Geraldine Ng, Arne Ohlsson

This is an update of a review last published by Cochrane in June 2012 entitled "Cromolyn sodium for the prevention of chronic lung disease in preterm infants", which included two studies. This 2016 update identified no further studies.Chronic lung disease (CLD) frequently occurs in preterm infants and has a multifactorial aetiology including inflammation. Cromolyn sodium is a mast cell stabiliser that inhibits neutrophil activation and neutrophil chemotaxis and therefore may have a role in the prevention of CLD. To determine the effect of prophylactic administration of cromolyn sodium on the incidence of CLD at 28 days or 36 weeks' postmenstrual age (PMA), mortality, or the combined outcome of mortality and CLD at 28 days or 36 weeks' PMA in preterm infants. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1966 to 12 May 2016), Embase (1980 to 12 May 2016), and CINAHL (1982 to 12 May 2016). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We included randomised or quasi-randomised controlled clinical trials involving preterm infants. Initiation of cromolyn sodium administration was during the first two weeks of life. The intervention had to include administration of cromolyn sodium by nebuliser or metered dose inhaler with or without spacer device versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: overall mortality, CLD at 28 days, CLD at 36 weeks' PMA, or the combined outcome mortality and CLD at 28 days.  DATA COLLECTION AND ANALYSIS: We used the standard method for Cochrane as described in the Cochrane Handbook for Systematic Reviews of Interventions. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous data. The meta-analysis used a fixed-effect model. We examined heterogeneity using the I(2) statistic. We assessed the quality of evidence for the main comparison at the outcome level using the GRADE approach. We identified two eligible studies with small numbers of infants enrolled (64 infants). Prophylaxis with cromolyn sodium did not result in a statistically significant effect on the combined outcome of mortality and CLD at 28 days (typical RR 1.05, 95% CI 0.73 to 1.52; typical RD 0.03, 95% CI -0.20 to 0.27; 2 trials, 64 infants; I(2) = 0% for both RR and RD); mortality at 28 days (typical RR 1.31, 95% CI 0.52 to 3.29; I(2) = 73% typical RD 0.06, 95% CI -0.13 to 0.26; I(2) = 87%; 2 trials, 64 infants) (very low quality evidence); CLD at 28 days (typical RR 0.93, 95% CI 0.53 to 1.64; I(2) = 40%; typical RD -0.03, 95% CI -0.27 to 0.20; I(2) = 38%; 2 trials, 64 infants) or at 36 weeks' PMA (RR 1.25, 95% CI 0.43 to 3.63; RD 0.08, 95% CI -0.29 to 0.44; 1 trial, 26 infants). There was no significant difference in CLD in survivors at 28 days (typical RR 0.97, 95% CI 0.58 to 1.63; typical RD -0.02, 95% CI -0.29 to 0.26; I(2) = 0% for both RR and RD; 2 trials, 50 infants) or at 36 weeks' PMA (RR 1.04, 95% CI 0.38 to 2.87; RD 0.02, 95% CI -0.40 to 0.43; 1 trial, 22 infants). Prophylaxis with cromolyn sodium did not show a statistically significant difference in overall neonatal mortality, incidence of air leaks, necrotising enterocolitis, intraventricular haemorrhage, sepsis, and days of mechanical ventilation. There were no adverse effects noted. The quality of evidence according to GRADE was very low for one outcome (mortality to 28 days) and low for all other outcomes. The reasons for downgrading the evidence was due to design (risk of bias in one study), inconsistency between the two studies (high I(2) values for mortality at 28 days for both RR and RD), and lack of precision of estimates (small sample sizes). Further research does not seem to be justified. There is currently no evidence from randomised trials that cromolyn sodium has a role in the prevention of CLD. Cromolyn sodium cannot be recommended for the prevention of CLD in preterm infants.