Randomized and quazi-randomized controlled trials comparing digoxin to placebo treatment.

Premature infants (< 37 weeks gestation) at risk of developing respiratory distress syndrome (infants delivered by cesarean section, infants of diabetic mothers, and low birth weight infants) or infants with a clinical diagnosis of RDS.

Infants were randomized to receive digoxin (initial digitalizing dose followed by 72 hours of maintenance therapy) or placebo treatment.

Primary outcomes

Secondary outcomes

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

Both review authors separately extracted, assessed and coded all data for each study using a form that was designed specifically for this review. For each included study, information was collected regarding the method of randomization, blinding, drug intervention, stratification, and whether the trial was conducted at a single center or multiple centers. Information regarding inclusion criteria, including gestational age, postnatal age at the time of treatment, and disease severity criteria was noted. Information on clinical outcome included only mortality. Differences in assessment were resolved by discussion. For each study, final data was entered into RevMan by one review author (RFS) and then checked by a second review author (EO). Any disagreements were resolved by discussion.

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 Characteristics of Included Studies table. 

In addition, for the update in 2010, the following issues were evaluated and entered into the Risk of Bias table: 

1) Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated? For each included study, we categorized the method used to generate the allocation sequence 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); 

- unclear.  

(2) Allocation concealment (checking for possible selection bias). Was allocation adequately concealed? For each included study, we categorized the method used to conceal the allocation sequence as:  

- adequate (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);  

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

- unclear.  

(3) Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment? For each included study, we categorized the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We categorized 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). Were incomplete outcome data adequately addressed? For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods as:  

- adequate (< 20% missing data);  

- inadequate (≥ 20% missing data):  

- unclear.  

(5) Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting? 

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed 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. Was the study apparently free of other problems that could put it at a high risk of bias? 

For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as: 

- yes; no; or unclear.   

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

The standard methods of the Neonatal Review Group were used. 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.

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 I-squared statistic. 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. We planned to use a fixed effects model for meta-analysis.

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.

Subgroups analyses (if available):

• premature infants less than 30 weeks gestation.
• infants with established RDS.