Li J and Bo T were responsible for the study concept and design. Shen L and Luo SL assisted the data retrieval. Zhang RL supervised the included literatures, performed statistical analysis, and wrote the manuscript. All authors approved the final version of the manuscript.
Accepted Jan A meta-analysis of published randomized controlled trials investigating the long-term effect of dexamethasone on the nervous system of preterm infants. Key words were preterm infants and dexamethasone in English and Chinese. Selected studies were randomized controlled trials assessing the effect of intravenous dexamethasone in preterm infants. The quality of the included papers was evaluated and those without the development of the nervous system and animal experiments were excluded.
Quality assessment was performed through bias risk evaluation in accordance with Cochrane Handbook 5. The homogeneous studies were analyzed and compared using Revman 5. Those papers failed to be included in the meta-analysis were subjected to descriptive analysis. Nervous system injury in preterm infants.
Ten randomized controlled trials were screened, involving 1, subjects. Among them cases received dexamethasone treatment while cases served as placebo control group and blank control group. Dexamethasone may affect the intelligence of preterm infants in the early stages after birth, but may lead to hearing impairment at later stages after birth.
More reliable conclusions should be made through large-size, multi-center, well-designed randomized controlled trials. Acute adverse reactions of glucocorticoids include high blood pressure, high blood sugar and adrenal insufficiency[ 2 , 3 ], but the majority of these acute adverse effects are transient. However, glucocorticoids, especially dexamethasone, have attracted increasing attention because of the long-term effects on the development of the nervous system in preterm infants.
Dexamethasone has been reported to increase the risk of cerebral palsy in preterm infants[ 4 ] and affect motor function, cognitive function[ 5 , 6 ] and academic performance[ 7 , 8 ] in children at school age. Owing to these potential and serious adverse reactions, the American Academy of Pediatrics and the Canadian Pediatric Society do not recommend postnatal dexamethasone therapy in preterm infants, with exceptions for maintaining essential oxygenation using large-volume, high concentrations of oxygen[ 9 ].
By contrast, some scholars also found that dexamethasone significantly attenuated lipopolysaccharide-induced inflammation in neonatal rat brain, promoted myelin basic protein expression, inhibited lateral ventricle dilatation, and significantly reduced behavioral abnormalities[ 10 ].
In addition, dexamethasone plays a neuroprotective role through the upregulation of the expression of neurotrophic factors and anti-apoptosis genes, such as nerve growth factor, basic fibroblast growth factor, and vascular endothelial growth factor[ 11 , 12 ].
We speculate that glucocorticoids have a long-term impact on the development of the nervous system and increase the incidence of cerebral palsy in preterm infants.
The existing studies concerning the role of dexamethasone in preterm infants are insufficiently reliable owing to short follow-up periods and small sample sizes in clinical studies, or the absence of randomized controlled trials. The present study aims to quantitatively analyze the long-term effect of dexamethasone on nervous system development in preterm infants through a meta-analysis involving a large sample size in a broader attempt to provide evidence for clinical application of dexamethasone in preterm infants.
Data and Methods Literature retrieval A literature search was independently performed by two researchers according to the Handbook RCT search strategy in the Cochrane Collaboration. The Chinese Academic Journal Full-text database between January and June was also retrieved using preterm infants, dexamethasone and randomized controlled trial as the search terms. The presence of bias in the included literature was evaluated by the third researcher.
Meanwhile, we manually retrieved all unpublished literature or papers without available full-text, and collected related data from ongoing research or trials. Repetition of the same experiment was excluded. Inclusion and exclusion criteria Inclusion criteria 1 Literature type: All published or to-be-published studies in international journals addressing randomized controlled trials about the effect of dexamethasone treatment in preterm infants were included, with language and nation not specified.
Preterm infants gestational age is less than 37 weeks suffering from neonatal respiratory distress syndrome, in urgent need of mechanical ventilation for oxygen support, and at a high risk of chronic lung disease, were included.
Those with congenital heart disease and sepsis after birth were excluded. Literature concerning a dexamethasone treatment and a blank control or placebo group were included. The outcome variables are odds ratio OR , relative risk RR or mean difference MD in treatment and control groups at the end of follow-up. Exclusion criteria 1 Repeatedly published literature, only pertaining to one paper with long-term follow-up period, large sample volume and full-scale data.
Data extraction Two independent reviewers inspected the titles and abstracts of the included studies, and screened the selected literature according to inclusion and exclusion criteria. Where disputes arose owing to no subject words found in titles and abstracts, we acquired the full report for more detailed scrutiny to assess their relevance to this review.
Again, where disagreement occurred we attempted to resolve this through the third researcher or through discussion. The extracted data included author's name, publication year, sample size, interventions, the number of cases at the final follow-up, outcome variables cerebral palsy, visual impairment, hearing loss and intelligence quotient values , and follow-up time.
Quality assessment The quality of methodological reporting of selected studies was assessed using bias analysis of randomized controlled trials.
Criteria for quality assessment were based on recommendations from the Cochrane Handbook 5. Main outcome measurements The prevalence of nervous system adverse consequences cerebral palsy, visual impairment, hearing loss and the development of intelligence intelligence quotient values after dexamethasone treatment were detected.
Statistical analysis Meta-analysis was performed using RevMan 5. Meanwhile the sensitivity of analysis results was detected. Results Data retrieval After preliminary retrieval, 1, studies addressing dexamethasone treatment in preterm infants were initially identified through electronic and manual searches. After reading their titles, abstracts and full-text, ten randomized controlled trials were considered potentially relevant for further inspection[ 8 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].
They were all published in English. Data retrieval procedures are shown in Figure 1.