Intra‐amniotic surfactant for women at risk of preterm birth for preventing respiratory distress in newborns

Abstract

Background

Early surfactant reduces mortality and pulmonary complications in preterm infants with respiratory distress syndrome. However, current surfactant administration strategies require endotracheal intubation with or without continued mechanical ventilation. Bronchopulmonary dysplasia and chronic lung disease (CLD) are associated with mechanical ventilation and potentially life‐long effects. Non‐invasive methods of surfactant administration including intra‐amniotic surfactant may avoid endotracheal intubation and mechanical ventilation, potentially preventing development of CLD.

Objectives

To determine if intra‐amniotic instillation of surfactant for women at risk of preterm birth, compared to placebo or no treatment or post‐delivery tracheal surfactant instillation, reduces morbidity or mortality, or both, in preterm infants. If intra‐amniotic instillation is effective, in subgroup analysis to determine the effect of 1) gestational age; 2) type of surfactant; 3) dose; 4) timing; 5) indication; and 6) multiple pregnancy.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (August 2009), MEDLINE (1950‐August 2009), handsearched the Proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Pediatric Research) from 1990‐2009 in Pediatric Research Journal and Abstracts online and the Proceedings of Perinatal Society of Australia and New Zealand (PSANZ) (1996‐2009). We also searched the Science Citation Index (Web of Science) (August 2009) and checked reference lists of identified studies. We contacted Abbott Laboratories, Inc for unpublished studies.

Selection criteria

Published, unpublished and ongoing randomised controlled, cluster‐randomised or quasi‐randomised trials of intra‐amniotic instillation of surfactant for women at risk of preterm birth, compared to placebo or no treatment or post‐delivery tracheal surfactant instillation.

Data collection and analysis

Three review authors independently assessed study eligibility and quality.

Main results

We found no trials were found met the inclusion criteria for this review.

Authors' conclusions

We identified no randomised trials that evaluated the effect of intra‐amniotic instillation of surfactant for women at risk of preterm birth. Evidence from animal and observational human studies suggest that intra‐amniotic surfactant administration is potentially safe, feasible and effective. Well designed trials of intra‐amniotic instillation of surfactant for women at risk of preterm birth are needed.

Plain language summary

Intra‐amniotic surfactant for women at risk of preterm birth for preventing respiratory distress in newborns

There is no current evidence from randomised controlled trials to guide the use of intra‐amniotic instillation of surfactant for women at risk of preterm birth. 
 
 Respiratory distress syndrome caused by a deficiency of natural lung detergent (surfactant) occurs mainly in infants born before term (37 weeks' gestation). The usual treatment includes instilling artificial surfactant directly into the newborn infant's airway followed by mechanical ventilation. However, this process can lead to lung injury, which can affect the infant's long‐term health. A potential alternative strategy is to inject surfactant into the amniotic fluid around the fetus close to the infant's mouth and nostrils before birth. Preliminary animal and human study suggests that surfactant enters the fetal lungs through fetal breathing efforts. This has the potential to reduce the need to support the infant's breathing after birth, as well as lung damage caused by mechanical ventilation. This review found no randomised controlled trials of intra‐amniotic instillation of surfactant for women at risk of preterm birth. In view of the encouraging results from animal studies and preliminary human study, high‐quality studies of intra‐amniotic instillation of surfactant for women at risk of preterm birth are needed.

Background

Description of the condition

Respiratory distress syndrome (RDS), resulting from a deficiency of pulmonary surfactant, is one of most important causes of morbidity and mortality in very preterm infants. Strategies to prevent and treat RDS may include single or multiple prenatal corticosteroid course administration (Crowther 2007; Roberts 2006); prophylaxis or selective surfactant replacement via endotracheal tube (Soll 2001; Soll 2002; Soll 2009; Stevens 2007); oscillatory or conventional mechanical ventilation (Bhuta 1998; Greenough 2002; McCallion 2005) and continuous distending pressure (CDP) (Ho 2002; Morley 2008). However, despite the benefits of these strategies, many infants progress to develop bronchopulmonary dysplasia (BPD), resulting in chronic lung disease (CLD).

Ventilation‐mediated lung injury has a central role in pathogenesis of CLD (Jobe 2001). It has been shown that endotracheal intubation and positive pressure ventilation (PPV) of the immature, surfactant‐deficient lung is harmful and may exacerbate the development of BPD (Björklund 1997; Jobe 2000; Van Marter 2000). As few as six breaths can damage the lung and blunt the effect of surfactant replacement in the immature lamb (Björklund 1997; Grossmann 1986) and six hours' ventilation is enough to cause marked airway epithelial injury in very preterm and near term fetal sheep (Fleckonoe 2008).

Description of the intervention

The main strategy used to avoid endotracheal intubation and PPV in premature infants, and thus potentially reduce CLD, is application of CDP immediately following birth (Ho 2002; Morley 2008). Recent studies suggest CDP may reduce CLD compared to elective intubation, surfactant and PPV (Aly 2001; Deklerk 2001). Similarly, reviews of trials of nasal intermittent positive pressure ventilation (NIPPV) found trials reported a reduced rate of extubation failure (Davis 2001) and frequency of apnea (Lemyre 2002), with some evidence that NIPPV may result in a reduction in CLD compared to ongoing conventional ventilation (Bhandari 2007; Davis 2009). Although CDP and NIPPV strategies avoid endotracheal intubation and PPV, it precludes surfactant administration, which is a standard and proven treatment for RDS (Gortner 1998; Seger 2009; Soll 1998a; Soll 1998b; Soll 1999; Soll 2001a; Soll 2001b; Soll 2002; Soll 2009; Stevens 2007). Furthermore, early CDP and NIPPV may fail in 25% to 50% of preterm infants (Kugelman 2007; Morley 2008; Reininger 2005).

Non‐invasive methods of surfactant administration have the potential to reduce the need for intubation and endotracheal surfactant administration. Potential strategies include:

1. intra‐amniotic instillation (Cosmi 1996a; Cosmi 1996b; Cosmi 1996c; Cosmi 1997; Lisawa 2003; Petrikovsky 1995; Zhang 2002);

2. pharyngeal instillation (Kattwinkel 2004);

3. laryngeal mask airway surfactant (Trevisanuto 2005);

4. administration via thin endotracheal catheter without NIPPV (Kribs 2007);

5. nebulised surfactant administration in spontaneously breathing infants (Jorch 1997).

This review will focus on intra‐amniotic instillation of surfactant. Surfactant is instilled intra‐amniotically in pregnant women at risk of preterm birth. Typically, this procedure involves installation of surfactant through a percutaneous amniocentesis needle under ultrasound guidance (Cosmi 1996a; Cosmi 1996b; Cosmi 1996c; Cosmi 1997; Zhang 2002) or vaginally through fiberscope under endoscopic visual control (Petrikovsky 1995). The instillation is usually directed towards the fetal mouth and nostrils so that it undergoes uniform distribution within the fetal pulmonary liquid compartment. Aminophylline can be given to the mother prior to the surfactant instillation to stimulate fetal breathing movements (Cosmi 1996a).

In the series described by Petrikovsky, the procedure took 11 to 16 minutes and the infants were delivered vaginally or via caesarean section after 12 to 180 minutes (Petrikovsky 1995). In the series described by Cosmi, most of the women were delivered via caesarean section 60 to 150 minutes after the administration of surfactant (Cosmi 1996a; Cosmi 1996b; Cosmi 1996c; Cosmi 1997).

How the intervention might work

Instillation of surfactant by direct injection into amniotic fluid close to the fetal mouth and nostrils has the expectation that fetal breathing will result in uniform distribution within the fetal lung compartment. The goal is to achieve sufficient surfactant concentrations so as to prevent RDS and avoid endotracheal intubation. This surfactant administration strategy, in conjunction with prenatal steroid administration and CDP, may offer a potential synergy to treat RDS, avoiding endotracheal intubation and PPV, reducing lung injury that may lead to CLD.

Animal studies indicate that intra‐amniotic instillation of surfactant may be as effective as post‐delivery intratracheal administration in prevention of RDS (Galan 1992; Galan 1993). The physiological basis for this has been shown in studies of fetal breathing movement in both animals and humans (Duenhoelter 1974; Kalache 1997; Pollack 2003). A tidal flow of 1.3 to 5 ml of intratracheal fluid has been reported during each respiratory cycle in human fetuses from 28 to 38 weeks' gestation (Kalache 1997). Uptake of intra‐amniotic radio labelled surfactant by guinea pig and rabbit lungs (7%) has been shown (Galan 1992; Hallman 1997; Illia 2004). Stimulation of fetal respiration increases the lung capture (Illia 2004). Preliminary reports have shown intra‐amniotic instillation of surfactant is safe, feasible and potentially effective (Cosmi 1996a; Cosmi 1996b; Cosmi 1996c; Cosmi 1997; Lisawa 2003; Petrikovsky 1995; Zhang 2002). Potential risks of the intervention include traumatic complications to the fetus and the mother; abruption; stillbirth; antepartum haemorrhage and chorioamnionitis.

Why it is important to do this review

Despite significant advances in neonatal intensive care, neonatal CLD still occurs in 40% of infants born at 24 weeks and in 5% at 31 weeks' gestation (Bolisetty 2006). CLD is associated with chronic respiratory difficulties (Doyle 2006; Kilbride 2003); prolonged and recurrent hospitalisation (Chye 1995; Furman 1996); increased incidence of neurodevelopmental disabilities; cerebral palsy (Hughes 1999; Majnemer 2000; Singer 1997; Skidmore 1990) and poor cognitive outcomes (Hughes 1999; O'Shea 1996; Singer 1997). CLD has a major impact on the daily life of families that persists beyond the neonatal period (Korhonen 1999).

Studies are needed to assess the effectiveness of alternative strategies for preventing CLD, including intra‐amniotic surfactant installation in women at risk of preterm birth, to reduce morbidity and/or mortality of preterm infants at risk of RDS.

Objectives

To determine if intra‐amniotic instillation of surfactant for women at risk of preterm birth, compared to placebo or no treatment or post‐delivery tracheal surfactant instillation, reduces morbidity or mortality, or both, in preterm infants. If intra‐amniotic instillation is effective, to determine if the following factors affect efficacy:

1. gestational age at time of intra‐amniotic surfactant administration;

2. type of surfactant instilled;

3. dose of intra‐amniotic surfactant administered;

4. time from administration of intra‐amniotic surfactant to delivery;

5. indication for intra‐amniotic surfactant administration ‐ reason woman was considered to be at risk for preterm birth at trial entry;

6. multiple pregnancy.

Methods

Criteria for considering studies for this review

Types of studies

We considered all published, unpublished and ongoing randomised controlled, cluster‐randomised or quasi‐randomised trials eligible for inclusion in this review.

Types of participants

Women at risk of preterm birth (e.g. due to ruptured membranes, antepartum haemorrhage, preterm labour, cervical incompetence, pre‐eclampsia, growth restriction or as defined by the authors) before 37 weeks' gestation where fetal lung maturity has not been confirmed.

Types of interventions

Intra‐amniotic instillation of any type of surfactant before delivery at any dose, compared with either placebo or no treatment or post‐delivery tracheal instilled surfactant.

Types of outcome measures

Primary outcomes

Primary outcomes include clinically important measures of effectiveness and safety, including serious outcomes, for both women and their infants. These include any of the following:

1. chronic lung disease (CLD) at 36 weeks' postmenstrual age (PMA) ‐ defined as need for respiratory support or oxygen at 36 weeks' PMA;

2. neurodevelopmental disability at 18 months or more postnatal age, defined as neurological abnormality, including: cerebral palsy on clinical examination; developmental delay more than two standard deviations below population mean on any standard test of development; blindness (visual acuity less than 6/60); or deafness (any hearing impairment requiring amplification) at any time after term corrected age.

Secondary outcomes

Secondary outcome measures include other measures of effectiveness, complications, satisfaction with care and health service use for both women and their infants. These include any of the following:

A. Infants

1. mortality prior to hospital discharge (stillbirths, neonatal deaths and infant deaths prior to hospital discharge);

2. need for neonatal resuscitation (bag and mask, positive pressure ventilation, cardiopulmonary resuscitation, adrenaline);

3. respiratory distress syndrome (RDS) (however defined by authors);

4. need for mechanical ventilation;

5. number of infants receiving post‐delivery surfactant;

6. doses of post‐delivery surfactant per infant;

7. days of any respiratory support (mechanical ventilation, continuous positive airway pressure (CPAP), high flow oxygen or air, nasal cannula);

8. days of supplemental oxygen;

9. air leak (pulmonary interstitial emphysema, pneumothorax);

10. CLD defined as need for oxygen at 28 days of age;

11. need for rescue treatment for respiratory distress (e.g. high frequency oscillatory ventilation, jet ventilation, extracorporeal membrane oxygenation, postnatal corticosteroids);

12. need for prophylaxis or rescue treatment for CLD including diuretics, postnatal corticosteroid;

13. birthweight and small for gestational age (birthweight less than 10th percentile) ‐ if delivery delayed in one arm of trial;

14. Apgar score less than seven at five minutes;

15. metabolic acidaemia (pH less than 7.05 and/or base deficit greater than 12 mmol/L) in cord artery blood;

16. neonatal mortality (less than 28 days of age);

17. intraventricular haemorrhage (any and severe ‐ Papile grade greater than or equal to three);

18. symptomatic patent ductus arteriosus or treated with cyclo‐oxygenase inhibitors or surgical ligation;

19. proven necrotising enterocolitis (Bell stage greater than or equal to two);

20. retinopathy of prematurity (any and severe ‐ stage greater than or equal to three);

21. systemic infection ‐ early (first 48 hours of life) and late;

22. apnea treated with methylxanthines or CPAP;

23. postnatal growth failure (e.g. weight at discharge less than 10^th percentile);

24. days of hospitalisation;

25. side effects of intervention or maternal analgesia given for the intervention (e.g. fetal trauma, bradycardia);

26. discontinuation of intervention because of fetal side effects (e.g. bradycardia).

B. Women

1. Maternal death;

2. maternal complication related to surfactant/placebo administration procedure (including abruption, antepartum haemorrhage, chorioamnionitis and puerperal sepsis, however defined by authors);

3. interval from intra‐amniotic surfactant administration to delivery;

4. admission to intensive care unit;

5. length of maternal hospitalisation;

6. side effects of intervention or maternal analgesia given for the intervention (including nausea, vomiting, hypertension, pain at the injection site, bruising at the injection site, hematoma at injection site);

7. discontinuation of intervention because of maternal side effects;

8. maternal satisfaction or stress as measured on validated scale.

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (August 2009). 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:

1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. handsearches of 30 journals and the proceedings of major conferences;

4. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords. 

In addition, we searched MEDLINE using the search strategy given in Appendix 1.

Searching other resources

We searched the following sources:

1. ClinicalTrials.gov and Current Controlled Trials for ongoing trials;

2. the Proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Pediatric Research) from 1990‐2009 in Pediatric Research Journal and Abstracts online and the Proceedings of Perinatal Society of Australia and New Zealand (PSANZ) from 1996‐2009;

3. reference lists of identified studies that examined the effect of intra‐amniotic surfactant installation; and

4. the Science Citation Index (Web of Science) for authors quoting key references of observational studies.

We planned to contact the corresponding investigator for information had we identified any unpublished trial. We considered unpublished studies eligible for review if methods and data could be confirmed by the author. We planned also to contact the corresponding authors of identified RCTs for additional information about their studies had further data been required. We contacted the companies (Abbott Laboratories, Inc) that developed different types of surfactant for possible unpublished studies using their product.

Data collection and analysis

We used the standard systematic review methods of The Cochrane Collaboration documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

Selection of studies

Two review authors (MEA and DO) independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion.

Data extraction and management

We intended to use the methods described in the protocol for the included trials. We designed a form to extract data; however, there were no eligible studies. The methods to be used in subsequent updates of this review, as data become available, are outlined in Appendix 2.

Results

Description of studies

Results of the search

The search of the Pregnancy and Childbirth Group's Register found one trial report for consideration (Zhang 2004). Additional searching did not find any other trials.

Included studies

We did not include any studies.

Excluded studies

We excluded one study from the review, as it was a matched‐case control study (Zhang 2004). The group allocation was not random. It was based on economic affordability of the cost of the intra‐amniotic surfactant.

Risk of bias in included studies

There are no trials that meet the inclusion criteria for this review.

Effects of interventions

There are no trials that meet the inclusion criteria for this review.

Discussion

Animal studies indicate that intra‐amniotic instillation of surfactant may be as effective as post‐delivery intratracheal administration in prevention of respiratory distress syndrome (Galan 1992; Galan 1993). The physiological basis for this is discussed in the Background above.

All identified human studies (Cosmi 1996a; Cosmi 1996b; Cosmi 1996c; Cosmi 1997; Lisawa 2003; Petrikovsky 1995; Zhang 2002 ) were observational studies (case‐control, case reports or case series). The largest study, a matched case‐control study by Zhang 2004, included 15 at‐risk women (one twin pregnancy) who were treated with intra‐amniotic Exosurf or Curosurf. In this study, intra‐amniotic surfactant was associated with lower rate of respiratory distress syndrome, respiratory support and duration of hospitalisation and was not associated with any major maternal or neonatal complications. The other case series and case reports showed similar results. However, there are no randomised trials to conclusively prove or disprove this.

These observational studies show that intra‐amniotic instillation of surfactant for women at risk of preterm birth is potentially safe, feasible and effective. Well‐designed randomised controlled trials are needed to evaluate the effect of intra‐amniotic surfactant.

Summary of main results

There are no trials that meet the inclusion criteria for this review.

Overall completeness and applicability of evidence

There are no trials that meet the inclusion criteria for this review.

Quality of the evidence

There are no trials that meet the inclusion criteria for this review.

Potential biases in the review process

There are no trials that meet the inclusion criteria for this review.

Agreements and disagreements with other studies or reviews

We have identified no trials in other reviews.

Authors' conclusions

Implications for practice.

We found no randomised trials that evaluated the effect of intra‐amniotic instillation of surfactant for women at risk of preterm birth. The use of intra‐amniotic surfactant should be limited to randomised controlled trials.

Implications for research.

Evidence from animal and observational human studies suggest that intra‐amniotic surfactant administration is potentially safe, feasible and effective. Well designed trials of intra‐amniotic instillation of surfactant for women at risk of preterm birth are needed.

What's new

Date	Event	Description
16 May 2012	Amended	Contact details updated.

Appendices

Appendix 1. MEDLINE search strategy

MEDLINE (1950 to August 2009) ‐ search carried out by authors:

#1 exp pregnancy 
 #2 exp infant newborn 
 #3 exp obstetric labor, premature  
 #4 exp premature birth 
 #5 pregnan*.mp OR prematur*.mp OR preterm.mp OR neonat*.mp OR infant*.mp OR newborn.mp 
 #6 #1 OR #2 OR #3 OR #4 OR #5 
 #7 intraamniotic.mp 
 #8 intra‐amniotic.mp 
 #9 intrapartum.mp OR antenatal.mp OR prenatal.mp OR ante‐natal.mp OR pre‐natal.mp 
 #10 intra‐partum.mp 
 #11 #7 OR #8 OR #9 OR #10 
 #12 exp pulmonary surfactants 
 #13 surfactant*.mp OR Beractant.mp OR Poractant.mp OR Curosurf.mp OR Survanta.mp OR Exosurf.mp OR Lucinactant.mp 
 #14 #12 or #13 
 #15 #6 AND #11 AND #14

Appendix 2. Methods to be used in subsequent updates of this review

Data extraction and management  

We will design a form to extract data. For eligible studies, review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a review arbiter. We will enter data into Review Manager software (RevMan 2008) and check them for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies  

All three review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We will resolve any disagreement by discussion or by involving a review arbiter. We plan to assess the following.

(1) Sequence generation (checking for possible selection bias)

We will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the methods as:

• adequate (any truly random process, e.g. random number table; computer random number generator);

• inadequate (any non random process, e.g. odd or even date of birth; hospital or clinic record number); or

• unclear.   

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

• adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• inadequate (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

• unclear.   

(3) Blinding (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We planned to judge studies to be at low risk of bias if they were blinded, or if we judge that the lack of blinding could not have affected the results. We planned to assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

• adequate, inadequate or unclear for participants;

• adequate, inadequate or unclear for personnel;

• adequate, inadequate or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we plan to re‐include missing data in the analyses which we undertake. We will assess methods as:

• adequate (less than 20% missing data);

• inadequate;

• unclear.

(5) Selective reporting bias

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

• adequate (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);

• inadequate (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

• unclear.

(6) Other sources of bias

We will describe for each included study any important concerns we have about other possible sources of bias (e.g. early termination of trial due to data‐dependant process, extreme baseline imbalance, etc). We will assess whether each study was free of other problems that could put it at risk of bias. We will assess other sources of bias as:

• yes;

• no;

• unclear.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses ‐ see Sensitivity analysis. 

Measures of treatment effect  

We will analyze treatment effects in the individual trials using Review Manager software (RevMan 2008).

Dichotomous data

For dichotomous data, we will present results as risk ratios and risk differences (RD) with 95% confidence intervals (CI). If there is a statistically significant reduction in RD then we will calculate the number needed to treat and associated 95% CI.

Continuous data

For continuous data, we will use the mean difference if outcomes were measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.  

Unit of analysis issues  

The unit of analysis will preferably be the unit of randomization. However, we will report outcomes in multiple pregnancies according to treatment. That is, for monoamniotic multiples we will report the individual outcomes independently. Where diamniotic twins are randomized separately, we will analyze each multiple as randomized and treated. In a diamniotic pregnancy where both sacs are randomized together to the same treatment, we will still use the infant as the unit of analysis. Some studies may have multiple treatment groups; in this case, we will use the relevant data separately in each comparison (intra‐amniotic surfactant versus placebo, intra‐amniotic surfactant versus no treatment, intra‐amniotic surfactant versus post‐delivery tracheal surfactant). Where more than one active treatment group is eligible for inclusion in a comparison, we will collapse the groups into a single arm for comparison against the control group.

Cluster‐randomised trials

We will include cluster‐randomised trials in the analyses along with individually randomised trials. We will analyse them using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) using an estimate of the intra‐cluster correlation co‐efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources were used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we will synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta‐analysis.

Dealing with missing data  

The primary analysis will be an intention to treat analysis reporting only available data (excluding cases where data is missing). For included studies, we will note levels of attrition. We will obtain missing data from the authors when possible. Where data remains missing, we will conduct sensitivity analysis to determine if results are sensitive to assumptions regarding losses, using imputation (both best and worst scenarios) method and last observation carried forward to the final assessment (LOCF) for dichotomous and continuous outcome data respectively.

Assessment of heterogeneity  

We planned, had there been trials identified for inclusion, to use the I² statistic to measure heterogeneity among the trials in each analysis. Had we identified substantial heterogeneity, we planned to explore it by pre‐specified subgroup analysis. We planned to grade the degree of heterogeneity as 0% to 30% (might not be important); 31% to 50% (moderate heterogeneity); 51% to 75% (substantial heterogeneity); 76% to 100% (considerable heterogeneity).

Assessment of reporting biases  

We will investigate reporting and publication bias by examining the degree of asymmetry of a funnel plot. Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a Sensitivity analysis.

Data synthesis  

We will carry out statistical analysis using the Review Manager software (RevMan 2008). We will use fixed‐effect inverse variance meta‐analysis for combining data where trials examine the same intervention, and the trials population and methods are judged similar. Where we suspect clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we will use random‐effects meta‐analysis. If we identify substantial heterogeneity in a fixed‐effect meta‐analysis, we will note this and repeat the analysis using a random‐effects method. We will assess the possible source(s) of heterogeneity using subgroup and sensitivity analysis.

Subgroup analysis and investigation of heterogeneity  

If sufficient data are available, we will explore potential sources of clinical heterogeneity through the following a priori subgroup analyses:

1. gestational age at time of intra‐amniotic surfactant administration (less than 28, 28 to 31, 32 to 34 and greater than or equal to 35 completed weeks' gestation);

2. antenatal steroid use (none, less than 24 hours, within last seven days, greater than seven days, multiple courses);

3. type of surfactant instilled (synthetic, natural, recombinant);

4. dose of intra‐amniotic surfactant administered;

5. indication for intra‐amniotic surfactant administration ‐ reason woman was considered to be at risk for preterm birth at trial entry (e.g. presence or absence of ruptured membranes, antepartum haemorrhage, preterm labour, cervical incompetence, pre‐eclampsia, growth restriction);

6. multiple pregnancy (singleton, twin or higher order multiple pregnancy).

For fixed‐effect meta‐analyses we will conduct planned subgroup analyses classifying whole trials by interaction tests as described by Deeks 2001. For random‐effects meta‐analyses we will assess differences between subgroups by inspection of the subgroups’ confidence intervals; non‐overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.

Sensitivity analysis  

We will explore methodological heterogeneity through the use of sensitivity analysis. We will assess studies at low risk of bias as those with adequate sequence generation, allocation concealment, and less than 10% losses with intention‐to‐treat analysis.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Zhang 2004

Matched‐case control study. Group allocation was not random. Women assigned to groups based on whether they could afford the cost of intra‐amniotic surfactant (cases) or not (control). Surfactant administered intra‐amniotically through amniocentesis needle under ultrasound guidance in the proximity of fetal nostrils and mouth in 15 pregnant women (16 infants) at mean (SD) gestation of 28.4 (3.4) weeks, with immature amniotic fluid indices of fetal lung maturity, and whose delivery was imminent. Intravenous aminophylline was administered to some mothers after administration of surfactant.

SD: standard deviation

Differences between protocol and review

None.

Contributions of authors

Mohamed E Abdel‐Latif wrote the first draft of the review and revised subsequent drafts; assessed study eligibility, carried out data extraction, and entered data.

David A Osborn assessed study eligibility, entered data, carried out data extraction, checked data, commented on drafts of the review and supervised the whole project.

Daniel Challis assessed study eligibility and commented on drafts of the review.

Declarations of interest

None known.

Edited (no change to conclusions)