Introduction

Preterm birth complications are the most common cause of death in children aged 5 years or less. Out of the 6.3 million children who died before age 5 in 2013, about 1 million (15.4%) died because of these conditions.1 The major morbidities that result in deaths in preterm neonates include respiratory distress syndrome (RDS), intraventricular hemorrhage and necrotizing enterocolitis. RDS, in addition to being a direct cause of mortality, also contributes indirectly by increasing the risk of intraventricular hemorrhage, bronchopulmonary dysplasia (BPD) and nosocomial infections such as ventilator-associated pneumonia.2

RDS is caused by the deficiency of pulmonary surfactant in preterm neonates. Its incidence increases with decreasing gestational age, the risk being 60% in less than 28 weeks and 30% between 28 and 34 weeks of gestation. If left untreated, it leads to high mortality; the reported case fatality is 57 to 89% in low- and middle-income countries (LMICs).3 The assessment of the burden of RDS, in general, and in LMICs, in particular, is difficult. Assuming the incidence of RDS to be 1% of all live births—a relatively conservative estimate—approximately 1.4 million neonates develop RDS every year across the globe (total live births 137 688 million per year).1

In addition to optimal respiratory support in the form of continuous positive airway pressure (CPAP) or mechanical ventilation and good supportive care, surfactant replacement therapy (SRT) forms the mainstay in the management of RDS. Since the report by Fujiwara in 1980 of the first successful use of SRT,4 numerous randomized controlled trials (RCTs) and their meta-analyses have established its efficacy in reducing mortality and air leak syndromes in RDS.5, 6 Almost all the trials evaluating the role of SRT were conducted in high-income countries (HICs). Not surprisingly, SRT is the standard of care in neonates with RDS in these countries.

Can we extrapolate the evidence from HICs to LMICs and recommend SRT as the standard of care? The answer to this question is critical because the high cost of the drug, lack of skilled personnel and a sub-optimal support system7 preclude an immediate and effective roll-out of the intervention in most neonatal units of LMICs. The paucity of evidence for efficacy and/or safety of SRT in these settings further adds to the complexity. With the lack of skilled manpower and optimal respiratory support, SRT may not be as effective; moreover, there may be safety concerns due to inadequate supervision and monitoring. The present systematic review therefore aimed to synthesize the evidence on the efficacy, safety, feasibility and cost effectiveness of implementing SRT in LMIC settings. The findings of the review should help policy makers and other stakeholders to make an informed decision regarding the introduction and/or scaling-up of the intervention in different LMIC settings.

Methods

Objectives

The two major objectives of this review were to evaluate (1) the efficacy and safety of SRT and (2) the feasibility and cost effectiveness of introducing and implementing SRT in LMIC settings.

Types of studies

For objective 1, we included all studies—both observational and experimental (RCTs and quasi-randomized trials)—from LMICs that compared the effects of SRT with no or placebo therapy in preterm neonates with RDS. For objective 2, we included all studies that reported the use of SRT in preterm neonates with or at-risk of RDS.

Interventions

All studies that compared the effect of single or multiple doses of surfactant therapy by the intratracheal route (animal-derived or synthetic surfactant preparation) with no/placebo treatment in eligible neonates were included.

Outcomes

Table 1 provides the list of critical outcomes and their definitions.

Table 1 Objectives and outcomes
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Search methods for identification of studies

We used two different strategies to identify the relevant studies. First, we updated two Cochrane reviews on the effects of animal-derived surfactant5 and synthetic surfactant.6 We searched the electronic bibliographic databases including MEDLINE, Cochrane CENTRAL, Embase and CINAHL from year 1998 to July 2013 using the search terms 'surfactant' OR 'pulmonary surfactant'. The search was limited by using the filters ‘human studies’, ‘clinical trial’ and ‘newborn’. No language restrictions were used. In addition, we also scanned the list of excluded studies in the Cochrane reviews for any observational studies on SRT.

In the second strategy, we searched PubMed, Cochrane CENTRAL and WHOLIS till July 2013. We used the following search terms for searching PubMed—(surfactant OR pulmonary surfactant) AND 'LMIC'. The search terms for LMIC were adapted from two earlier reviews.8, 9 Similar terms were used for searching the other databases. For both strategies, we updated the search to December 2014. Because of practical difficulties, we could search EMBASE and CINAHL from 2007 to 2013 only.

We scanned the title and abstract of the retrieved citations to exclude those that were obviously irrelevant. We obtained the full text of the remaining studies to identify relevant articles.

Data extraction and management

Two review authors (MJS and NG) independently identified and assessed the studies for inclusion in this review. Each reviewer separately extracted data using the standardized data extraction forms. Any disagreements were resolved through discussion with the third author (RA).

Methodological quality

We independently evaluated the methodological quality of the included studies using the standard methods of the Cochrane Review Group including allocation concealment, blinding and completeness of follow up (classified as yes, no or unclear). For objective 2, we did not carry out any quality assessment (because of the nature of the studies included).

Statistical analysis

Meta-analysis was performed using Stata 11.2 software (StataCorp, College Station, TX, USA). Pooled estimates were calculated from the relative risks (RRs) and 95% CIs of the individual studies by generic inverse variance method with the user-written ‘metan’ command in Stata. We examined heterogeneity among the included studies by eyeballing the forest plots and quantified it using the I2 statistic. If significant heterogeneity existed in both direction and magnitude of the effect sizes of individual studies, we did not pool them. If heterogeneity was essentially due to a difference in the magnitude and not in the direction of effect sizes, we pooled the studies by the random effects model.

Results

Figure 1 depicts the number of studies identified by the two search strategies.

Figure 1
figure 1

Flow chart depicting the selection of studies included in the meta-analysis.

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The Cochrane review on animal-derived surfactant treatment included 13 RCTs conducted in level-3 neonatal intensive care units (NICUs) of HICs.5 The other review on synthetic surfactant treatment in established RDS included six RCTs and was last updated in 1998.6 Upon updating the two reviews, we did not identify any additional eligible studies for inclusion in our review.

After screening the title/abstract or assessing the full text of potentially eligible articles identified by the second search strategy, we included a total of 38 studies: two RCTs, 12 before-and-after studies, eight each of concurrent control and case-control studies, and eight case-series from LMICs. Descriptions of the observational studies have been provided as and when applicable in the subsequent sections.

Effect on mortality

We identified two RCTs from LMICs that examined the effect of surfactant therapy on mortality in preterm neonates with RDS. One RCT compared the effect of synthetic surfactant with no surfactant and found no difference in the risk of mortality (RR 0.73; 95% CI 0.37 to 1.42).10 In another RCT, preterm neonates (24–31 weeks gestation) with signs of respiratory distress within 60 min of birth were randomized into nasal intermittent positive pressure ventilation (NIPPV)+surfactant or NIPPV alone. Both groups were initially stabilized with CPAP and were switched to NIPPV within the first hour. Surfactant therapy was administered to either group (repeat dose for NIPPV+surfactant group and first dose for NIPPV group) if the infants needed a FiO2 of >0.45 to maintain the targeted saturation. There was no statistically significant difference in mortality between the two groups (RR 0.52; 95% CI 0.05 to 5.40).11

A total of 22 observational studies reported the effect of SRT on in-hospital or neonatal mortality in preterm neonates with RDS (Table 2). These studies can be broadly categorized into three groups: before and after time-series/comparison with historical controls, comparison with concurrent controls—those who received and those who did not receive surfactant therapy—and case-control studies (‘typical’ case-control or analysis of prospective data as though it were a case-control study).

Table 2 Studies on effectiveness and feasibility of SRT in LMIC settings
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Before-and-after studies/comparison with historical controls

Eleven studies compared the in-hospital/neonatal mortality of neonates with RDS admitted in two time periods—before and after introduction of SRT.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 Of these studies, nine reported a significant reduction in mortality between the two time periods.13, 14, 15, 16, 17, 18, 20, 21, 22 One study from South Africa, which compared the mortality of neonates born between 1991 and 1992 with those born between 1989 and June 1991, did not report any difference (RR 0.86; 95% CI 0.41 to 1.78).12 However, surfactant was administered only in severe RDS with a high FiO2 requirement in the former period; about 41% of neonates with RDS did not receive surfactant. Another study from Curaçao compared the outcomes of very low birth weight (VLBW) neonates admitted between 1994 and 1998 with those admitted between 1991 and 1994 and found no significant difference in mortality.19

Comparison of concurrent controls

Eight studies compared the risk of mortality between neonates who received SRT with those who did not receive it (Table 2).23, 24, 25, 26, 27, 28, 29, 30 In most studies, the decision to administer surfactant was based on financial considerations. Six studies reported a significant reduction in mortality in the surfactant treated group, the RRs varying from 0.43 to 0.76.23, 24, 25, 26, 27, 30 Two studies from China that compared surfactant therapy with NIPPV/CPAP with only NIPPV/CPAP reported no significant reduction in mortality.28, 29

Case-control studies

Three studies compared the odds of receiving surfactant therapy in those who died with those who survived to discharge.31, 32, 33 The proportion of neonates who received surfactant was low (<25%) in two studies;31, 32 it was not reported in the third.33 Although one study reported significantly lower odds of mortality in neonates who received SRT(32),31 the other two did not report any reduction.32, 33

Pooled analysis of all the studies including the two randomized trials showed a significant reduction in the risk of mortality at the last available time point in neonates who received surfactant therapy (pooled RR 0.67; 95% CI 0.57 to 0.79; Figure 2).

Figure 2
figure 2

Pooled effect of surfactant replacement therapy on mortalitya in studies from low- and middle-income countries settings.

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Effect on BPD

The randomized trial on NIPPV+surfactant vs NIPPV alone found no difference in the incidence of BPD (RR 0.95; 95% CI 0.50 to 1.80).11 A total of six before-and-after/cohort studies reported the effect of SRT on the risk of BPD (Table 2).12, 14, 16, 18, 19, 24 Of these, three did not show any significant benefit.12, 16, 19 One prospective study from India reported a significantly lower incidence of BPD in the surfactant group.24 Another study that compared the outcomes of neonates at two different time points—before and after introduction of surfactant—also reported a significant improvement in the incidence of survival without BPD.18 In contrast, the study from a network of NICUs in Latin America reported a significantly higher risk of BPD in neonates who received surfactant therapy.14

Six case-control studies compared the odds of receiving surfactant therapy in VLBW neonates who developed BPD with those who did not (Table 2).33, 34, 35, 36, 37, 38 One study found no association between surfactant use and BPD.34 Another study reported significantly higher odds of BPD in those who received surfactant therapy, but the effect was not adjusted for key confounders such as gestation and birth weight.32 The other four studies reported significantly higher odds of BPD in those who received SRT even after adjusting for potential confounders by multivariate regression analysis. The adjusted odds ratios varied from 1.4 to 7.5.

Given the huge heterogeneity, we did not attempt to pool the results of individual studies.

Effect on air leaks

A total of six studies—four observational and two randomized trials—compared the risk of air leaks in neonates who received surfactant therapy with those who did not receive it (Table 2).10, 11, 12, 16, 18, 24 Of these, four did not show any significant difference.10, 16, 18, 24 One study from South Africa reported a significantly lower incidence of pneumothorax in the surfactant group.12 Pooled analysis of the five studies with complete data showed a significant reduction in the risk of air leaks following SRT (pooled RR 0.51; 95% CI 0.29 to 0.90; Figure 3).

Figure 3
figure 3

Pooled effect of surfactant replacement therapy on air leaks in studies from low- and middle-income countries settings.

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Safety of SRT

One RCT reported the incidence of pulmonary hemorrhage and found no difference between SRT and control groups.10 We identified one observational study from Uruguay that compared the outcomes of neonates who received SRT with those of historical controls in 19 NICUs across five Latin American countries.14 The proportion of neonates with pulmonary hemorrhage (and patent ductus arteriosus) was significantly higher in neonates who received surfactant. In contrast, another study from Chile that reported data from the network of NICUs participating in the national program on surfactant use found no difference in the proportion of neonates developing pulmonary hemorrhage before and after introduction of SRT.20 However, the proportion with pulmonary hemorrhage was very high—about 30% in both groups (Table 3). One study from Thailand compared the proportion of neonates with pulmonary hemorrhage in two time periods—immediately after introduction of surfactant (1999 to 2002) with 1 to 3 years after (2003 to 05).39 The authors reported a significant reduction in pulmonary hemorrhage in the latter period (RR 0.36; 95% CI 0.17 to 0.76). Five case-series from Brazil, India, South Africa and Turkey reported the proportion of neonates developing pulmonary hemorrhage during/after SRT (Table 3)40, 41 which varied from 5 to 12%. All of them were conducted in level-3 NICUs. None of the included studies reported the incidence of apnea or cardiac arrest during or immediately after SRT.

Table 3 Studies on safety of SRT in LMIC settings
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Feasibility of introducing SRT

None of the included studies specifically reported the proportion of neonates receiving surfactant dose(s) successfully. One study from a neonatal unit in South Africa with no backup ventilation facilities (Table 2) reported the proportion of neonates who needed referral following SRT.42 The study included extremely low birth weight neonates born at or after 25 weeks’ gestation who were intubated, administered surfactant and then immediately extubated (InSurE strategy) to CPAP. The proportion of neonates who failed InSurE and required mechanical ventilation/referral was 34% (95% CI 24 to 45%; n=33). Another case-series from Iran employed the InSurE technique in VLBW neonates (25 to 32 weeks’ gestation).43 About 40% failed to improve and required mechanical ventilation (95% CI 28 to 52%). One case-series from Turkey employed the InSurE method in neonates born before 32 weeks’ gestation and having an FiO2 requirement of >0.4 in the first 2 h of life.41 About 45% of the enrolled neonates required mechanical ventilation in the first 72 h (95% CI 35 to 55%). A recently published case-series from India reported almost the same figures for failure of InSurE (43%; 95% CI 24 to 63%).44

Cost-effectiveness

None of the studies from LMICs reported this outcome.

Discussion

Introduction of SRT in the management of RDS is one of the most important advancements in the field of neonatology. However, in the absence of an evidence base from LMICs, completely confidence about the efficacy and safety of SRT in LMIC settings is not possible. We found two RCTs that did not find any difference in mortality following therapy with synthetic surfactant.10 Pooled analysis of all studies—observational as well as randomized—showed a significant reduction in the risk of mortality at the last available time point (RR 0.67; 95% CI 0.57 to 0.79) and air leaks (RR 0.51; 95% CI 0.29 to 0.90) in neonates who received SRT. These results are quite consistent with the data from HICs where there is moderate quality evidence from randomized trials that SRT reduces the risk of neonatal mortality (RR 0.68; 95% CI 0.57 to 0.82) and air leaks (RR 0.47; 95% CI 0.39 to 0.58) in preterm neonates with RDS.5

There is low-quality evidence from HICs that SRT does not reduce the risk of BPD.5 However, the studies from LMICs that compared the risk of BPD in neonates who received SRT with those who did not receive surfactant produced contrasting results. Although some cohort studies reported significantly lower risk of BPD, majority of the case-control studies demonstrated significantly higher odds of exposure to SRT in VLBW neonates with BPD. In contrast, a randomized trial did not find any significant difference in the incidence of BPD.11 One possible reason for this discrepancy is that more immature neonates, who would have otherwise died, survived following SRT and developed BPD. The uncertain risk of BPD following SRT has practical implications in LMIC settings because of the long duration of hospital stay with its associated cost implications.

The proportion of neonates developing pulmonary hemorrhage varied from 5 to 12% in LMIC settings.40, 41, 45, 46, 47 In contrast, the two studies from HICs that compared early vs late surfactant therapy reported an incidence of 5.9%[ref. 48] and 6.3%,49 respectively. However, the reduction in the proportion of neonates developing pulmonary hemorrhage by almost two-thirds after 1 to 3 years of implementing SRT in Thailand39 highlights the fact that the incidence is likely to be higher in LMIC settings that are just beginning to implement SRT but it might decrease with increasing experience. There is no information about the development of apnea or cardiac arrest following SRT from either LMIC or HIC settings. Transient desaturations invariably occur following SRT. Non-availability of this data may reflect its genuine non-existence, but there is need for vigilance about these potential complications, especially during initial implementation of SRT in LMIC settings.

There are no data on the proportion of neonates who received surfactant dose(s) successfully. This could possibly indicate that all neonates who were to receive surfactant therapy received it successfully without the need to stop because of immediate complications. Given that most studies were conducted in level-3 NICUs, this possibility seems more likely. About 40% of preterm neonates with RDS across different gestation categories receiving surfactant by InSurE failed and required mechanical ventilation. The possible reasons of such high failure rates are (1) inclusion of more immature neonates; (2) inadequate manpower resulting in sub-optimal monitoring; and (3) limited experience and expertize of doctors and nursing staff in most LMIC settings. But the number of studies reporting the failure rates is small (n=4)—it is possible that the failure rates are lower in other settings from LMICs. Nevertheless, the high risk of failure highlights the importance of provision of mechanical ventilation or referral, if ventilation facilities are not available. The paucity of studies from level-2 facilities without ventilation backup precludes any comment about the feasibility of SRT in these settings. None of the studies from LMICs reported on the cost effectiveness of SRT.

Implications for policy makers

With significant benefits observed in terms of reduction of mortality and air leaks without major harm, policy makers and other stakeholders are likely to give a high value to the use of SRT in the management of RDS in all resource-restricted countries. This is reflected by the inclusion of surfactant in the World Health Organization’s Essential drug list.50 However, the most important concern lies in the cost of SRT, which varies from US$ 100 to 500 in different countries. Surfactant therapy could also increase the total cost of care of preterm neonates in a health facility because of increased survival of more immature infants who are likely to have a prolonged hospital stay. Still, the incremental cost effectiveness ratio is likely to be favorable if the quality adjusted life years for survivors of preterm births are taken into account.51

Various other factors, including availability of skilled personnel and an optimal support system, need to be ensured for an effective roll-out of the intervention. SRT should be reserved for symptomatic neonates with RDS who do not improve with CPAP or require intubation and assisted ventilation due to worsening disease. Even the recent trials on SRT52, 53, 54, 55 do not support the use of prophylactic SRT in extremely preterm neonates. However, all these trials were conducted in HICs in very preterm neonates (<28 weeks) where the use of antenatal steroid coverage was >90%.52, 53, 56, 57

Implications for researchers

The results of this review are primarily on the basis of observational studies with a dearth of high-quality evidence, including RCTs, from LMIC settings. Given the nature of studies included in the present review, the quality of evidence is considered to be low. There is a need to generate more evidence on the cost effectiveness of SRT and its effect on BPD in LMIC settings. Although it may not be ethical to carry out RCTs, large, multicenter, high-quality observational studies are quite feasible in these settings.

There is definitely a need to search for the exact timing of administering rescue surfactant in symptomatic infants with RDS especially among moderately preterm infants (28 to 33 weeks) who constitute the major portion of the beneficiaries in LMIC settings. Administering rescue surfactant early in the course of disease will result in its overuse when the majority of symptomatic infants can be managed with CPAP alone. However, late administration may result in the reduction or complete loss of its beneficial effect. Some data support early addition of surfactant as compared with CPAP alone by reducing the need for subsequent mechanical ventilation.58, 59

There is also a need to explore alternate simpler methods of administering surfactant which do not involve intubation. These minimally invasive techniques will be very useful for LMIC settings where inadequately trained health-care professionals are one of the major challenges for the successful administration of SRT. Various methods such as the ‘minimally invasive surfactant therapy’,60, 61 ‘aerosol technique’,62 surfactant administration via laryngeal mask airway63 or nasopharyngeal installation64 have been tried. Preliminary data on these ‘minimally invasive techniques’ are promising; more evidence is required before they can be adopted in LMIC settings.

Strengths and weaknesses

Ours is possibly the first attempt to systematically review and synthesize the available evidence on the efficacy, safety, feasibility and cost effectiveness of SRT in low-resource settings. The studies in this review are limited by their study design and quality and are predominantly from single centers confined to level-3 neonatal units. Some of the observational studies had the limitation of using surfactant therapy based on the financial status of the parents, which could introduce serious bias in the results. Lastly, the small number of studies included in the review belie the fact that use of SRT is quite common in most resource-constricted settings.

Conclusion

Available evidence suggests that SRT is an effective, safe and feasible intervention in level-3 neonatal units and has the potential to reduce neonatal mortality and air leaks in low-resource settings also. SRT should be provided in settings where there is adequate manpower, professional skills and desired infrastructure to administer surfactant. To achieve maximum gains, it should be combined with more cost-effective therapies such as antenatal steroids and use of early/delivery room CPAP.