|Year : 2019 | Volume
| Issue : 3 | Page : 162-165
Caffeine use for apnea of prematurity in moderate and late preterm infants: A systematic review
Mohammed Bahari1, Jose Carlos Aldana1, Robin Featherstone2, Manoj Kumar1
1 Department of Pediatrics, University of Alberta, Edmonton, Canada
2 Alberta Research Centre for Health Evidence, Alberta SPOR SUPPORT Unit Knowledge Translation Platform, University of Alberta, Edmonton, Canada
|Date of Web Publication||6-Aug-2019|
Dr. Manoj Kumar
Department of Pediatrics, University of Alberta, Edmonton, T5H 3V9
Source of Support: None, Conflict of Interest: None
Objective: The objective is to perform a systemic review of the literature on the use of caffeine for the management of apnea of prematurity (AOP) in moderate and late preterm infants. Data Sources: In May 2016, we searched the following databases from the beginning of the year 1980: Medline, Embase, CENTRAL, CINAHL, ProQuest Dissertations and theses Global, and PubMed. Additional citations were searched in the clinical trial registries and from the bibliography of the selected articles. We updated our search in May 2018 to identify any new citations. Methods: Studies were included if they were randomized controlled trials (RCTs) involving preterm infants ≥32 weeks gestation and compared caffeine with placebo, reporting any of the prespecified clinical outcomes. Search strategies combined controlled vocabulary and keywords terms for apnea, caffeine, and preterm infants. No language restriction was applied. Two researchers independently reviewed the retrieved articles for inclusion. Disagreements were resolved by consensus among the review team. Results: The search strategy identified 839 citations after removing duplicates. We did not identify any published RCT that described the use of caffeine for AOP in moderate to late preterm infants. The updated search also did not identify an RCT. Conclusions: There is a lack of good quality evidence for the use of caffeine for the management of AOP in moderate and late preterm infants. An RCT is urgently needed to investigate the clinical benefits of caffeine use in this population and the potential savings in health-care resource utilization.
Keywords: Apnea, caffeine, infant, intensive care units, neonatal, neonatology, premature
|How to cite this article:|
Bahari M, Aldana JC, Featherstone R, Kumar M. Caffeine use for apnea of prematurity in moderate and late preterm infants: A systematic review. J Clin Neonatol 2019;8:162-5
|How to cite this URL:|
Bahari M, Aldana JC, Featherstone R, Kumar M. Caffeine use for apnea of prematurity in moderate and late preterm infants: A systematic review. J Clin Neonatol [serial online] 2019 [cited 2020 Jan 17];8:162-5. Available from: http://www.jcnonweb.com/text.asp?2019/8/3/162/264037
| Introduction|| |
Apnea of prematurity (AOP) is common in premature infants. The improved survival of the premature infants over the past few decades has led to an increased incidence of the prematurity-associated morbidities, including the AOP. The AOP often leads to the need for respiratory support and in-hospital continuous cardiorespiratory monitoring in this population, often resulting in a longer hospital stay and a significant increase in health-care costs.,
In the past 40 years, there has been abundant research into drugs for the management of AOP.,, Caffeine, a methylxanthine derivative, has been used in the neonatal intensive care units (NICU) to treat AOP since the mid-seventies.,,,, Over the years, it has nearly replaced theophylline for this indication as it is considered to be safer than theophylline, due to its higher therapeutic index and it being a more potent stimulant for the respiratory center. The caffeine for apnea of prematurity (CAP) trial demonstrated the effectiveness of caffeine in treating apnea in extremely preterm infants, in terms of lesser duration of ventilator and oxygen dependency, and a better disability-free survival. The CAP trial also showed a significant benefit in the caffeine group in terms of motor skills compared with the placebo group at the age of 11 years.
Caffeine is a relatively inexpensive drug., While the AOP is less likely to occur in moderate and late preterm infants (and less likely to be associated with the type of clinical benefits described in the CAP trial participants), its occurrence in this population is still associated with an increase in the length of hospital stay and the hospital costs. In the United States, over 300,000 infants born late preterm, and up to 12% of them have apnea during their initial hospital course. In an economic evaluation simulation that compared two groups of late-preterm infants with ongoing AOP, one discharged home on caffeine treatment and the other group observed in the hospital without initiating caffeine until the apnea resolved, showed that the use of caffeine in this population would reduce health-care costs. This study estimated that inpatient hospital costs due to the delay in discharge to the home could be as high as USD 2422 in this population. Despite the significant use of health-care resources associated with the management of the AOP in the late-preterm infants, there is limited use of caffeine in clinical practice for this population.
Our objective was to perform a systematic review of the randomized controlled trials (RCTs) on the use of caffeine in the management of AOP in moderate and late-preterm infants.
| Methods|| |
An initial electronic search was conducted in May 2016. The following database was searched: Ovid Medline, Ovid Embase, CENTRAL through Cochrane library, CINAHL Plus with Full Text through EBSCOhost, ProQuest Dissertations and theses Global, and PubMed. Search strategies combined controlled vocabulary (e.g., Medical Subject Headings) and keywords (title and abstract) terms for apnea, caffeine, and preterm infants. Searches also employed study design filters for RCTs and a date range limit from the beginning of 1980. Supplemental searches were conducted for trial registry records in ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform, and proceedings from the Society for Pediatric Research and the European Society for Pediatric Research for abstracts (2011–2016). No language restriction was applied. Bibliography of retrieved full-text articles was searched for additional studies. An updated search was conducted in May 2018 to identify additional articles during the intervening period, using the same search strategy as described above. The complete search strategy is discussed in Appendix 1.
Studies were eligible for inclusion if they were RCTs comparing caffeine use with placebo (or no intervention) in moderate (gestation at birth between ≥32 and <34 weeks) and/or late preterm infants (gestation at birth between ≥34 and <37 weeks) for the clinical outcomes. Clinical outcomes of interest were as follows: the need for respiratory support in the NICU, duration of respiratory support, length of hospital stay, corrected gestation age at discharge to home, and any significant side effects noted. We excluded studies that described their population based on the birth weight alone without providing birth gestation of the individuals enrolled. We also excluded studies where some enrolled infants may have been moderate or late preterm infants if the authors could not provide us with separate data for this population for our analysis.
Articles were reviewed independently by two researchers (MB and JA). The initial screening was based on the title and the abstracts of the retrieved citations. When it was not possible to ascertain the inclusion or exclusion of an article from this step, the article was assessed in full text. Disagreements between the reviewers were resolved with the help of the third reviewer (MK). The process involved a discussion among the review team to reach a final decision by consensus.
We planned to extract data from the included trials into an electronic spreadsheet. The data were to be extracted into an excel spreadsheet by one reviewer (MB) and checked for accuracy by the second reviewer (JA). Disagreements between these reviewers were to be resolved by discussion and consensus with the help of the third reviewer (MK).
Assessment of bias
We planned to assess the methodological quality of the included trials as per the Cochrane risk-of-bias tool, This 6-item tool includes items for the adequacy of random sequence generation, allocation concealment, blinding, loss to follow-up, selective reporting, or other biases. Discrepancies were resolved by discussion and consensus.
We planned to pool the data from the identified studies for meta-analyses, using random-effects model. For the testing of heterogeneity of effects between studies, we planned to use Cochran Chi-square (Cochran Q) test. We planned to assess for publication bias by reviewing the funnel plots of the results from the individual studies.
No ethical approval was required for this study.
| Results|| |
The initial search identified 839 citations after removing the duplicates. Thirty-two studies were assessed in the full text. [Figure 1] shows the flow of the studies through this systematic review. We did not find any RCT that met the eligibility criteria for inclusion into the systematic review. [Supplementary Table 1] presents the 32 articles that were assessed in full text along with the reasons for their exclusion.
|Figure 1: Flow chart demonstrating the process of articles review and exclusion|
Click here to view
The updated search in May 2018 identified an additional 101 citations after removing of the duplicates. However, no new RCT was identified that met the eligibility criteria for inclusion in the systematic review.
| Discussion|| |
We conducted a systematic review of literature to identify RCTs of caffeine use in moderate and late premature infants for the management of AOP. We did not find any RCT that provided data for the use of Caffeine in moderate and late premature infants. It is unlikely that we missed any relevant study as our search strategy, undertaken with the help of a research librarian, was comprehensive and involved several electronic databases.
Our review shows that there is a lack of high-quality evidence for the use of caffeine in moderate to late premature infants. The majority of the studies identified through this review process were focused on premature infants with <32 weeks of gestation at birth or very low birth weight (VLBW) infants. The development of apnea in these infants was associated with increased length of stay, increased healthcare costs,,,, and increased parental anxiety and interference with bonding and establishment of breastfeeding.,,
Early caffeine use has been proven to be safe and effective for the management of apnea in very premature or VLBW infants, along with documented long-term benefits in terms of neurodevelopmental outcomes. Based on those data, we believe that there could be likely benefits from caffeine use in moderate and late preterm infants for prevention or treatment of AOP, without significant associated risks.
While we could not find any RCT that answered to our review question, we identified an ongoing clinical trial that would assess the use of Caffeine in late preterm and term infants for early discharge from the hospital (ClinicalTrials.gov/show/NCT02408328). According to the study protocol, the investigators will enroll late preterm (≥34weeks of gestation) and term infants with AOP for randomization. The intervention group will receive Caffeine and will be discharged home early with an apnea monitor, whereas the infants in the control group, which will remain in hospital under observation until their apnea resolve. The outcomes of interest listed for this trial are significant respiratory events, parents' quality of life, and hospital stay.
We want to incite an often-quoted medical maxim “absence of evidence does not necessarily constitute evidence of absence of effect,” to put the finding of this review in perspective. Given the potential benefits of Caffeine use in moderate and late preterm infants, there is a clear need for RCTs in this population, both as prophylaxis and for the treatment of AOP in this population. These studies could consider targeting all infants or restrict enrolment to infants that require respiratory support at onset. Some of the suggested outcomes of interest in the future studies are the need for invasive and noninvasive ventilation, duration of ventilation, need for supplemental oxygen and its duration, postmenstrual age (PMA) for the last significant apnea episode, PMA for discharge home, length of hospital stay, the cost of hospital stay, and the readmission rate in the neonatal period.
Our systematic review has a few limitations. There were a few studies that enrolled some moderate and late preterm infants along with very preterm infants or tested Caffeine use after 32 weeks gestation; however, the data were not separately available for the targeted population. We tried contacting primary authors of those studies to see if they could provide us with the desired data, but met with no success., Similarly, many of the studies that were reviewed in full-text enrolled patients according to a specific birth weight cut off.,,,,,,, Although the mean gestation of the infants enrolled in these trials was <32 weeks, it is possible that some of the individuals enrolled in these trials could be moderate and late preterm infants.
| Conclusions|| |
There is a lack of good quality evidence for the efficacy of the use of caffeine in moderate to late preterm infants despite the significant impact of their admissions on the intensive care resources. There is an urgent need for adequately powered clinical trials of caffeine use in this population for clinically relevant outcomes, as suggested above.
This work was supported by the Alberta Strategy for Patient-Oriented Research (SPOR) SUPPORT Unit Knowledge Translation Platform, which is funded by Alberta Innovates and the Canadian Institutes of Health Research. This work was funded by the Women and Children's Health Research Institute (WCHRI) through the generous support of the Stollery Children's Hospital Foundation.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hascoet JM, Hamon I, Boutroy MJ. Risks and benefits of therapies for apnoea in premature infants. Drug Saf 2000;23:363-79.
Montenegro BL, Amberson M, Veit L, Freiberger C, Dukhovny D, Rhein LM. Economics of home monitoring for apnea in late preterm infants. Respir Care 2017;62:42-8.
Aujard Y. Caffeine in the treatment of apnea in premature infants. Arch Fr Pediatr 1990;47:763.
Alpan G, Eyal F, Sagi E, Springer C, Patz D, Goder K. Doxapram in the treatment of idiopathic apnea of prematurity unresponsive to aminophylline. J Pediatr 1984;104:634-7.
Yamazaki T, Kajiwara M, Itahashi K, Fujimura M. Low-dose doxapram therapy for idiopathic apnea of prematurity. Pediatr Int 2001;43:124-7.
Aranda JV, Canal D, Beharry KD, Valencia GB. Caffeine, the magic bullet in neonatology. J Matern Fetal Neonatal Med 2012;25:1.
Kreutzer K, Bassler D. Caffeine for apnea of prematurity: A neonatal success story. Neonatology 2014;105:332-6.
Abdel-Hady H, Nasef N, Shabaan AE, Nour I. Caffeine therapy in preterm infants. World J Clin Pediatr 2015;4:81-93.
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al.
Caffeine therapy for apnea of prematurity. N
Engl J Med 2006;354:2112-21.
Schmidt B, Roberts RS, Anderson PJ, Asztalos EV, Costantini L, Davis PG, et al.
Academic performance, motor function, and behavior 11 years after neonatal caffeine citrate therapy for apnea of prematurity: An 11-year follow-up of the CAP randomized clinical trial. JAMA Pediatr 2017;171:564-72.
Dukhovny D, Lorch SA, Schmidt B, Doyle LW, Kok JH, Roberts RS, et al.
Economic evaluation of caffeine for apnea of prematurity. Pediatrics 2011;127:e146-55.
Johnston KM, Gooch K, Korol E, Vo P, Eyawo O, Bradt P, et al.
The economic burden of prematurity in Canada. BMC Pediatr 2014;14:93.
Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. Ver. 5.1.0. The Cochrane Collaboration; 2011. Available from: http://www.handbook.cochrane.org
. [Last accessed on 2019 Jun 25].
Russell GA, Cooke RW. Randomised controlled trial of allopurinol prophylaxis in very preterm infants. Arch Dis Child Fetal Neonatal Ed 1995;73:F27-31.
Gilbert WM, Nesbitt TS, Danielsen B. The cost of prematurity: Quantification by gestational age and birth weight. Obstet Gynecol 2003;102:488-92.
Rhein L, Dobson N, Darnall R, Corwin M, Heeren T, McEntire B. Extended use of caffeine decreases intermittent hypoxia in preterm infants. In: Proceedings of the Pediatric Academic Societies (PAS) 2013 Annual Meeting; 2013 May 4-7; Washington DC. Itasca, IL: American Academy of Pediatrics; 2013. Available from: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-00998040/full
. [Last accessed on 2019 Jul 12].
Faramarzi F, Shiran M, Rafati M, Farhadi R, Salehifar E, Nakhshab M. The efficacy and safety of two different doses of caffeine in respiratory function of preterm infants. Caspian J Intern Med 2018;9:46-53.
Cherif A, Klouz A, Zouari B, Belkahia C, Boukef-Larguèche S. Monohydrated caffeine: Which dosage is effective in the treatment of apnea of prematurity? Arch Pediatr 2003;10:734-5.
Fuglsang G, Nielsen K, Kjaer Nielsen L, Sennels F, Jakobsen P, Thelle T. The effect of caffeine compared with theophylline in the treatment of idiopathic apnea in premature infants. Acta Paediatr Scand 1989;78:786-8.
Patel RM, Leong T, Carlton DP, Vyas-Read S. Early caffeine therapy and clinical outcomes in extremely preterm infants. J Perinatol 2013;33:134-40.
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al
. Caffeine for apnea of prematurity trial group. long-term effects of caffeine therapy for apnea of prematurity. N
Engl J Med 2007;357:1893-902.
Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau R, Asztalos E, et al
. The caffeine for apnea of prematurity (CAP) trial: Outcomes at 5 years. Paediatr Child Health 2011;16:11A.
Schmidt B, Davis PG, Roberts RS. Timing of caffeine therapy in very low birth weight infants. J Pediatr 2014;164:957-8.