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Review
. 2023 Oct 4;10(10):CD015462.
doi: 10.1002/14651858.CD015462.pub2.

Caffeine versus other methylxanthines for the prevention and treatment of apnea in preterm infants

Luca Moresco #  1 , Alice Sjögren #  2 , Keri A Marques  3 , Roger Soll  4 , Matteo Bruschettini  5   6
Affiliations
Review

Caffeine versus other methylxanthines for the prevention and treatment of apnea in preterm infants

Luca Moresco et al. Cochrane Database Syst Rev. .

Abstract

Background: Methylxanthines, including caffeine, theophylline, and aminophylline, work as stimulants of the respiratory drive, and decrease apnea of prematurity, a developmental disorder common in preterm infants. In particular, caffeine has been reported to improve important clinical outcomes, including bronchopulmonary dysplasia (BPD) and neurodevelopmental disability. However, there is uncertainty regarding the efficacy of caffeine compared to other methylxanthines.

Objectives: To assess the effects of caffeine compared to aminophylline or theophylline in preterm infants at risk of apnea, with apnea, or in the peri-extubation phase.

Search methods: We searched CENTRAL, MEDLINE, Embase, Epistemonikos, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in February 2023. We also checked the reference lists of relevant articles to identify additional studies.

Selection criteria: Studies: randomized controlled trials (RCTs) and quasi-RCTs Participants: infants born before 34 weeks of gestation for prevention and extubation trials, and infants born before 37 weeks of gestation for treatment trials Intervention and comparison: caffeine versus theophylline or caffeine versus aminophylline. We included all doses and duration of treatment.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR), risk difference (RD), and 95% confidence intervals (CI) for categorical data, and mean, standard deviation, and mean difference for continuous data. We used the GRADE approach to evaluate the certainty of evidence.

Main results: We included 22 trials enrolling 1776 preterm infants. The indication for treatment was prevention of apnea in three studies, treatment of apnea in 13 studies, and extubation management in three studies. In three studies, there were multiple indications for treatment, and in one study, the indication for treatment was unclear. In 19 included studies, the infants had a mean gestational age between 28 and 32 weeks and a mean birth weight between 1000 g and 1500 g. One study's participants had a mean gestational age of more than 32 weeks, and two studies had participants with a mean birth weight of 1500 g or more. Caffeine administrated for any indication may result in little to no difference in all-cause mortality prior to hospital discharge compared to other methylxanthines (RR 1.12, 95% CI 0.68 to 1.84; RD 0.02, 95% CI -0.05 to 0.08; 2 studies, 396 infants; low-certainty evidence). Only one study enrolling 79 infants reported components of the outcome moderate to severe neurodevelopmental disability at 18 to 26 months. The evidence is very uncertain about the effect of caffeine on cognitive developmental delay compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.37; RD -0.12, 95% CI -0.24 to 0.01; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on language developmental delay compared to other methylxanthines (RR 0.76, 95% CI 0.37 to 1.58; RD -0.07, 95% CI -0.27 to 0.12; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on motor developmental delay compared to other methylxanthines (RR 0.50, 95% CI 0.13 to 1.96; RD -0.07, 95% CI -0.21 to 0.07; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on visual and hearing impairment compared to other methylxanthines. At 24 months of age, visual impairment was seen in 8 out of 11 infants and 10 out of 11 infants in the caffeine and other methylxanthines groups, respectively. Hearing impairment was seen in 2 out of 5 infants and 1 out of 1 infant in the caffeine and other methylxanthines groups, respectively. No studies reported the outcomes cerebral palsy, gross motor disability, and mental development. Compared to other methylxanthines, caffeine may result in little to no difference in BPD/chronic lung disease, defined as 28 days of oxygen exposure at 36 weeks' postmenstrual age (RR 1.40, 95% CI 0.92 to 2.11; RD 0.04, 95% CI -0.01 to 0.09; 3 studies, 481 infants; low-certainty evidence). The evidence is very uncertain about the effect of caffeine on side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of methylxanthines compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.32; RD -0.29, 95% CI -0.57 to -0.02; 1 study, 30 infants; very low-certainty evidence). Caffeine may result in little to no difference in duration of hospital stay compared to other methylxanthines (median (interquartile range): caffeine 43 days (27.5 to 61.5); other methylxanthines 39 days (28 to 55)). No studies reported the outcome seizures.

Authors' conclusions: Although caffeine has been shown to improve important clinical outcomes, in the few studies that compared caffeine to other methylxanthines, there might be little to no difference in mortality, bronchopulmonary dysplasia, and duration of hospital stay. The evidence is very uncertain about the effect of caffeine compared to other methylxanthines on long-term development and side effects. Although caffeine or other methylxanthines are widely used in preterm infants, there is little direct evidence to support the choice of which methylxanthine to use. More research is needed, especially on extremely preterm infants born before 28 weeks of gestation. Data from four ongoing studies might provide more evidence on the effects of caffeine or other methylxanthines.

PubMed Disclaimer

Conflict of interest statement

LM has no interest to declare.

AS has no interest to declare.

KM has no interest to declare.

RS is Co‐ordinating Editor of Cochrane Neonatal Group but did not participate in the editorial assessment of this review. RS has a grant from the Gerber Foundation to update reviews on interventions for pain and discomfort.

MB is an Associate Editor with Cochrane Neonatal Group, but did not participate in the editorial assessment of this review.

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 1: All‐cause mortality prior to hospital discharge
1.2
1.2. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 2: Moderate to severe neurodevelopmental disability at 18 to 26 months ‐ developmental delay more than two SDs below population mean on a standardized test of development: cognitive
1.3
1.3. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 3: Moderate to severe neurodevelopmental disability at 18 to 26 months ‐ developmental delay more than two SDs below population mean on a standardized test of development: language
1.4
1.4. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 4: Moderate to severe neurodevelopmental disability at 18 to 26 months ‐ developmental delay more than two SDs below population mean on a standardized test of development: motor
1.5
1.5. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 5: Bronchopulmonary dysplasia/chronic lung disease: defined as 28 days of oxygen exposure at 36 weeks' postmenstrual age
1.6
1.6. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 6: Side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of methylxanthines
1.7
1.7. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 7: Failure to extubate within one week of commencing treatment
1.8
1.8. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 8: Failed apnea reduction after two to seven days (less than 50% reduction in apnea), for infants treated for apnea
1.9
1.9. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 9: Apnea: number of episodes (defined as interruption of breathing for more than 20 seconds) after 24 hours from commencing treatment over a 24‐hour period
1.10
1.10. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 10: Apnea: number of episodes (defined as interruption of breathing for more than 20 seconds) after one week
1.11
1.11. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 11: Apnea: number of infants with at least one episode (defined as interruption of breathing for more than 20 seconds) after 24 hours of commencing treatment after one week
1.12
1.12. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 12: Number of days of respiratory support (mechanical ventilation; continuous positive airway pressure [CPAP]; high‐flow nasal cannula; non‐invasive positive‐pressure ventilation [NIPPV])
1.13
1.13. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 13: Number of days of supplemental oxygen
1.14
1.14. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 14: Intraventricular hemorrhage on brain ultrasound (any; and severe [Papile grade 3 to 4])
1.15
1.15. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 15: Periventricular leukomalacia
1.16
1.16. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 16: Necrotizing enterocolitis (proven = Bell stage 2 or greater)
1.17
1.17. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 17: Patent ductus arteriosus (PDA) requiring treatment (cyclo‐oxygenase inhibitors or surgical ligation)
1.18
1.18. Analysis
Comparison 1: Caffeine versus other methylxanthines, Outcome 18: Retinopathy of prematurity (ROP) (any ROP; and severe ROP [stage 3 or greater])
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Shivakumar 2017a {published data only}
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    1. Khurana S, Shivakumar M, Sujith Kumar Reddy GV, Jayashree P, Ramesh Bhat Y, Lewis LE. Long-term neurodevelopment outcome of caffeine versus aminophylline therapy for apnea of prematurity. Journal of Neonatal-Perinatal Medicine 2017;10(4):355-62. [DOI: 10.3233/NPM-16147] [PMID: ] - DOI - PubMed
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    1. CTRI/2012/08/002904. A clinical trial to study the effect of two drugs, caffeine & aminophylline in preterm babies with cessation of breathing due to prematurity. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2012/08/002904 (first received 22 August 2012).
    1. Shivakumar M, Najih M, Bhat YR, Jayashree P, Lewis LE, Kamath A, et al. Prophylactic methylxanthines for preventing extubation failure in the preterm neonates with the gestational age of ≤30 weeks: a randomized controlled trial. Iranian Journal of Neonatology 2017;8(3):11-18. [DOI: 10.22038/ijn.2017.23031.1281] [EMBASE: L618446599] - DOI
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References to studies excluded from this review

Armanian 2016 {published data only}
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References to studies awaiting assessment

Bairam 1986 {published data only}
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References to ongoing studies

CTRI/2015/06/005904 {published data only}
    1. CTRI/2015/06/005904. Setting of appropriate dosage and comparing the effectiveness of caffeine and aminophylline in premature babies with pause of breathing for 15 to 20 seconds [Population pharmacokinetic and pharmacodynamic study of aminophylline and caffeine in premature newborns with Apnea]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2015/06/005904 (first received 10 June 2015). [CENTRAL: CN-01884087]
CTRI/2018/05/014329 {published data only}
    1. CTRI/2018/05/014329. Study to compare caffeine and aminophylline in the management of apnea of prematurity [Comparative study to evaluate efficacy and adverse effects of caffeine and aminophylline in the management of apnea of prematurity]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/05/014329 (first received 31 May 2018). [CENTRAL: CN-01905078]
DRKS00020404 {published data only}
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References to other published versions of this review

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