.L. Kelly E.A. Ford G.W. Davis N.M. et al.Methylxanthines and sensorineural outcome at 14 years in children < 1501 g birthweight.J Paediatr Child Health. 2000; 36: 47-50Crossref PubMed Scopus (23) Google Scholar suggested an association between cerebral palsy and theophylline exposure, among children without severe sequel, those who had received theophylline achieved higher psychological test scores. The study of Tey et al7Tey S.L. Lee W.T. Lee P.L. Lu C.C. Chen H.L. Neurodevelopmental outcomes in very low birth weight infants using aminophylline for the treatment of apnea.Pediatr Neonatol. 2016; 57: 41-46Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar suggested that aminophylline therapy for apnea of prematurity had no apparent risk on the neurodevelopmental outcomes of very low birth weight infants at corrected age of 18 months. The results of this analysis may come as a relief for many neonatologists who still use aminophylline extensively for the treatment of apnea of prematurity. However, there are several limitations to this study. First, the retrospective nature of this analysis precluded conclusive elimination of aminophylline as a risk factor for poor neurological outcome. Second, the short outcome follow-up at 18 months of age may not accurately predict neurological function later in childhood. Finally, although this study enrolled premature babies of birth body weight of < 1500 g, the mean birth body weight (BBW) and GA of their participants were relatively high (mean BBW: 1219 g and GA: 29 weeks). Thus, whether their result may be applied to smaller premature infants with extreme low birth body weight remains doubtful. In conclusion, aminophylline/theophylline have been used extensively for the treatment of apnea of prematurity in Taiwan and many other Asian countries. Since so many highly vulnerable infants have been exposed regularly to these methylxanthines, there is a great need for more clinical trials with larger numbers of extremely low birth weight infants, to demonstrate the safety of aminophylline/theophylline treatment with respect to neurodevelopmental outcome. The author declares no conflicts of interest.