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Doxapram versus methylxanthine for 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]
2School of Medicine, Faculty of Health Sciences, University of Queensland, Children's Health Services District, Queensland Health, Brisbane, Australia [top]

Citation example: Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD000075. DOI: 10.1002/14651858.CD000075.

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: 08 February 2010
Date of Search: 08 February 2010
Next Stage Expected: 08 February 2012
Protocol First Published: Issue 2, 1996
Review First Published: Issue 3, 1997
Last Citation Issue: Issue 4, 2000

What's new

Date / Event Description
11 March 2010
Updated

This updates the review "Doxapram versus methylxanthine for apnea in preterm infants" (Henderson-Smart 2000).

One new trial has been added.

No change to conclusions.

History

Date / Event Description
08 February 2010
Amended

Converted to new review format.

27 April 2009
Updated

Updated with one new included studiy and no change in conclusion.

14 May 2007
Updated

This updates the review "Methylxanthine treatment for apnea in preterm infants" published in the Cochrane Database of Systematic Reviews, Issue 4, 2000 (Henderson-Smart 2004).

No new trials have been included and the conclusions are unchanged.

Two trials are awaiting assessment:
Moeller 1999 requires more data from the author.
Wang 2000 requires translation from Chinese and author clarification.

03 August 2000
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. Doxapram and methylxanthine drugs have been used to stimulate breathing and thereby prevent apnea and its consequences.

Objectives

To assess the effects of doxapram compared with methylxanthine in preterm infants with recurrent apnea.

Search methods

The Cochrane Collaboration Clinical Trials Register, MEDLINE, EMBASE and CINAHL, reference lists of relevant articles and conference proceedings. Search updated in February 2010.

Selection criteria

Randomised and quasi-randomised trials of doxapram compared with methylxanthine (e.g. theophylline, aminophylline or caffeine) for the treatment of apnea in preterm infants.

Data collection and analysis

The methodological quality of each trial was reviewed by the two reviewer trial authors. Additional information was requested from authors. Each reviewer extracted the data separately, then they were compared and differences resolved. Meta-analysis was carried out with use of relative risk and risk difference.

Results

Four trials involving 91 infants were included. No difference was detected between intravenous doxapram or methylxanthine in the incidence of failed treatment within 48 hours [typical relative risk 0.91, 95% confidence interval (95% CI) 0.45, 1.85]. Only one trial reported results at 7 days and there was no difference in results. No infants were reported to have been given mechanical ventilation on either treatment. No adverse effects were reported.

Authors' conclusions

Intravenous doxapram and intravenous methylxanthine appear to be similar in their short term effects for treating apnea in preterm infants, although these trials are too small to exclude an important difference between the two treatments or to exclude the possibility of less common adverse effects. Long term outcome of infants treated in these trials has not been reported. Further studies would require a large number of infants to clarify whether there might be differences in responses or adverse effects with these two drugs at different ages.

Plain language summary

Doxapram versus methylxanthine for apnea in preterm infants

Doxapram and methylxanthine stimulate breathing in infants with apnea. Infant apnea is a pause in breathing of greater than 20 seconds. This can be harmful to the developing brain and cause dysfunction of the gastrointestinal tract or other organs. Drugs such as doxapram and methylxanthine are thought to stimulate breathing and are given to reduce apnea. The review of four small trials found that there was no large difference between the drugs in the short term. There is not enough evidence to exclude a small difference in benefit, long term effects or a difference in less common adverse effects. More research is needed into the long term and adverse effects of these drugs.

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Background

Description of the condition

Infant apnea has been defined as a pause in breathing of greater than 20 seconds, or one of less than 20 seconds associated with bradycardia and/or cyanosis or pallor (AAP 2003). Recurrent episodes of apnea are common in preterm infants and the incidence and severity is greater in those born at lower gestational ages. Although apnea can occur spontaneously and be attributed to prematurity alone, apnea can also be provoked or made more severe if there is some additional insult such as infection, hypoxemia or intracranial pathology (Henderson-Smart 1995).

If prolonged, apnea can lead to hypoxemia and reflex bradycardia that 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 gastrointestinal tract or other organs. 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).

Description of the intervention

Methylxanthines are thought to stimulate breathing efforts and have been used in clinical practice to reduce apnea since the 1970s. Theophylline, caffeine and aminophylline are three forms that have been used and meta-analysis of the RCTs evaluating the effect against placebo or no treatment indicates a large reduction in apnea and in the use of IPPV (Henderson-Smart 2001; Henderson-Smart 2004).

How the intervention might work

Caffeine and theophyline effectiveness for apnea have been assessed in other reviews. Doxapram also appears to stimulate breathing and may be an alternative treatment. It appears to act both on the peripheral chemoreceptors and central nervous system to augment breathing efforts (Blanchard 1992). In one small placebo controlled trial, doxapram has been shown to reduce apnea in the short term (Henderson-Smart 2004).

Short term side effects of doxapram, such as hypertension, excessive central nervous system stimulation, gastrointestinal disturbances (Tay-Uyboco 1991) and heart block (De Villiers 1998) have been reported. No studies of long term effects on growth and development have been reported.

Why it is important to do this review

This updates the review "Doxapram versus methylxanthine for apnea in preterm infants" (Henderson-Smart 2000). One additional trial (Wang 2000) has been found to be eligible and included.

Objectives

To assess the effects of doxapram compared with methylxanthine in preterm infants with recurrent apnea.

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Methods

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials.

Types of participants

Preterm infants with recurrent apnea. There must have been an effort to exclude specific causes of apnea. Measures of the severity of apnea as well as the response to treatment must have been consistent with an evaluation of 'clinical apnea', as defined above (AAP 2003).

Types of interventions

Doxapram compared with methylxanthine (e.g. theophylline, aminophylline or caffeine) for the treatment of apnea. Trials evaluating the use of doxapram or theophylline to assist extubation are reviewed elsewhere (Henderson-Smart 2000a; Henderson-Smart 2000b)

Types of outcome measures

Primary outcomes
  1. Failed treatment (no clinically important 50% reduction in apnea or use of IPPV or death during study).
  2. Use of IPPV
Secondary outcomes
  1. Side effects such as tachycardia, seizures or hypertension.
  2. Long-term growth and development.

Search methods for identification of studies

The standard search strategy of the Neonatal Review Group was used.

This included searches of the Oxford Database of Perinatal Trials, Cochrane Collaboration Clinical Trials Register (Cochrane Library issue 4, 2009), MEDLINE (1966 to Feb. 2010), EMBASE (1982 to Feb 2010) and CINAHL (1982 to Feb. 2010) using MeSH terms, doxapram, methylxanthines, premature infants and text terms apnea or apnoea), previous reviews including cross references, abstracts in conferences and symposia proceedings (Society for Pediatric Research 1996 to 2009 and European Society for Pediatric research 1996 to 2009), expert informants, journal hand searching in all languages.

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used to select trials, assess quality and to extract and synthesize data. Additional information was requested from authors to clarify methodology.

Selection of studies

All randomized and quasi-randomized controlled trials fulfilling the selection criteria described in the previous section were included. Both authors reviewed the results of the search and separately selected the studies for inclusion. The review authors resolved any disagreement by discussion.

Data extraction and management

The review authors separately extracted, assessed and coded all data for each study using a form that was designed specifically for this review. Any standard error of the mean was replaced by the corresponding standard deviation. For each study, final data was entered into RevMan by one review author and then checked by a second review author. Any disagreement was resolved by discussion.

Assessment of risk of bias in included studies

The standard methods of the Cochrane Neonatal Review Group were employed. The methodological quality of the studies were assessed using the following key criteria: allocation concealment (blinding of randomization), blinding of intervention, completeness of follow-up, and blinding of outcome measurement/assessment. For each criterion, assessment was yes, no, can't tell. Two review authors separately assessed each study. Any disagreement was resolved by discussion. This information was added to the table, Characteristics of Included Studies.

In addition, the following issues were evaluated and entered into the Risk of Bias Table:

  1. Sequence generation: Was the allocation sequence adequately generated?
  2. Allocation concealment: Was allocation adequately concealed?
  3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
  4. Incomplete outcome data: Were incomplete outcome data adequately addressed?
  5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
  6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?

Measures of treatment effect

Statistical analyses were performed using Review Manager software. Categorical data were analyzed using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). Continuous data were analyzed using weighted mean difference (WMD). The 95% confidence interval (CI) was reported on all estimates.

Assessment of heterogeneity

We estimated the treatment effects of individual trials and examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. If statistical heterogeneity was detected, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses.

Data synthesis

Meta-analysis was performed using Review Manager software (RevMan 5), supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed effect model.

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Results

Description of studies

Studies included Eyal 1985; Peliowski 1990; Romeo 1991; Wang 2000. Details are given in the table, Characteristics of Included Studies. Three studies (Eyal 1985; Romeo 1991; Wang 2000) compared doxapram with aminophylline and one (Peliowski 1990) compared doxapram with theophylline. All drugs were given intravenously and all studies evaluated apnea at about 48 hours after commencement of treatment and one (Peliowski 1990) also evaluated apnea at seven days.

One potentially eligible study (Moller 1999) requires author clarification before the data can be used. Fifty-two infants with recurrent apnea/bradycardia, birth weights less than 1500 grams and gestational ages less than 35 weeks at birth were randomized to intravenous doxapram or theophylline. Thirty-five per cent of infants were excluded after randomization (usually due to loss of intravenous access) and median rates of apnea are presented for the seven day study period. As a result this study must be excluded at present. The author is helping with analysis of missing subjects, but the data is not yet available.

Risk of bias in included studies

Details of the methodological quality of each trial are in the included studies table.

The number of infants in each study was small. Although patients were similar at entry, the method of randomization was not stated in the trial of Romeo et al. (Romeo 1991). There was a risk of bias in this trial since the treatments were not blinded to the caretakers or analyzers and clinical charts were used to assess response. The trial by Eyal et al. (Eyal 1985) also used clinical charts to assess response, but the treatment was blinded. In Wang 2000 The randomization method was unclear although methods were stated as double blind.

Effects of interventions

In the four included trials involving 91 preterm infants with apnea of prematurity, failed treatment in the first 48 hours (Outcome 1.1) occurred in eleven of 44 infants receiving doxapram and twelve of 45 infants receiving methylxanthine. This result is consistent across trials and is not significantly different (typical relative risk 1.16, 95% CI 0.43, 3.13). One trial (Peliowski 1990) of 28 infants reported failed treatment at seven days (Outcome 1.2) and found no difference (typical RR 1.30, 95% CI 0.72, 2.36).

Use of mechanical ventilation and long-term follow-up was not reported in any trial.

Discussion

Evidence of the efficacy of doxapram and of methylxanthines compared with control for the treatment of apnea in preterm infants has been reviewed elsewhere showing that they are effective (Henderson-Smart 2001; Henderson-Smart 2004). Although no difference in effectiveness of Doxapram and methylxanthines was found, the overall number of subjects is insufficient to exclude the possibility that doxapram, compared to methylxanthine, could result in even a 50% relative risk reduction for treatment failure in the first 48 hours.

Theoretically, the use of intravenous methylxanthine (aminophylline or caffeine) has the advantage of being easily converted to the enteral route (theophylline), where as doxapram is poorly absorbed and causes gastrointestinal disturbance when given orally (Tay-Uyboco 1991) and is therefore usually administered intravenously. Furthermore, short term side effects of doxapram, such as hypertension, excessive central nervous system stimulation, and heart block (De Villiers 1998) have been reported.

Authors' conclusions

Implications for practice

Intravenous doxapram and intravenous methylxanthine appear to be similar in their short term effects for treating apnea in preterm infants, although these trials are too small to exclude an important difference between the two treatments or to exclude the possibility of less common adverse effects. Long-term outcome of infants treated in these trials has not been reported.

Implications for research

Further studies would require a large number of infants, stratified by gestation, to clarify which infants are likely to benefit and whether there might be differences in responses or side effects with these two drugs at different ages. It would be valuable to include important clinical outcomes such as use of mechanical ventilation as well as subsequent growth and development in future studies. Responses to treatment would have to take account of co-interventions, such as nasal continuous positive airway pressure.

Acknowledgements

Dr. Barbara Schmidt kindly translated a study published in German (Moller 1999). Dr Moller has assisted with information about his trial data.
Vanessa Chu provided translation of the Wang Chinese article to English.

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

Both review authors developed the protocol, evaluated trials and extracted data.
Henderson-Smart wrote the review and entered data into RevMan.
Henderson-Smart has now been responsible for searching for trials and updating the review with approval of Steer.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Eyal 1985

Methods

Blinding of randomization: yes; apnea/bradycardia assessed by blinded nursing observations of infants and monitors, exclusions not mentioned.
Blinding of intervention: yes
Complete follow-up: can't tell
Blinding of outcome measurement: yes

Participants

16 preterm infants (9 doxapram, 7 theophylline), mean gestational age 30 weeks, with apnea associated with cyanosis and bradycardia < 100 bpm.

Interventions

Doxapram 2.5 mg/kg/hr IV vs aminophylline 6 mg/kg load and 1.5 mg/kg/8 hrly. Each treatment was given for 48 hrs.

Outcomes

Apnea/bradycardia < 50% reduction.

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

Blinding of randomization: yes

Blinding? Yes

Blinding of intervention: yes
Blinding of outcome measurement: yes
Apnea/bradycardia assessed by blinded nursing observations of infants and monitors

Free of selective reporting? Unclear

Complete follow-up: can't tell

Free of other bias? Unclear

Peliowski 1990

Methods

Concealed randomisation; placebo controlled; Three withdrawals, groups not specified.
Blinding of randomization: yes
Blinding of intervention: yes
Complete follow-up: can't tell
Blinding of outcome measurement: yes

Participants

28 (13 doxapram, 15 theophylline) preterm infants (< 35 weeks gestation) with apnea; ( apnea > 20 sec with > 25% fall in heart rate and 10% fall in oxygen saturation or 5 torr or more fall in transcutaneous oxygen tension; 0.33 or more events per hr, = 8 or more per day) ; other causes of apnea excluded; similar mean gestational age (30.7 vs 31.3 weeks), birth weight (1441 vs 1303 g), postnatal age at study entry (4.8 vs 2.9 days) and baseline apnea rate (0.94 vs 0.70/hr)

Interventions

Doxapram intravenously; 3 mg/kg load and 1.5 mg/kg/hr vs intravenous theophylline 8 mg/kg load followed by 0.5 mg/kg/hr.

Outcomes

Apnea (failure of rate of events to fall below 0.33/hr or use of mechanical ventilation); use of mechanical ventilation

Notes

Additional treatment with CPAP allowed - no information on who received this. Cross over design and simultaneous comparison with doxapram - not evaluated here.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Concealed randomisation; placebo controlled

Allocation concealment? Yes

Blinding of randomization: yes

Blinding? Yes

Blinding of intervention: yes
Blinding of outcome measurement: yes

Free of selective reporting? Unclear

Complete follow-up: can't tell

Three withdrawals, groups not specified.

Free of other bias? Unclear

Unclear

Romeo 1991

Methods

Random allocation method not specified, not blinded, clinical assessment by unblinded staff, exclusions not mentioned.
Blinding of randomization: can't tell
Blinding of intervention: no
Complete follow-up: can't tell
Blinding of outcome measurement: no

Participants

19 (10 doxapram, 9 aminophylline) preterm infants with 3 or more episodes of apnea >10 sec with cyanosis and bradycardia (< 40 bpm below baseline) in 8 hours. Mean gestational ages 29.6 weeks for aminophylline group and 29.9 weeks for doxapram group.

Interventions

Doxapram 1.5 mg/kg/hr vs aminophylline 5 mg/kg load and 2.5 mg/kg ?frequency.

Outcomes

Apnea < 50% reduction by 48 hours after treatment.

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Random allocation method not specified

Allocation concealment? No

Random allocation method not blinded

Blinding? No

Blinding of intervention: no
Blinding of outcome measurement: no
Clinical assessment by unblinded staff

Free of selective reporting? Unclear

Complete follow-up: can't tell
Exclusions not mentioned

Free of other bias? Unclear

Unclear

Wang 2000

Methods

Concealed randomization - ?

Blinding treatment - yes

Completeness of participant analysis - yes

Blinding outcome assessment - yes?

Participants

28 preterm infants with 'asphyxia' related to apnea

Interventions

Doxapram

Outcomes

Failed reduction of apnea by 50%

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Yes

Allocation concealment? Unclear

Concealed randomization - unclear - described as double blind trial

Blinding? Yes

Blinding treatment - yes
Blinding outcome assessment - yes

Free of selective reporting? Yes

Completeness of participant analysis - yes

Free of other bias? Unclear

Unclear

Characteristics of excluded studies

Moller 1999

Reason for exclusion

Exclusion of randomized infants was too high at 36% with significant differences in numbers of infants in outcome assessment (20 vs. 14). Also significant differences in 7 of 12 baseline characteristics between groups (examples gestational ages and birth weights).

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References to studies

Included studies

Eyal 1985

Eyal F, Alpan G, Sagi E, Glick B, Peleg O, Dgani Y, Arad I. Aminophylline vs doxapram in idiopthic apnea of prematurity; a double-blind controlled study. Pediatrics 1985;75:709-13.

Peliowski 1990

Peliowski A, Finer NN. A blinded, randomized, placebo-controlled trial to compare theophylline and doxapram for the treatment of apnea of prematurity. Journal of Pediatrics 1990;116:648-53.

Romeo 1991

Romeo MG, Proto N, Tina LG, Parisi MG, Distefano G. Comparison of the effectiveness of aminophylline and doxapram in the prevention of idiopathic apnea in preterm infants (transl.). La Pediatria Medica e Chirurgica 1991;13:77-82.

Wang 2000

Wang HB, Yan YP, Wang TY. Observation of curative effects of Doxapram and Aminophylline on primary premature apnea. Hebei Medicine 2000;6:981-2.

Excluded studies

Moller 1999

Moller JC, Austing A, Pust B, Kohl M, Reiss I, Iven H, Gortner L. A comparative study about the therapeutic effect of theophylline and doxapram in apnoeic disorders [Vergleichende untersuchung zur wirkung von theophyllin und doxapram bei apnoean]. Klinische Pädiatrie 1999;211:86-91.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

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, 1992:352-370.

De Villiers 1998

De Villiers GS, Walele A, Van der Merwe P-L, Kallis NN. Second-degree atrioventricular heart block after doxapram administration. Journal of Pediatrics 1998;133:149-50.

Henderson-Smart 1995

Henderson-Smart DJ. Recurrent apnoea. In: Yu VYH, editor(s). Pulmonary Problems in the Perinatal Period and their Sequelae. Vol. 3, No. 1. London: Bailliere Tindall, 1995:203-222.

Henderson-Smart 2000a

Henderson-Smart DJ, Steer PA. Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD001966. DOI: 10.1002/14651858.CD001966.

Henderson-Smart 2000b

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthine for extubation in preterm infants. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD000139. DOI: 10.1002/14651858.CD000139.

Henderson-Smart 2001

Henderson-Smart DJ, Steer PA. Methylxanthine treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 3. Art. No.: CD000140. DOI: 10.1002/14651858.CD000140.

Henderson-Smart 2004

Henderson-Smart DJ, Steer PA. Doxapram treatment for apnea in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD000074. DOI: 10.1002/14651858.CD000074.pub2.

Tay-Uyboco 1991

Tay-Uyboco J, Kwiatkowski K, Cates DB, Seifert B, Hasan SU, Rigatto H. Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity. Biology of the Neonate 1991;59:190-200.

Other published versions of this review

Henderson-Smart 1997

Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 2. Art. No.: CD000075. DOI: 10.1002/14651858.CD000075.

Henderson-Smart 2000

Henderson-Smart DJ, Steer PA. Doxapram versus methylxanthine for apnea in preterm infants. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD000075. DOI: 10.1002/14651858.CD000075.

Classification pending references

  • None noted.

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Data and analyses

1 Doxapram vs aminophylline

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Failed treatment in the first 48 hrs 4 91 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.45, 1.85]
1.2 Failed treatment before 7 days 1 28 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.72, 2.36]

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Sources of support

Internal sources

  • Mater Children's Hospital, Brisbane, Australia
  • NSW Centre for Perinatal Health Services Research, Sydney, Australia
  • Royal Prince Alfred Hospital, Sydney, Australia

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 5, 2010 (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.