Key messages
• We did not find enough good‐quality evidence about the use of superoxide dismutase in newborns born too early: only three studies for the prevention of lung disease.
• The evidence is very uncertain about the effect of superoxide dismutase on bronchopulmonary dysplasia, also known as chronic lung disease, death, retinopathy of prematurity (eye damage which might cause blindness) compared to a placebo or no treatment.
• No studies reported bronchopulmonary dysplasia or death at 36 weeks' postmenstrual age, need for giving oxygen, and long-term development. Postmenstrual age is the combination of gestational age (length of pregnancy) and chronological age the day after the birth of the baby.
What is bronchopulmonary dysplasia?
Newborns born too early ("preterm"), especially babies born before 28 weeks of pregnancy, have a higher risk for death, lung disease and brain impairment than those born at or near term. For instance, some of these babies develop intellectual disabilities, blindness or deafness. Bronchopulmonary dysplasia, also known as chronic lung disease, is a common problem in preterm babies who are mechanically ventilated (machine assisted breathing) and consists of being dependent of oxygen or breathing machines. Free oxygen radicals, i.e. products of chemical reactions that use oxygen, are believed to cause bronchopulmonary dysplasia because they are very unstable, so they can damage other cells.
What is superoxide dismutase?
Superoxide dismutase is a protein normally present in the body to provide a defense against free radicals, but preterm infants do not have a sufficient supply to provide natural resistance. Giving superoxide dismutase to preterm infants may therefore prevent bronchopulmonary dysplasia.
What did we want to find out?
We wanted to find out if superoxide dismutase could reduce the risk of:
• bronchopulmonary dysplasia
• death
• the combination of bronchopulmonary dysplasia and death
What did we do?
We searched for studies that looked at superoxide dismutase in babies born too early. We compared and summarized the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We included three studies in our review, with a total of 380 preterm newborns at risk of bronchopulmonary dysplasia. It is unclear whether superoxide dismutase reduces bronchopulmonary dysplasia, death, or the combination of bronchopulmonary dysplasia and death. The dose ranged from 0.25 mg/kg to 5.0 mg/kg. Superoxide dismutase was given to the babies by injection under the skin or directly into the trachea. There are no ongoing studies.
What are the limitations of the evidence?
We are not confident in the evidence on bronchopulmonary dysplasia and death because the studies were small and used methods likely to introduce errors in their results. Overall, the results of the studies are unlikely to reflect the results of all the studies that have been conducted in this area, some of which have not made their results public yet.
How up to date is this evidence?
The evidence is up-to-date to September 2022.
The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality and mortality prior to discharge compared to placebo. No studies reported BPD or death at 36 weeks' postmenstrual age and need for supplemental oxygen. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage and severe retinopathy of prematurity. No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months.
The effects of SOD in preterm infants has not been reported in any trial in the last few decades, considering that the most recent trial on SOD in preterm infants was conducted in 1997/1998, and no new studies are ongoing. In the light of the limited available evidence, new data from preclinical and observational studies are needed to justify the conduction of new RCTs. Observational studies might report how SOD is administered, including indication, dose and association with relevant outcomes such as mortality, BPD and long-term neurodevelopment.
Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring enzyme which provides a defense against such oxidant injury. Providing supplementary SOD has been tested in clinical trials to prevent BPD in preterm infants.
To determine the efficacy and safety of SOD in the prevention and treatment of BPD on mortality and other complications of prematurity in infants at risk for, or having BPD.
We searched CENTRAL, PubMed, Embase, and three trials registers on 22 September 2022 together with reference checking, citation searching and contact with study authors to identify additional studies.
Randomized, quasi-randomized and cluster-randomized controlled trials (RCTs) where the participants were preterm infants who had developed, or were at risk of developing BPD, and who were randomly allocated to receive either SOD (in any form, by any route, any dose, anytime) or placebo, or no treatment.
We used standard Cochrane methods. Our primary outcomes were BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality, mortality prior to discharge, and BPD or death at 36 weeks' postmenstrual age. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for the dichotomous outcomes. We used GRADE to assess certainty of evidence for each outcome.
We included three RCTs (380 infants) on SOD administration in preterm infants at risk for BPD, and no studies in preterm infants with evolving BPD / early respiratory insufficiency.
The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days (RR 1.09, 95% CI 0.94 to 1.26; RD 0.06, 95% CI -0.05 to 0.16, 1 study, 302 infants; I2 for RR and RD not applicable), BPD defined as oxygen at 36 weeks' postmenstrual age (RR 0.96, 95% CI 0.72 to 1.29; RD -0.01, 95% CI -0.11 to 0.09, 2 studies, 335 infants; I2 for RR and RD = 0%), neonatal mortality (RR 0.98, 95% CI 0.57 to 1.68; RD -0.00, 95% CI -0.08 to 0.07, 2 studies, 335 infants; I2 for RR and RD = 0%), and mortality prior to discharge (RR 1.20, 95% CI 0.53 to 2.71; RD 0.04, 95% CI -0.14 to 0.23, 2 studies, 78 infants; I2 for RR and RD = 0%). No studies reported BPD or death at 36 weeks' postmenstrual age. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage (RR 0.95, 95% CI 0.78 to 1.15; RD -0.03, 95% CI -0.15 to 0.08, 2 studies, 335 infants; I2for RR = 0%, I2 for RD = 8%), and severe retinopathy of prematurity (ROP) (RR 0.97, 95% CI 0.57 to 1.65; RD -0.01, 95% CI -0.10 to 0.09, 1 study, 244 infants; I2 for RR and RD not applicable). No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. Certainty of evidence was very low for all outcomes.
We identified no ongoing trials.