CENTRAL indicates Cochrane Central Register of Controlled Trials; CINAHL, Cumulative Index to Nursing and Allied Health Literature; RCT, randomized clinical trial.
A, Chronic lung disease and/or death; B, chronic lung disease alone; C, death alone; D, air leakage; and E, severe intraventricular hemorrhage. The analyses were conducted using random-effects models (Mantel-Haenszel test) without adjustment. INSURE indicates intubate-surfactant-extubate; NCPAP, noninvasive continuous positive airway pressure; and M-H random, Mantel-Haenszel random-effect methods.
eAppendix. Study Protocol
eTable 1. Search Strategies for MEDLINE
eTable 2. The Incidence of the Outcomes and the Number of Missing Data in Included Studies
eTable 3. Risk of Bias of the Included Studies for Prevention of Chronic Lung Disease in Preterm Infants by INSURE vs NCPAP
eTable 4. Sensitivity Analyses for Prevention of Chronic Lung Disease in Preterm Infants by INSURE vs NCPAP
eTable 5. Optimal Information Sizes for Each Outcome
eFigure 1. Forrest Plots for Predefined Subgroup Analyses
eFigure 2. Forrest Plots for a Post Hoc Subgroup Analyses Stratified by Fio2 Threshold for NCPAP Failure in the NCPAP Group
eFigure 3. Funnel Plots
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Isayama T, Chai-Adisaksopha C, McDonald SD. Noninvasive Ventilation With vs Without Early Surfactant to Prevent Chronic Lung Disease in Preterm Infants: A Systematic Review and Meta-analysis. JAMA Pediatr. 2015;169(8):731–739. doi:10.1001/jamapediatrics.2015.0510
Controversy exists regarding which of the 2 major strategies currently used to prevent chronic lung disease (CLD) in preterm infants is optimal: noninvasive continuous positive airway pressure (NCPAP) or intubate-surfactant-extubate (INSURE). Preterm infants often require surfactant administration because of respiratory distress syndrome.
To evaluate whether early INSURE or NCPAP alone is more effective in preventing CLD, death, or both.
We searched the MEDLINE, EMBASE, Cochrane Controlled Trials Register, and Cumulative Index to Nursing and Allied Health Literature databases from their inception to January 2, 2015, along with conference proceedings and trial registrations.
Randomized clinical trials that compared early INSURE with NCPAP alone in preterm infants who had never been intubated before the study entry were selected. Among 1761 initially identified articles, 9 trials (1551 infants) were included.
Data Extraction and Synthesis
Duplicate study selection and data extraction were performed. Meta-analysis was conducted using random-effects models with quality-of-evidence assessment according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.
Main Outcomes and Measures
Seven main outcomes were selected a priori to be assessed according to GRADE, including a composite outcome of CLD and/or death, CLD alone, death alone, air leakage, severe intraventricular hemorrhage, neurodevelopmental impairment, and a composite outcome of death and/or neurodevelopmental impairment.
There were no statistically significant differences between early INSURE and NCPAP alone for all outcomes assessed. However, the relative risk (RR) estimates appeared to favor early INSURE over NCPAP alone, with a 12% RR reduction in CLD and/or death (RR, 0.88; 95% CI, 0.76-1.02; risk difference [RD], −0.04; 95% CI, −0.08 to 0.01; moderate quality of evidence), a 14% decrease in CLD (RR, 0.86; 95% CI, 0.71-1.03; RD, −0.03; 95% CI, −0.06 to 0.01; moderate quality of evidence), and a 50% decrease in air leakage (RR, 0.50; 95% CI, 0.24-1.07; RD, −0.03; 95% CI, −0.06 to 0.00; very low quality of evidence). The sample size was less than the optimal information size.
Conclusions and Relevance
Currently, no evidence suggests that either early INSURE or NCPAP alone is superior to the other. INSURE does not appear to increase CLD and/or death, CLD alone, and air leakage and may reduce these adverse outcomes compared with NCPAP alone. Further adequately powered trials are required.
Chronic lung disease (CLD), also called bronchopulmonary dysplasia, is one of the most important morbidities in preterm infants, characterized by a prolonged need for supplemental oxygen and/or respiratory support.1 Infants with CLD have higher risks of postdischarge mortality and respiratory morbidity along with neurodevelopmental impairments later in life.2 Approximately 30% of very low-birth-weight infants develop CLD,3 and the rate reaches 40% for those born at 28 weeks’ gestation or less. Regardless of the improvement in survival of very low-birth-weight infants in the last 2 decades, the CLD rate has not decreased3 or even increased.4 Although CLD is a multifactorial disease, prematurity and ventilator-induced lung injuries from volutrauma, barotrauma, and oxygen toxicity accompanied with prolonged mechanical ventilations are a major cause of CLD.1 Approximately two-thirds of preterm infants born at less than 33 weeks’ gestations have respiratory distress syndrome5 shortly after birth and often require intubations for surfactant administration followed by ventilatory support.6
Several previous systematic reviews7-9 of randomized clinical trials of preterm infants found that the early use of noninvasive continuous positive airway pressure (NCPAP) to avoid mechanical ventilation decreased CLD, death, or both compared with the respiratory management using routine intubation. Accordingly, clinical practice guidelines from the European Association of Perinatal Medicine6 and the American Academy of Pediatrics10 added a recommendation for the early use of NCPAP, avoiding intubation, as an alternative to a routine or early surfactant administration recommended in their previous guidelines.11,12 However, one major disadvantage of this NCPAP strategy without intubation is a lack or delay of the administration of surfactant that is generally given via an endotracheal tube after intubation.13 Early surfactant compared with delayed administration for respiratory distress syndrome is effective in preventing CLD14 and recommended.6 Therefore, physicians who treat preterm infants with or at high risk of respiratory distress syndrome currently have a difficult dilemma: avoiding intubation using NCPAP alone without early surfactant administration or intubate to administer surfactant.
Given this clinical dilemma, there has been increasing interest in an intermediate strategy called intubate-surfactant-extubate (INSURE), in which infants are intubated for surfactant administration and immediately extubated to NCPAP. Early INSURE is a promising strategy because it enables early administration of surfactant while avoiding prolonged mechanical ventilation that can lead to CLD.13 However, it is not clear whether early INSURE is superior to NCPAP. Therefore, this systematic review and meta-analysis of randomized clinical trials aimed to examine whether early INSURE, compared with NCPAP alone, is more effective in preventing death, CLD, or both in preterm infants with or at high risk of respiratory distress syndrome.
This systematic review aimed to compare the effectiveness of the 2 major strategies currently used to prevent chronic lung disease (CLD) of preterm infants: intubate-surfactant-extubate (INSURE) and noninvasive continuous positive airway pressure (NCPAP).
Although there were no statistically significant differences, the relative risk (RR) estimates appeared to favor early INSURE over NCPAP alone for CLD and/or death, CLD alone, and air leakage, with RRs (95% CIs) of 0.88 (0.76-1.02), 0.86 (0.71-1.03), and 0.50 (0.24-1.07), respectively.
There is no evidence suggesting that either early INSURE or NCPAP alone is superior to the other; however, INSURE at least does not appear to increase CLD and/or death, CLD alone, and air leakage and may reduce these adverse outcomes compared with NCPAP alone.
The protocol of this systematic review, written before the literature search, is available in the eAppendix in the Supplement. This systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions15 and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.16
All published and unpublished randomized clinical trials were included with no language restrictions. This systematic review included studies that compared early INSURE vs NCPAP alone for preterm infants born at less than 37 weeks’ gestational age with or at high risk of respiratory distress syndrome who had never been intubated before the study entry. Infants in the early INSURE group were intubated, given surfactant, and extubated to NCPAP within 1 hour after intubation. Infants in the NCPAP alone group continued to receive NCPAP initially and, when NCPAP was not tolerated, rescued by intubation followed by mechanical ventilation or INSURE.
This systematic review excluded the following: studies using surfactant administration methods without intubation, such as nebulized surfactant17 or instillation via a thin catheter inserted directly into the trachea or a laryngeal mask airway18; studies in which infants in both the early INSURE and NCPAP alone groups were not routinely administered NCPAP; and duplicated studies or data and studies without sufficient data regarding the outcomes to be summarized.
Seven important patient outcomes were selected a priori to be assessed in this systematic review, including (1) a composite outcome of CLD (the most important respiratory outcome of preterm infants, which was defined as is typical as oxygen use and/or reparatory support at 36 weeks’ postmenstrual age) and/or death at discharge, (2) CLD alone, (3) death at discharge alone, (4) air leakage (pneumothorax and/or pulmonary interstitial emphysema), (5) severe intraventricular hemorrhage (grade 3 or 4),19 (6) neurodevelopmental impairment (cerebral palsy, cognitive deficit, hearing loss, or blindness) at 18 months or older, and (7) a composite outcome of death and/or neurodevelopmental impairment at 18 months or older.
The literature searches were conducted in MEDLINE (1946 to January 2, 2015), EMBASE (1980 to January 2, 2015), Cochrane Central Register of Controlled Trials (CENTRAL, January 2, 2015), and Cumulative Index to Nursing and Allied Health Literature (1991 to January 2, 2015) and through hand searching of references in narrative and systematic reviews. The search strategy used for MEDLINE, which was modified for other databases, is available in eTable 1 in the Supplement. Search terms included 3 concepts: (1) newborns or infants (population), (2) surfactant (intervention), and (3) randomized clinical trials (study design). Abstracts or conference proceedings of the Pediatric Academic Society (2002-2014) and International Workshop on Surfactant Replacement (2006-2014) were searched. Trial registrations, including ClinicalTrials.gov20 and World Health Organization International Clinical Trials Registry Platform,21 were searched to find unpublished or recent completed relevant trials.
All records found in the literature search were screened by titles and abstracts. Potentially relevant records were selected for full-text review. Data were extracted using a data collection form designed for this systematic review. We contacted authors for missing data or clarifications, if needed.
The risk of bias was assessed for each outcome in all included studies using the Cochrane Systematic Review Handbook.15 The risk of bias was evaluated for random sequence generation, allocation concealment, masking of participants and personnel (performance bias), masking of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other risk of bias.15
The study selection, data extraction, and risk of bias assessment were independently conducted by 2 authors (T.I. and C.C.-A.). The agreements between these 2 reviewers for the study selection and risk of bias assessment were evaluated using a weighted κ statistic and the percentage of overall agreement. The disagreements between the 2 reviewers were resolved through discussion, with a third reviewer available for adjudication if needed (S.D.M.).
To incorporate heterogeneity among studies and potentially yield more conservative results, primary meta-analyses were conducted with Mantel-Haenszel random-effects methods as planned a priori using Review Manager (RevMan), version 5.1 (The Nordic Cochrane Centre, The Cochrane Collaboration).15 The pooled results were summarized as relative risks (RRs), risk differences (RDs), and 95% CIs along with forest plots for each outcome. A 2-sided P < .05 was used to determine statistical significance, and as is typical of systematic reviews, there was no adjustment for multiple outcomes. Heterogeneity among the included studies was assessed by examination of forest plots, the I2 statistic, and χ2 tests for heterogeneity. Three preplanned subgroup analyses were conducted to explore the potential sources of heterogeneities stratified by (1) mean (or median) gestational age of infants (<29 vs ≥29 weeks), (2) back-up measures in the NCPAP group (intubation followed by prolonged mechanical ventilation vs INSURE), and (3) timing of the interventions (≤1 vs >1 hour). These subgroup analyses were based on a priori hypotheses that the RR of CLD, death, or both in the early INSURE group compared with the NCPAP group would be lower in the following subgroups: groups that included very premature infants (gestational age of <29 weeks), the NCPAP back-up measure of intubation followed by prolonged mechanical ventilation, and early interventions (INSURE or NCPAP alone within 1 hour). In addition, a post hoc subgroup analysis was conducted, stratifying by the threshold of fraction of inspired oxygen for NCPAP failure in NCPAP alone group (>40% vs ≤40%). The statistical test for the reporting bias was planned for outcomes with at least 10 included studies.15 Missing data were assessed for each outcome in each study, and complete-case analyses were used in this systematic review. Four sensitivity analyses were conducted to evaluate the robustness of the study results: (1) using random-effects models with Knapp-Hartung adjustment (using R, version 3.1.2, with the metaphor package),22,23 (2) using fixed-effects methods (Mantel-Haenszel test), (3) excluding studies with high risk of biases, or (4) using a broader definition of mortality, including death within 7 or 28 days.
The quality of evidence was assessed and rated using 4 levels (high, moderate, low, or very low) for each outcome across studies and summarized as an evidence profile table according to GRADE.24 The quality of evidence of randomized clinical trials was preliminarily evaluated as high-quality evidence and was downgraded for a risk of bias, imprecision, inconsistency, indirectness, and publication bias for each outcome.25 For the assessment of imprecision, the sample size required to detect a 20% RR reduction, called optimal information sizes, was calculated using total event rates in the control groups of included studies.26
The searches of the electronic databases and gray literature identified 1761 nonduplicate records, among which 62 articles were selected for full-text review (Figure 1) and 9 trials met the inclusion criteria,27-35 with a total of 1551 preterm infants. The agreement of the study selection between the 2 reviewers was excellent, with a κ of 0.828 and a raw agreement of 95.2%. All included studies were randomized clinical trials with 2 parallel groups except for one study,28 which examined 3 parallel groups, from which only 2 groups (early INSURE and NCPAP alone) were included in this systematic review. Authors of 4 included studies28-31,34 provided additional study information related to missing data and outcome definitions for this systematic review. There were variations in the study maternal or infant characteristics (eg, antenatal corticosteroid rate varied from 50% to 99% and gestational age at birth ranged from 25 to 35 weeks), timing of the interventions (from shortly after birth to 72 hours after birth), and back-up measures for NCPAP failure (Table 1). The rates of successful extubation within 1 hour of intubation in the early INSURE group were more than 90% (range, 90.5%-100%) except for one study28 with a slightly lower rate (83.3%). Failure rates (intubation rates) in the NCPAP group varied among included studies (15%-84.8%) but were mostly high (>40% in 7 of 9 trials). The rates of infants who required reintubation after the successful INSURE in the early INSURE group were low (10%-26%) except for in the trials by Verder et al34 (39%), Dunn et al28 (42%), and Reininger et al31 (50%). The incidence of the outcomes and the number of missing data in included studies are given in eTable 2 in the Supplement.
None of the included studies used masking of the interventions except for one trial.31 The lack of masking of health care professionals could have affected clinical care and was considered an unclear risk of bias for performance bias. Because all the outcomes were objective, the detection bias attributable to the lack of masking was considered low risk for most of the outcomes except for CLD, whose diagnoses might be affected by the different criteria of oxygen administration among physicians.36 The data for CLD in the study by Dilmen et al27 and for severe intraventricular hemorrhage in the study by Verder et al35 were judged as being at high risk of attrition bias due to missing data (>10%). Two studies34,35 were stopped early for significant findings that may overestimate intervention effects37 and, hence, were considered at high risk of bias. Two other studies28,31 were stopped early because of slow patient enrollment and were considered at low risk of bias. The consensus of the risk of bias assessment in the included studies between the 2 reviewers (T.I. and C.C.-A.) is reported in eTable 3 in the Supplement. The overall κ and raw agreements with quadratic weighting for the risk of bias between the 2 authors (T.I. and C.C.-A.) were 0.71 and 0.85, respectively.
Although no statistically significant differences were detected, the RR estimates and absolute rates appeared to favor early INSURE over NCPAP alone (Figure 2). There was a 12% reduction in RR estimate of CLD and/or death (RR, 0.88; 95% CI, 0.76-1.02; P = .10; I2 = 0%; RD, −0.04; 95% CI, −0.08 to 0.01; 6 trials with 1250 infants), 14% decrease in CLD (RR, 0.86; 95% CI, 0.71-1.03; P = .10; I2 = 0%; RD, −0.03; 95% CI, −0.06 to 0.01; 6 trials with 1128 infants), and 50% decrease in air leakage (RR, 0.50; 95% CI, 0.24-1.07; P = .07; I2 = 28%; RD, −0.03; 95% CI, −0.06 to 0.00; 9 trials with 1547 infants). The 95% CIs of the RR covered widely more than 1.00 for death (RR, 0.94; 95% CI, 0.67-1.32; P = .72; I2 = 0%; RD, 0.01; 95% CI, −0.02 to 0.03; 7 trials with 1396 infants) and severe intraventricular hemorrhage (RR, 0.79; 95% CI, 0.45-1.39; P = .42; I2 = 0%; RD, −0.00; 95% CI, −0.02 to 0.01; 7 trials with 1325 infants). No study reported neurodevelopmental impairment at 18 months or older.
Three predefined subgroup analyses, based on the mean or median gestational ages, the NCPAP backup measures, and the timing of interventions, and a post hoc subgroup analysis stratified by the fraction of inspired oxygen found no significant differences among the subgroups for any of the 5 outcomes, with P values ranging from .13 to .98 (eFigure 1 and eFigure 2 in the Supplement). The sensitivity analyses found results similar to the primary analyses except for the significant result for CLD in the first sensitivity analysis with Knapp-Hartung adjustment (RR, 0.86; 95% CI, 0.74-0.99) and the wide variation in 95% CIs for the RRs for air leakage (eTable 4 in the Supplement).
The quality of evidence was evaluated across included studies for each outcome and was summarized in a GRADE evidence profile table (Table 2).24,38 The risk of bias was considered not serious for all outcomes except for air leakage because the sensitivity analyses that excluded studies with a high risk of bias found results similar to those in the primary analyses. For air leakage, the risk of bias was considered serious because the sensitivity analyses changed the meta-analysis result. The imprecision was considered serious for all outcomes because the total sample size for each outcome was less than the sample size required for a 20% RR reduction (optimal information size),26 which would be 1440, 2080, 7212, 11 136, and 17 022 infants for CLD and/or death, CLD alone, death alone, air leakage, and severe intraventricular hemorrhage, respectively (eTable 5 in the Supplement). The inconsistency was judged as serious for air leakage because the point estimate of the RR in the study by Sandri et al33 was different from the other studies (Figure 2D). Publication bias was not detected in the funnel plots for any of the outcomes (eFigure 3 in the Supplement). Statistical tests were not conducted because this systematic review included fewer than 10 studies and would have too low a power to detect funnel plot asymmetry.15 The serious imprecision downgraded the quality of evidence from high to moderate for all outcomes. The serious risk of bias and inconsistency downgraded the quality of evidence further by 2 levels for air leakage from moderate to very low.
To our knowledge, this is the first systematic review and meta-analysis that directly compares the effect of early INSURE and NCPAP, the 2 currently recommended forms of management for respiratory distress in preterm infants, representing a dilemma for health care professionals.6,10 This systematic review did not find statistically significant differences between the 2 managements; however, the pooled risk estimates suggested that early INSURE at the very least did not increase and may reduce CLD and/or death, CLD alone, and air leakage, potentially by 12%, 14%, and 50%, respectively. Although the results fell slightly short of statistical significance because of the severity of the outcomes, the findings are likely still clinically important to most health care professionals and patients.
The main strength of this systematic review was the robust methods of systematic review and meta-analysis based on the GRADE system16 and the Cochrane Handbook for Systematic Reviews of Interventions.15 The GRADE system developed as a structured and transparent method to rate and grade quality of evidence for systematic reviews and guidelines. To minimize the risk of bias caused by missing information, the authors of 4 of the included studies28,30,31,34 provided additional study information for this systematic review. Furthermore, similar results obtained in sensitivity analyses indicated a robustness of the findings. However, several limitations are worth noting. First, the sample sizes were less than the optimal information sizes.26 Second, although the heterogeneity among included studies was low (I2 = 0%-28%), some of the study characteristics varied among the included studies, such as infant gestational age, timing of the study enrollment or intervention, and NCPAP back-up measures. We attempted to explore this through 3 preplanned subgroup analyses and did not find any significant between-subgroup differences, possibly because of insufficient sample size.
Although several previous systematic reviews have examined the early INSURE or NCPAP alone, they differed from ours in important ways. A previous Cochrane systematic review39 that included 6 trials with total of 664 preterm infants, with 2 trials overlapping our systematic review,31,34 compared early INSURE with conventional management (control group) in which surfactant was selectively given only to infants who required higher respiratory support. The systematic review found that early INSURE compared with conventional management reduced the RR of supplemental oxygen use at 28 days after birth and air leakage by 49% and 48%, respectively. These results do not contradict our findings that early INSURE did not increase, or might reduce, respiratory morbidity, including CLD and air leakage compared with NCPAP alone. This previous systematic review included studies whose control group did not routinely use NCPAP and likely overestimated the effectiveness of early INSURE because routine NCPAP use has recently become a standard measure to prevent CLD in preterm infants. Furthermore, the systematic review did not evaluate CLD at 36 weeks’ postmenstrual age, the most important respiratory outcome. Two other systematic reviews7,9 reported that the NCPAP alone compared with early routine intubation (including INSURE) for preterm infants significantly reduced the RR of CLD and/or death by 9% and 17%, respectively. Because these systematic reviews did not differentiate INSURE and prolonged mechanical ventilation in their intubation group, it was impossible to assess the effectiveness of early INSURE alone. In addition, unlike the early INSURE group in our systematic review, surfactant administration was not mandatory in the routine intubation group, which might underestimate the effectiveness of the routine intubation management. Another systematic review8 compared the prophylactic surfactant administration and NCPAP alone with late selective surfactant administration in preterm infants. Unlike our systematic review, all infants in the intervention group (prophylactic surfactant) were routinely given mechanical ventilatory assistance after surfactant administration. This systematic review found a significant increase in CLD and/or death and a near-significant increase of CLD in the prophylactic early surfactant (intubation) group compared with NCPAP use with late selective surfactant administration. All the aforementioned 3 systematic reviews7-9 concluded that early intubation with or without prophylactic surfactant increased the risk of death and/or CLD compared with the NCPAP alone. Of interest, their conclusions contrasted with the results in our systematic review, which concluded that early INSURE (requiring early intubation) did not increase and potentially reduced death and/or CLD and CLD alone compared with NCPAP alone. This difference in the results may be due to the differences in the intubation groups in the previous systematic reviews, all of which included studies that used routine prolonged mechanical ventilation, a well-known risk factor for CLD.1
Unlike the recent findings from other systematic reviews reporting that early intubation increased CLD and/or death compared with NCPAP alone, this systematic review revealed that early INSURE (one of the early intubation strategies) did not increase CLD and/or death, CLD alone, and air leakage and may be more effective than NCPAP alone to prevent these outcomes. Given the relative complexity and costliness of early INSURE procedures that require intubation, surfactant administration, and immediate extubation to NCPAP compared with simple NCPAP placement, some health care professionals, especially in those resource-limited environments, may prefer to try NCPAP alone first. On the other hand, considering the potential relative effectiveness of early INSURE along with the high NCPAP failure rates, some health care professionals may prefer early INSURE to try to avoid the delay of surfactant administration to prevent CLD. Because the total sample size of included studies did not reach the optimal information size, resulting in serious imprecision, further studies will be needed to obtain more precise effect estimates.
Accepted for Publication: June 8, 2015.
Corresponding Author: Tetsuya Isayama, MD, Department of Newborn and Developmental Paediatrics, Sunnybrook Health Science Centre, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada (firstname.lastname@example.org).
Published Online: June 8, 2015. doi:10.1001/jamapediatrics.2015.0510.
Author Contributions: Dr Isayama had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Isayama.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Isayama.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Isayama.
Administrative, technical, or material support: Chai-Adisaksopha.
Study supervision: McDonald.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study is supported by Canadian Institutes of Health Research New Investigator Salary Award CNI95357 (Dr McDonald).
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Additional Contributions: The 5 first authors of the included studies (Michael Dunn, MD, Hemasree Kandraju, DNB, Srinivas Murki, DM, Carl D’Angio, MD, and Henrik Axel Verder, DMSc) provided additional study information for this systematic review. Neera Bhatnagar, MLIS, and Vanessa Kitchin, MI, from the Health Science Library of the McMaster University assisted with the development of the literature search strategies. The lecturers and tutors of a systematic review course at the McMaster University provided advice on this systematic review.
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