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Prophylactic caffeine to prevent postoperative apnoea following general anaesthesia 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


1Central Clinical School, Faculty of Medicine, University of Sydney, 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. Prophylactic caffeine to prevent postoperative apnoea following general anaesthesia in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD000048. DOI: 10.1002/14651858.CD000048.

Contact person

David J Henderson-Smart

Central Clinical School
Faculty of Medicine, University of Sydney
Sydney
NSW
2006
Australia

E-mail: davidhs@perinatal.usyd.edu.au

Dates

Assessed as Up-to-date: 19 January 2011
Date of Search: 16 January 2011
Next Stage Expected: 19 January 2013
Protocol First Published: Issue 2, 1996
Review First Published: Issue 3, 1997
Last Citation Issue: Issue 4, 2001

What's new

Date / Event Description
19 January 2011
Updated

This updates the review "Prophylactic caffeine to prevent postoperative apnoea following general anaesthesia in preterm infants" (Henderson-Smart 2004).

Search updated in January 2011. One new related reference (Krane 1995) has been added to additional references and the risk of bias tables have been completed.

History

Date / Event Description
15 August 2008
Updated

This updates the review "Prophylactic caffeine to prevent postoperative apnea following general anesthesia in preterm infants" published in the Cochrane Database of Systematic Reviews, Issue 2, 2004 (Henderson-Smart 2004).

Updated search in July 2008 found no new eligible trials for inclusion.

No changes to conclusions.

15 July 2008
Amended

Converted to new review format.

18 February 2004
Updated

This updates the existing review of "Prophylactic caffeine to prevent postoperative apnea following general anaesthesia in preterm infants" which was last updated in July 2001 (Henderson-Smart 2001). The search for trials was repeated in January 2004. No new trials were found. Two new additional references have been added.

16 July 2001
New citation: conclusions changed

Substantive amendment

Abstract

Background

Growing ex-preterm infants who undergo general anaesthesia for surgery at about term-equivalent age may have episodes of apnoea, cyanosis and bradycardia during the early postoperative period. A breathing stimulant such as caffeine given at the time of operation might prevent these episodes.

Objectives

To determine the effect of the prophylactic use of caffeine to prevent episodes of apnoea, cyanosis and bradycardia during the postoperative period in ex-preterm infants who undergo general anaesthesia for surgery.

Search methods

The standard strategy of the Neonatal Review Group was used. This included searches of the The Cochrane Library, Oxford Database of Perinatal Trials, MEDLINE, EMBASE, CINAHL and abstracts of the Society for Pediatric Research. Seach updated in January 2011.

Selection criteria

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

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used to select trials, evaluate trial quality and to extract data. Each review author extracted data separately, and then compared and resolved any differences. Meta-analysis used relative risk and risk difference.

Results

Three eligible trials were found. In each trial apnoea/bradycardia occurred in fewer infants treated with caffeine. The typical estimate for relative risk is 0.09 (95% CI 0.02 to 0.34). The typical estimate for absolute risk difference is -0.58 (95% CI -0.74 to -0.43) indicating that fewer than two infants have to be treated with caffeine to expect to prevent one with postoperative apnoea. In two trials (Welborn 1989; LeBard 1989), continuous recordings of oxygen saturation detected hypoxaemic episodes (< 90%) in fewer treatment than control infants [typical RR 0.13 (95% CI 0.03 to 0.63)]. No infant in any trial required intubation and mechanical ventilation. No adverse effects were reported.

Authors' conclusions

Implications for practice. After general anaesthesia, caffeine can be used to prevent postoperative apnoea/bradycardia and episodes of oxygen desaturation in growing preterm infants if this is deemed clinically necessary. In view of the small numbers of infants studied in these trials and uncertainty concerning the clinical significance of the episodes, caution is warranted in applying these results to routine clinical practice.

Implications for research. There is a need to determine which infants might benefit most by this treatment. Studies confined to those most at risk of apnoea (prior history, younger postmenstrual age) and those that might require mechanical ventilation or chronic lung disease would be of value.

Plain language summary

Prophylactic caffeine to prevent postoperative apnoea following general anaesthesia in preterm infants

Caffeine may be able to prevent postoperative apnoea and bradycardia in preterm babies. Growing babies who were born too early (preterm) and who undergo general anaesthetic for surgery may have complications, including episodes of apnoea (pauses in breathing), cyanosis (from lack of oxygen in the blood), and bradycardia (slow heartbeat). Caffeine, a methylxanthine drug, is thought to stimulate breathing, and so possibly prevent apnoea and subsequent problems. The review found some evidence that caffeine given at the time of surgery reduces apnoea, bradycardia, and cyanosis after anaesthetic, but the importance of this is unclear.

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Background

Description of the condition

Growing ex-preterm infants who undergo general anaesthesia for surgery at about term equivalent age may have episodes of apnoea, cyanosis and bradycardia during the early postoperative period.

The American Academy of Pediatrics defined infant apnoea 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). Recurrent episodes of apnoea are common in preterm infants and the incidence and severity increases at lower gestational ages. By term equivalent postnatal age infants have usually 'outgrown' their tendency to spontaneous apnoea. However, if some additional insult such as infection, or the administration of drugs that depress the central nervous system occurs (such as general anaesthetic agents, Liu 1983), apnoea and associated oxygen desaturations can recur. Attempts have been made to determine which infants are most at risk (Cote 1995; Spear 1992; Welborn 1994). Factors such as younger postmenstrual age and past history of apnoea seem important, although such risk scoring does not detect all infants who develop postanaesthesia problems (Cote 1995).

Description of the intervention

Methylxanthines such as caffeine are thought to stimulate breathing efforts and have been used in clinical practice to reduce apnoea in preterm infants since the late 1970's. Caffeine is better than theophylline in other attempts to reduce apnoea.

How the intervention might work

The mechanism of their 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. Other reviews on the effects of methylxanthines such as caffeine on apnoea, published in The Cochrane Library, include Henderson-Smart a; Henderson-Smart b; Henderson-Smart c and Henderson-Smart d. A systematic review has also been carried out on the effects of regional versus general anaesthesia on postoperative apnoea (Craven 2003).

Why it is important to do this review

If prolonged, apnoea can lead to hypoxaemia 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 gastrointestinal tract or other organs, although there are no data to support this. 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).

Objectives

To determine the effect of the prophylactic use of caffeine on episodes of apnoea, cyanosis and bradycardia during the postoperative period in ex-preterm infants who undergo general anaesthesia for surgery.

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Methods

Criteria for considering studies for this review

Types of studies

Trials utilising random or quasi-random patient allocation.

Types of participants

Preterm infants undergoing general anaesthesia for surgery at about term equivalent age.

Types of interventions

Caffeine given with general anaesthesia, compared with control, as prophylaxis for postoperative apnoea.

Types of outcome measures

  1. Episodes of apnoea and bradycardia consistent with clinical apnoea (AAP 2003).
  2. Episodes of oxygen desaturation (> 10% fall).
  3. Use of IPPV.
  4. Side effects.

Search methods for identification of studies

Electronic searches

We used the standard strategy of the Neonatal Review Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library January 2011, MEDLINE (1966 to January 2011), EMBASE (1980 to January 2011), CINAHL (1982 to January 2011). Search terms included text words 'apnoea', 'caffeine' and MeSH heading 'infant, premature'. We also searched previous reviews including cross references. We searched abstracts of the Society for Pediatric Research for the years 1996 to 2010 inclusive.

Clinical trials registries were also searched for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used to select trials, evaluate the quality of the trials and to extract data.

Selection of studies

The reviewers independently assessed for all the potential studies identified as a result of the search strategy for possible inclusion. The title and abstract of each retrieved study were examined. If there was uncertainty, the full paper was examined. Disagreements were resolved by discussion.

Data extraction and management

Each review author extracted data separately and then compared and resolved differences.

Assessment of risk of bias in included studies

We used the standard review methods of the Cochrane Neonatal Review Group External Web Site Policy to assess the methodological quality of included studies. Review authors independently assessed study quality and risk of bias using the following criteria documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  1. Sequence generation: was the allocation sequence adequately generated?
  2. Allocation concealment: was allocation adequately concealed?
  3. Blinding of participants, personnel and outcome assessors for each main outcome or class of outcomes: was knowledge of the allocated intervention adequately prevented during the study?
  4. Incomplete outcome data for each main outcome or class of outcomes: 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? We gave particular attention to completeness of follow-up of all randomised infants and to the length of follow-up studies to identify whether any benefits claimed are robust.

When necessary, we requested additional information and clarification of published data from the authors of individual trials. We assessed each trial for risk of bias based on the criteria listed above and marked as:

  1. low risk of bias;
  2. unclear risk of bias;
  3. high risk of bias.

We resolved any discrepancies by mutual discussion and consensus. We planned to provide information on levels of agreement between review authors and/or details of resolution of differences.

Measures of treatment effect

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

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using the I² and Chi² statistics. We regarded heterogeneity to be substantial if either I² was greater than 50% or there was a low P-value (less than 0.10) in the Chi² test for heterogeneity.

If we detected statistical heterogeneity, 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.

Subgroup analysis and investigation of heterogeneity

No subgroup analyses were planned.

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Results

Description of studies

Three eligible trials were found. Details are given in the table 'Characteristics of Included Studies'. In general, infants were born at 30 to 32 weeks gestation and studied at 40 to 44 weeks postmenstrual age. All three trials evaluated caffeine given intravenously in a single dose during general anaesthesia. The dosage varied from 5 mg/kg (Welborn 1988) to 10 mg/kg (LeBard 1989; Welborn 1989). In all three trials apnoea was defined as any apnoeic episodes of > 15 seconds duration, or shorter ones associated with bradycardia. In two trials, oxygen desaturations (< 90%) on pulse oximetry were recorded (LeBard 1989; Welborn 1989).

Risk of bias in included studies

This is detailed in the table 'Characteristics of Included Studies'.

Concealment at randomisation: all used formal randomisation, although the steps taken to fully conceal allocation assignment were not clear.

Blinding of treatment: in each trial a saline placebo was used.

Blinding of outcome assessment: in two trials apnoea/bradycardia was assessed blindly from a polygraphic recording. Methodology in the third trial (LeBard 1989) needs clarification as this has only been published in abstract form.

Completeness of follow-up: not clearly stated.

Effects of interventions

Three eligible trials were found. In each trial apnoea/bradycardia occurred in fewer infants treated with caffeine. The typical estimate for relative risk is 0.09 (95% CI 0.02 to 0.34). Absolute risk difference is -0.58 (95% CI -0.74 to -0.43) indicating that fewer than two infants have to be treated with caffeine to expect to prevent one with postoperative apnoea. In two trials (LeBard 1989; Welborn 1989) continuous recordings of oxygen saturation detected hypoxaemic episodes (< 90%) in fewer treatment than control infants [RR 0.13 (95% CI 0.03 to 0.63]. No infant in any trial required intubation and mechanical ventilation. No adverse effects were reported.

Discussion

Summary of main results

Caffeine reduces the occurrence of apnoea, bradycardia and oxygen desaturation after general anaesthesia, although it has yet to be determined whether these episodes are clinically important. If such episodes are detected by monitors, responded to promptly by nurses and do not lead to a need for mechanical ventilation, then these episodes are of uncertain significance. Apnea and hypoxaemia might be more important in infants at particularly high risk of respiratory failure, such as those with chronic lung disease. This has not been evaluated.

Overall completeness and applicability of evidence

No adverse effects of caffeine were reported, although the number of infants studied in these three trials is too small to exclude less common ones.

Quality of the evidence

One trial (LeBard 1989) have many unclear methodology and was only published as an abstract. The other two trials had good methodology.

Agreements and disagreements with other studies or reviews

Two randomised trials (Krane 1995; Welborn 1990) have suggested that apnoea is more common following general anaesthesia than following spinal anaesthesia without premedication in infants having inguinal hernia repair, one of the most common operative procedures in ex-preterm infants. A Cochrane review (Craven 2003) did not find evidence to support that hypothesis.

Variations in the type of general anaesthetic agents might affect postoperative ventilatory function. A trial (Sale 2006) compared two general anaesthetic agents (desflurane and sevoflurane) in terms of postoperative ventilatory events or in the number of apneas in the postoperative period and found no difference

Authors' conclusions

Implications for practice

After general anaesthesia caffeine can be used to prevent postoperative apnoea/bradycardia and episodes of oxygen desaturation in preterm infants if this is deemed clinically necessary. In view of the small numbers of infants studied in these trials and uncertainty concerning the clinical significance of the episodes, caution is warranted in applying these results to routine clinical practice.

Implications for research

There is a need to determine which infants might benefit most by this treatment. Studies confined to those most at risk of apnoea (prior history, younger postmenstrual age) and those that might require mechanical ventilation (chronic lung disease) would be of value.

Acknowledgements

Editorial support of the Cochrane Neonatal Review Group has been funded 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

The original protocol and review were done by Henderson-Smart and Steer. The current update was done by Henderson-Smart and approved by Steer.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

LeBard 1989

Methods

Randomisation method not specified, blinded treatment, blinding of assessment and exclusions not specified.

Participants

Preterm infants undergoing general anaesthesia.

Interventions

Caffeine 10 mg/kg vs saline placebo IV after induction of anaesthesia.

Outcomes

Apnea > 15 sec or with bradycardia < 80 bpm, oxygen desaturations < 90% on pulse oximetry.

Notes

Abstract only available.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Unclear

Allocation concealment (selection bias) Unclear risk

Unclear

Blinding (performance bias and detection bias) Unclear risk

Unclear

Incomplete outcome data (attrition bias) High risk

No

Selective reporting (reporting bias) High risk

Only reported as abstract

Other bias Unclear risk

Welborn 1988

Methods

Randomly assigned by pharmacy, double blind, blind assessment of continuous recordings of apnoea/bradycardia, no exclusions mentioned.

Participants

Preterm (< 38 weeks gestational age) undergoing general anaesthesia for inguinal hernia repair at 35 - 44 weeks post menstrual age. Infants ineligible if existing cardiac, neurological or metabolic disease.

Interventions

Caffeine 5 mg/kg vs saline placebo IV with induction of anaesthesia.

Outcomes

Apnea >15 sec and/or bradycardia < 100 bmp for 5 sec.

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk
Allocation concealment (selection bias) Low risk

Adequate

Blinding (performance bias and detection bias) Low risk

Yes

Incomplete outcome data (attrition bias) High risk

No

Selective reporting (reporting bias) Low risk
Other bias Low risk

Welborn 1989

Methods

Randomly assigned by pharmacy, double blind, blind assessment of continuous recordings of apnoea/bradycardia, no exclusions mentioned.

Participants

Preterm (< 38 weeks gestational age) undergoing general anaesthesia for inguinal hernia repair at 35 - 44 weeks post menstrual age. Infants ineligible if existing cardiac, neurological or metabolic disease.

Interventions

Caffeine 10 mg/kg vs saline placebo IV with induction of anaesthesia.

Outcomes

Apnea >15 sec and/or bradycardia < 100 bmp for 5 sec, oxygen desaturation < 90% during 12 hours post anaesthesia.

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Yes

Allocation concealment (selection bias) Low risk

Adequate

Blinding (performance bias and detection bias) Low risk

Yes

Incomplete outcome data (attrition bias) High risk

No

Selective reporting (reporting bias) Low risk

Yes

Other bias High risk

No

Characteristics of excluded studies

  • None noted.

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

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References to studies

Included studies

LeBard 1989

LeBard SE, Kurth CD, Spitzer AR, Downes JJ. Preventing postoperative apnea by neuromodulator antagonists. Anesthesiology 1989;71:A1026.

Welborn 1988

Welborn LG, De Soto H, Hannallah RS, Fink R, Ruttimann UE, Boeckx R. The use of caffeine in the control of post-anesthetic apnea in former premature infants. Anesthesiology 1988;68:796-8.

Welborn 1989

Welborn LG, Hannallah RS, Fink R, Ruttimann UE, Hicks JM. High-dose caffeine suppresses postoperative apnea in former preterm infants. Anesthesiology 1989;71:347-9.

References to excluded studies

  • None noted.

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;111:914-17.

Cote 1995

Cote CJ, Zaslavsky A, Downes JJ, Kurth CD, Welborn LG, Warner LO, Malviya SV. Postoperative apnea in former preterm infants after inguinal herniorrhaphy. Anesthesiology 1995;82:809-22.

Craven 2003

Craven PD, Badawi N, Henderson-Smart DJ, O'Brien M. Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003669. DOI: 10.1002/14651858.CD003669.

Henderson-Smart a

Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnoea in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD000140. DOI: 10.1002/14651858.CD000140.

Henderson-Smart b

Henderson-Smart DJ, Davis PG. Prophylactic methylxanthine for extubation in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD000139. DOI: 10.1002/14651858.CD000139.

Henderson-Smart c

Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for preventing of apnoea in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD000432. DOI: 10.1002/14651858.CD000432.

Henderson-Smart d

Henderson-Smart DJ, Steer PA. Caffeine versus theophylline for apnoea in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD000273. DOI: 10.1002/14651858.CD000273.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Krane 1995

Krane EJ, Haberkern CM, Jacobson LE. Postoperative apnea, bradycardia, and oxygen desaturation in formerly preterm infants: prospective comparison of spinal and general anesthesia. Anesthesia and Analgesia 1995;80:7-13.

Liu 1983

Liu LM, Cote CJ, Goudsouzian NG, Ryan JF, Firestone S, Dedrick DF, Liu PL, Todres ID. Life-threatening apnea in infants recovering from anesthesia. Anesthesiology 1983;59:506-10.

Sale 2006

Sale SM, Read JA, Stoddart PA and Wolf AR. Prospective comparison of sevoflurane and desflurane in formerly premature infants undergoing inguinal herniotomy. British Journal of Anaesthesia 2006;96:774–778.

Spear 1992

Spear RM. Anesthesia for premature and term infants: perioperative complications. Journal of Pediatrics 1992;120:165-76.

Welborn 1990

Welborn LG, Rice LJ, Hannallah RS, Broadman LM, Ruttimann UE, Fink R. Postoperative apnea in former preterm infants: prospective comparison of spinal and general anesthesia. Anesthesiology 1990;72:838-42.

Welborn 1994

Welborn LG, Greenspun JC. Anesthesia and apnea. Perioperative considerations in the former preterm infant. Pediatr Clin North Amer 1994;41:181-98.

Other published versions of this review

Henderson-Smart 2001

Henderson-Smart DJ, Steer PA. Prophylactic caffeine to prevent postoperative apnea in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000048. DOI: 10.1002/14651858.CD000048.

Henderson-Smart 2004

Henderson-Smart DJ, Steer PA. Prophylactic caffeine to prevent postoperative apnea in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD000048. DOI: 10.1002/14651858.CD000048.

Classification pending references

  • None noted.

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Data and analyses

1 Caffeine vs placebo with induction of general anesthesia

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Postoperative apnoea/bradycardia 3 78 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.02, 0.34]
1.2 Postoperative oxygen desaturations 2 58 Risk Ratio (M-H, Fixed, 95% CI) 0.13 [0.03, 0.63]

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Figures

  • None noted.

Sources of support

Internal sources

  • NSW Centre for Perinatal Health Services Research, Sydney, Australia
  • Royal Prince Alfred Hospital, Sydney, Australia
  • School of Medicine, Faculty of Health Sciences, University of Queensland, Children's Health Services District, Queensland Health, Brisbane, Australia
  • Co-author

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 7, 2011 (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.