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Prophylactic methylxanthine for prevention of apnea in preterm infants

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Authors

David J Henderson-Smart1, Peter A Steer2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1NSW Centre for Perinatal Health Services Research, Queen Elizabeth II Research Institute, Sydney, Australia [top]
2Pediatrics, McMaster Children's Hospital, Hamilton, Canada [top]

Citation example: Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for prevention of apnea in preterm infants. Cochrane Database of Systematic Reviews 1999, Issue 2. Art. No.: CD000432. DOI: 10.1002/14651858.CD000432.

Contact person

David J Henderson-Smart

NSW Centre for Perinatal Health Services Research
Queen Elizabeth II Research Institute
Building DO2
University of Sydney
Sydney
NSW
2006
Australia

E-mail: dhs@mail.usyd.edu.au

Dates

Assessed as Up-to-date: 16 June 2008
Date of Search: 16 June 2008
Next Stage Expected: 16 August 2010
Protocol First Published: Issue 2, 1996
Review First Published: Issue 2, 1999
Last Citation Issue: Issue 2, 1999

What's new

Date / Event Description
24 June 2008
Updated

This review updates the existing review of 'Prophylactic methylxanthine for prevention of apnea in preterm infants' published in The Cochrane Database of Systematic Reviews, Disk Issue 2, 2006 (Henderson-Smart 2006).

Outcomes have been updated. A new trial (CAP TRIAL 2006; 'Studies awaiting classification') has been added.

History

Date / Event Description
17 January 2006
Updated

This review updates the existing review of 'Prophylactic methylxanthine for prevention of apnea in preterm infants' which was published in The Cochrane Library, Disk Issue 2, 2002.

The search strategy has been updated to include the databases, EMBASE and CINAHL. One new trial was identified as a result of the most recent search and was excluded.

Therefore, there is no change in the conclusion that there is no evidence from randomized trials to support the use of prophylactic caffeine in preterm infants at risk of apnea, bradycardia or hypoxemic episodes.

04 February 1999
New citation: conclusions changed

Substantive amendment

Abstract

Background

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. In infants with apnea, methylxanthines have been successful as treatment to prevent further episodes. It is possible that prophylactic therapy, given to all very preterm infants from soon after birth, might prevent apnea, its associated hypoxemia and bradycardia and need for added ventilatory support.

Objectives

To determine the effect of prophylactic treatment with methylxanthine on apnea, bradycardia, episodes of hypoxemia, use of mechanical ventilation, and morbidity in preterm infants at risk for apnea of prematurity

Search methods

The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2008), Oxford Database of Perinatal Trials, MEDLINE (1966 - June 2008), CINAHL (1982 - June 2008) and EMBASE (1988 - June 2008) using MeSH term infant-newborn, and text terms methylxanthines, caffeine, theophylline, apnea, and premature as well as a search of previous reviews including cross references, and conference proceedings including abstracts from the Society for Pediatric Research meeting 2001 - 2008.

Selection criteria

All trials utilising random or quasi-random patient allocation, in which prophylactic methylxanthine (caffeine or theophylline) was compared with placebo or no treatment were eligible. Outcomes sought included the rate of apnea, bradycardia, hypoxemic episodes, use of IPPV, morbidity and side effects such as tachycardia or feed intolerance, as well as longer term abnormal growth and development.

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed independently by each review author. Each review author extracted data separately, then results were compared and differences resolved. The standard method of the Cochrane Neonatal Review Group was used to analyze the data, utilizing relative risk (RR) and risk difference (RD) .

Results

Two studies examining a total of 104 infants were found. Both studied the effects of prophylactic caffeine. There were no meaningful differences between the caffeine and placebo groups in the number of infants with apnea, bradycardia, hypoxemic episodes, use of IPPV or side effects in either of the studies. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no substantive differences between the groups. One large trial (CAP Trial 2006) of caffeine therapy in a heterogeneous group of infants at risk for and having apnea of prematurity has demonstrated an improved rate of survival without developmental disability at 18 - 21 months of age and is awaiting assessment for inclusion in this review.

Authors' conclusions

The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnea, bradycardia or hypoxemic episodes.

Any future studies need to examine the effects of prophylactic methylxanthines in preterm infants at higher risk of apnea, bradycardia or hypoxemic episodes. This should include examination of important clinical outcomes such as need for IPPV, neonatal morbidity, length of hospital stay and long-term development. Much of this data will be available on further subgroup analysis of the Caffeine for Apnea of Prematurity Trial (CAP Trial 2006).

Plain language summary

Prophylactic methylxanthine for prevention of apnea in preterm infants

Based on the current trials, there is no evidence to show the benefit of using caffeine to prevent apnea in premature babies considered at risk.
Apnea is a pause in breathing of greater than 20 seconds. It may occur repeatedly in preterm babies (born before 34 weeks). Methylyxanthines (such as theophylline and caffeine) are drugs that are believed to stimulate breathing efforts and have been used to reduce apnea. It has been suggested that preterm babies with apnea should receive prophylactic caffeine (as a preventative measure). The review of trials found no evidence to support the use of prophylactic caffeine for preterm babies at risk of apnea.

One large trial of Caffeine therapy in a large heterogeneous group of infants who received therapy for prevention, treatment and avoidance of post-extubation apnea of prematurity, benefited from therapy during the neonatal period and in developmental outcome at 18-21 months. However, because of the heterogeneous nature of the population, it is not possible to specifically state that the infants at risk for apnea of prematurity benefited from prophylactic therapy and if so, how much benefit they received. This trial is awaiting further assessment.

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Background

Recurrent episodes of apnea are common in preterm infants and the incidence as well as the severity increase at lower gestational ages (Henderson-Smart 1995). Although apnea can occur spontaneously and be attributed to prematurity alone, it can also be provoked or made more severe if there is some additional insult such as infection, hypoxemia or intracranial pathology. The American Academy of Pediatrics defines infant apnea as a pause in breathing of greater than 20 seconds, or one of less than 20 seconds and associated with bradycardia and/or cyanosis (AAP 2003). The definition, diagnosis, and treatment (drugs and assisted ventilation therapy) of apnea of prematurity has been reviewed (Finer 2006). Finer et al (Finer 2006) review the clinical care and therapeutic research needs regarding apnea of prematurity.

If prolonged, apnea can lead to hypoxemia and reflex bradycardia which may require active resuscitative efforts to reverse. There are clinical concerns that these episodes might be harmful to the developing brain or cause dysfunction of the gut or other organs (reviewed by Henderson-Smart 1995). Frequent episodes may be accompanied by respiratory failure of sufficient severity as to lead to intubation and the use of intermittent positive pressure ventilation (IPPV).

Methylxanthines are thought to stimulate breathing efforts and have been used in clinical practice to reduce apnea since the 1970's. Theophylline and caffeine are two forms of methylxanthine that have been used and they are effective for the treatment of infants with recurrent apnea (Henderson-Smart 2008b). Their mechanism of action is not certain. Possibilities include increased chemoreceptor responsiveness (based on increased breathing responses to CO2), enhanced respiratory muscle performance and generalised central nervous system excitation.

In the treatment of apnea, caffeine has similar effects to theophylline (Steer 2005) but has potential therapeutic advantages due to the larger gap between therapeutic blood levels and those associated with toxic effects, more reliable enteral absorption and the longer half life which allows once daily administration (Blanchard 1992).

Objectives

To determine the effect of prophylactic treatment with methylxanthine on apnea, bradycardia, episodes of hypoxemia, use of mechanical ventilation, and morbidity in preterm infants at risk for apnea of prematurity.

To evaluate a difference in response depending on quality of the study, type (caffeine or theophylline) or dose of methylxanthine, gestational age at birth, postnatal age at study entry, or duration of treatment?

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Methods

Criteria for considering studies for this review

Types of studies

All trials utilising random or quasi-random patient allocation, in which treatment was compared with placebo or no treatment, were eligible.

Types of participants

Preterm infants, particularly those born at less than 34 weeks gestation, who are at risk of developing recurrent apnea, bradycardia and hypoxic episodes.

Types of interventions

Prophylactic methylxanthine (caffeine or theophylline) vs. placebo or no treatment.

Types of outcome measures

Primary
  1. Occurrence of recurrent apnea, bradycardia and hypoxemia
  2. Use of CPAP and/or IPPV
  3. Death before hospital discharge
Secondary
  1. Acute drug side effects (tachycardia or feed intolerance leading to omission of treatment)
  2. Neonatal morbidity such as - patent ductus arteriosus requiring treatment, intracranial hemorrhage, necrotizing enterocolitis
  3. Duration of IPPV
  4. Duration of oxygen therapy
  5. Chronic lung disease indicated by respiratory support (oxygen &/or positive airway pressure) still given at 36 weeks postmenstrual age
  6. Longer term outcomes, such as growth and neurodevelopmental outcome

Search methods for identification of studies

The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2008), Oxford Database of Perinatal Trials, MEDLINE (1966 - June 2008), CINAHL (1982 - June 2008) and EMBASE (1988 - June 2008) using MeSH term infant-newborn, and text terms methylxanthines, caffeine, theophylline, apnea, and premature as well as a search of previous reviews including cross references, and conference proceedings including abstracts from the Society for Pediatric Research meeting 2001 - 2008.

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed by the second author blinded to trial authors and institution(s). Additional information was supplied by Bucher 1988 to clarify methodology. The manuscript reporting the unpublished results of a trial were supplied by Levitt 1988.

Each review author extracted data separately, then results were compared and differences resolved. An outcome was analysed if there was more than 80% ascertainment.

The standard method of the Cochrane Neonatal Review Group was used to analyze the data, utilizing relative risk (RR) and risk difference (RD).

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Results

Description of studies

Details of the two included studies are in the Table Characteristics of Included Studies. One study, Larsen 1995, was excluded due to not having a control group.

Bucher 1988 studied preterm infants of less than 33 weeks gestation (mean about 30 weeks). Levitt 1988 entered infants of less than 31 weeks gestation (mean about 29 weeks).

Both studies used a loading dose of 20 mg/kg of caffeine citrate but Levitt 1988 used 5 mg/kg/day as maintenance, half that used in Bucher 1988. While in Levitt treatment was continued until the infants reached 32 weeks post menstrual age, only 96 hours of treatment was given in Bucher 1988.

Bucher 1988 did not report apnea; instead, he recorded episodes of bradycardia and hypoxemia, which often occur during apnea. These were obtained from a computerised record of heart rate (bradycardia = more than 20% fall in heart rate over 20 sec.) and transcutaneous oxygen tension (hypoxemia = more than 20% fall in oxygen over 20 seconds). Levitt 1988 used a combination of clinical and polygraphic studies to record apnea [apnea of more than 20 seconds with bradycardia (less than 100 bpm)].

A new trial (CAP Trial 2006) comparing caffeine vs. placebo and reports outcomes at discharge and infant follow-up awaiting assessment. Despite one indication for inclusion of participants being appropriate (prophylactic caffeine for apnea of prematurity), it cannot be included in the review because two other indications for inclusion in the trial were methylxanthine treatment for apnea of prematurity or prophylactic methylxanthines for extubation in preterm infants. In the publication, outcomes included a summary of all three indications for caffeine treatment.

Risk of bias in included studies

Both studies are generally of high quality except that follow-up was incomplete in Levitt 1988.

Effects of interventions

Two trials examining a total of 104 infants were found and both studied the effects of prophylactic caffeine. There were no differences between the caffeine and placebo groups in either of the studies in the number of infants with apnea, bradycardia, hypoxemic episodes, use of IPPV or side effects. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no significant differences between the treatment and placebo groups.

One trial reported follow-up of 30 (56%) of 54 infants (Levitt 1988). This was not only incomplete but was reported by apnea incidence rather than by trial treatment group.

Discussion

The total number of infants (104) studied in these two trials is small. As a result, only large differences (e.g. 50% relative risk reduction) could be detected, even for outcomes which are common, such as bradycardia (> 24 /day) and hypoxemic episodes (> 12 /day) where, in the study of Bucher 1988, there is more than 60% incidence in the control group.

Although no effect of caffeine used as prophylaxis was found here, methylxanthines, including caffeine, are effective in reducing apnea and the use of IPPV when used to treat infants with apnea (Henderson-Smart 2008b). Another review has suggested that methylxanthines prior to extubation might be of benefit in reducing the rate of respiratory failure, which is due in part to hypoventilation and apnea (Henderson-Smart 2008a).

It is possible that failure to observe an effect of prophylactic caffeine in the Bucher 1988 trial was due to measurement of hypoxemia and mild bradycardia as primary outcomes - events associated with apnea, rather than apnea itself. It could be argued that such events might be increased in the treatment group if caffeine increased arousal, movements and metabolic rate. This would minimise any differences due to a reduction in apnea, if that occurred. In the Levitt 1988 trial, however, the clinical events of apnea and bradycardia were recorded and no differences were found between infants who received prophylactic caffeine and those on placebo.

The trials in this review did not allow subgroup analyses to determine whether the results varied by the type (caffeine or theophylline) or dose of methylxanthine, gestational or postnatal age at study entry, or duration of treatment. A major concern is the small numbers in each study which, while adequate to show the large effect on apnea, would not be able to detect less common adverse effects.

Of particularly concern is the lack of trial data on long-term growth and development. The CAP Trial (CAP Trial 2006) has published outcomes at discharge and growth and development at 18 to 21 months. These results include a large number of very low birthweight infants (Caffeine group 1006, placebo group 1000) with any one of the three indications for trial entry (prophylaxic prevention of apnea in 22%, treatment of apnea in 40% or prophylaxis for extubation in 38%). At present, the results cannot be specifically applied to this review on prophylactic methylxanthine for apnea, although they do provide a generalized effect of caffeine indicating that there is improved outcome at discharge and in neurodevelopment at follow-up. There is improved rate of survival without developmental disability at 18-21 months of age (adjusted odds ratio 0.77, 95% CI, 0.64, 0.93). The CAP trial authors have been requested to evaluate outcomes for each indication which will make the trial eligible for inclusion in this review and also the other two Cochrane reviews dealing with the other two indications (Henderson-Smart 2006a; Henderson-Smart 2006) and allow for a more precise understanding of the effects in these related but different populations.

Authors' conclusions

Implications for practice

The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnea, bradycardia or hypoxemic episodes.

Implications for research

Any future studies should address the effects of prophylactic methylxanthines in preterm infants at higher risk of apnea, bradycardia or hypoxemic episodes, and possibly address the question of whether a higher dose of caffeine might be more effective. This should include examination of important clinical outcomes such as need for IPPV, length of hospital stay and long term development. Much of this data may be available from further analysis of the CAP Trial (CAP Trial 2006),

Acknowledgements

Thanks to Dr Levitt for a copy of her unpublished paper and to Prof. Bucher for additional information about his study.

Contributions of authors

The initial protocol and review were developed by Henderson-Smart and Steer. This update was done by Henderson-Smart and approved by Steer.

Differences between protocol and review

This review update has increased the range of outcomes.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Bucher 1988

Methods

Concealment of randomization - yes; blinding of intervention - yes; follow up complete; blinding of outcome assessment - yes.

Participants

50 preterm infants < 33 weeks gestation (stratified into those born at 26-29, 30-32 weeks), 48 hrs old, spontaneous breathing for 24 hrs, in a single centre.

Interventions

Caffeine citrate 20 mg/kg load at 48 hrs and 10 mg/kg at 72 and 96 hrs of age. Total duration of study period 96hrs.
Saline placebo

Outcomes

Polygraph recording of bradycardia (>20% fall in heart rate over 20 sec); hypoxemic episodes (> 20% decrease over 20 sec); use of IPPV; tachycardia

Notes
Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Levitt 1988

Methods

Concealment of randomization - yes (off site in pharmacy); blinding of intervention - yes ; follow up 96% for apnea; blinding of outcome assessment - yes.

Participants

54 preterm infants born at < 31 weeks, ventilatory support discontinued by one week.
Exclusions - major congenital abnormality, intraventricular hemorrhage, congestive heart failure, metabolic disorder, septicemia.

Interventions

Caffeine citrate 20 mg/kg load and 5 mg/kg/day until 32 weeks post menstrual age.
Saline placebo

Outcomes

Apnea >20 sec with bradycardia (< 100 bpm) or cyanosis, use of IPPV, withdrawal for definitive caffeine treatment (open label), tachycardia, hyponatremia.

Notes

30 of 54 (56%) followed up to 16-36 months for neurodevelopmental assessment. Not reported by treatment group.

Risk of bias table
Item Judgement Description
Allocation concealment? Yes

A - Adequate

Characteristics of excluded studies

Larsen 1995

Reason for exclusion

This trial compared aminophyilline with caffeine citrate without a control group

Characteristics of studies awaiting classification

CAP Trial 2006

Methods

Concealment of randomization - yes (off site in pharmacy); blinding of intervention - yes ; follow up 96% for apnea; blinding of outcome assessment - yes.

Participants

2006 infants with birth weights of 500 to 1250 g during the
first 10 days of life who entered the trial because they were to given prophylactic therapy to prevent apnea, treatment of recurrent apnea

Interventions

Caffeine 20 mg per Kg (1006 infants) vs placebo of noemal saline (1000 infants)

Outcomes

The primary outcome of this study is a composite of death, cerebral palsy, cognitive delay, deafness, or blindness at a corrected age of 18 to 21 months. Short-term outcomes after the completion of recruitment and the initial hospitalization of the study infants, including bronchopulmonary
dysplasia, ultrasonographic signs of brain injury, necrotizing enterocolitis, retinopathy of prematurity, and growth.

Notes

Birth characterists of mothers and infants in the caffeine and pacebo grops were similar. Antenatal corticosteroids 88% vs 87%, chorioaminonitis 14% vs 13%, cesarian section 62% vs 63%.

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References to studies

Included studies

Bucher 1988

Published and unpublished data

Bucher HU, Duc G. Does caffeine prevent hypoxaemic episodes in premature infants? A randomized controlled trial. European Journal of Pediatrics 1988;147:288-91.

Levitt 1988

Published and unpublished data

Levitt GA, Harvey DR. The use of prophylactic caffeine in the prevention of neonatal apnoeic attacks. Unpublished manuscript.

Levitt GA, Mushin A, Bellman S, Harvey DR. Outcome of preterm infants who suffered neonatal apnoeic attacks. Early Human Development 1988;16:235-43.

Excluded studies

Larsen 1995

Larsen PB, Brendstrup L, Skov L, Flachs H. Aminophylline versus caffeine citrate for apnea and bradycardia prophylaxis in premature neonates. Acta Paediatrica 1995;84:360-4.

Studies awaiting classification

CAP Trial 2006

Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A., Solimano A, Tin W, for Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. New England Journal of Medicine 2006;354:2179-81.

Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, for Caffeine for Apnea of Prematurity Trial Group. Effects of caffeine therapy for apnea of prematurity. New England Journal of Medicine 2007;357:1893-1902.

Ongoing studies

Other references

Additional references

AAP 2003

American Academy of Pediatrics. Policy statement. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 2003;111:914-22.

Blanchard 1992

Blanchard PW, Aranda JV. Pharmacotherapy of respiratory control disorders. In: Beckerman RC, Brouillette RT, Hunt CE, editor(s). Respiratory Control Disorders in Infants and Children. Baltimore: Williams & Wilkins, 1992:352-70.

Finer 2006

Finer NN, Higgins R, Kattwinkel J, Martin RJ. Summary proceedings from the apnea-of-prematurity group. Pediatrics 2006;117 Pt 2:S47-51.

Henderson-Smart 1995

Henderson-Smart DJ. Recurrent apnea. In: Yu VYH, editor(s). Bailliere's Clinical Paediatrics. Vol. 3, No. 1 Pulmonary Problems in the Perinatal Period and their Sequelae. London: Bailliere Tindall, 1995:203-22.

Henderson-Smart 2008a

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthine for extubation in preterm infants. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD000139. DOI: 10.1002/14651858.CD000139.

Henderson-Smart 2008b

Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD000140. DOI: 10.1002/14651858.CD000140.

Samuels 1992

Samuels MP, Southall DP. Recurrent Apnea. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:385-97.

Steer 2005

Steer P, Henderson-Smart DJ. Caffeine vs theophylline treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD000273. DOI: 10.1002/14651858.CD000273.

Other published versions of this review

Henderson-Smart 1999

Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for prevention of apnea in preterm infants. Cochrane Database of Systematic Reviews 1999, Issue 2. Art. No.: CD000432. DOI: 10.1002/14651858.CD000432.

Henderson-Smart 2002

Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for prevention of apnea in preterm infants. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD000432. DOI: 10.1002/14651858.CD000432.

Henderson-Smart 2006

Henderson-Smart DJ, Steer PA. Cochrane Database of Systematic Reviews. Prophylactic methylxanthine for prevention of apnea in preterm infants. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD000432. DOI: 10.1002/14651858.CD000432.

Classification pending references

  • None noted.

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Data and analyses

1 All infants

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Apnea (more than 4/day) 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.52, 1.45]
1.2 Apnea (more than 10/day) 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.49, 1.50]
1.3 Bradycardia (more than 12/day) 1 50 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.4 Bradycardia (more than 24/day) 1 50 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.84, 1.64]
1.5 Hypoxemic episodes (more than 12/day) 1 50 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.89, 1.51]
1.6 Withdrawal for definitive caffeine treatment 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.40, 1.96]
1.7 Use of IPPV 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.15, 2.36]
1.8 Tachycardia 2 104 Risk Ratio (M-H, Fixed, 95% CI) 4.00 [0.48, 33.50]
1.9 Hyponatremia 1 54 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [0.80, 3.68]

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Sources of support

Internal sources

  • NSW Centre for Perinatal Health Services Research, University of Sydney, Australia
  • Mater Children's Hospital, Brisbane, Australia
  • Royal Prince Alfred Hospital, Sydney, Australia
  • Pediatrics, McMaster Children's Hospital, Hamilton, Canada

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2008 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent recent version of the review.