Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

  • Review
  • Intervention

Authors


Abstract

Background

Chronic lung disease remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat chronic lung disease because of their potent anti-inflammatory effects.

Objectives

To examine the relative benefits and adverse effects of postnatal corticosteroids commenced within the first seven days of life to preterm infants at risk of developing chronic lung disease.

Search methods

We sought randomised controlled trials (RCTs) of postnatal corticosteroid therapy from the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 8), MEDLINE (1966 to August 2013), handsearching paediatric and perinatal journals, and by examining previous review articles and information received from practising neonatologists. We contacted authors of all studies, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.

Selection criteria

We selected RCTs of postnatal corticosteroid treatment within the first seven days of life (early) in high-risk preterm infants for this review. Most studies evaluated the use of dexamethasone but we also included studies that assessed hydrocortisone, even if it was used primarily to manage hypotension.

Data collection and analysis

We extracted and analysed data regarding clinical outcomes that included mortality, chronic lung disease, death or chronic lung disease, failure to extubate, complications during the primary hospitalisation, and long-term health outcomes.

Main results

Twenty-nine RCTs enrolling a total of 3750 participants were eligible for inclusion in this review. The overall risk for bias was probably low as all were randomised controlled trials, and most trials have used rigorous methods. There were significant benefits for the following outcomes: lower rates of failure to extubate and decreased risks of chronic lung disease at both 28 days and 36 weeks' postmenstrual age, death or chronic lung disease at 28 days and 36 weeks' postmenstrual age, patent ductus arteriosus and ROP, including severe ROP. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis or pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects. The risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure were also increased. In the 12 trials that reported late outcomes, several adverse neurological effects were found at follow-up examinations, including developmental delay (not defined), cerebral palsy and abnormal neurological examination. However, major neurosensory disability was not significantly increased, either overall in the seven studies where this outcome could be determined, or in the two individual studies where the rates of cerebral palsy or abnormal neurological examination were significantly increased. Moreover, the rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability, were not significantly increased. Dexamethasone was used in most studies (n = 20); only nine studies used hydrocortisone. In subgroup analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone; hydrocortisone had little effect on any outcomes except for an increase in intestinal perforation and a borderline reduction in patent ductus arteriosus.

Authors' conclusions

The benefits of early postnatal corticosteroid treatment (≤ 7 days), particularly dexamethasone, may not outweigh the adverse effects of this treatment. Although early corticosteroid treatment facilitates extubation and reduces the risk of chronic lung disease and patent ductus arteriosus, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Long-term follow-up studies report an increased risk of abnormal neurological examination and cerebral palsy. However, the methodological quality of the studies determining long-term outcomes is limited in some cases; the surviving children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. Hydrocortisone in the doses and regimens used in the reported RCTs has few beneficial or harmful effects and cannot be recommended for the prevention of chronic lung disease.

Résumé scientifique

Corticothérapie postnatale précoce (< 8 jours) pour prévenir la maladie pulmonaire chronique chez les nouveau-nés prématurés

Contexte

La maladie pulmonaire chronique demeure un problème majeur dans les unités néonatales de soins intensifs. Une inflammation persistante des poumons constitue la pathogénie sous-jacente la plus probable. Les corticostéroïdes sont utilisés dans la prévention ou le traitement de la maladie pulmonaire chronique en raison de leurs puissants effets anti-inflammatoires.

Objectifs

Examiner les bénéfices et les effets indésirables relatifs d'une corticothérapie postnatale commencée dans les sept premiers jours de vie chez les nouveau-nés prématurés à risque de maladie pulmonaire chronique.

Stratégie de recherche documentaire

Nous avons recherché des essais contrôlés randomisés (ECR) portant sur une corticothérapie postnatale dans le registre Cochrane des essais contrôlés (CENTRAL, 2013, numéro 8) et MEDLINE (1966 - août 2013) ; une recherche manuelle a été effectuée dans des revues pédiatriques et périnatales et les articles des précédentes revues ainsi que les informations transmises par des néonatologistes en exercice ont été examinés. Nous avons contacté les auteurs de toutes les études, dans la mesure du possible, afin de confirmer les détails des études de suivi rapportées ou d'obtenir des informations concernant le suivi à long terme lorsque celui-ci n'était pas documenté.

Critères de sélection

Nous avons sélectionné pour cette revue des essais contrôlés randomisés portant sur l'administration d'une corticothérapie postnatale au cours des sept premiers jours de vie (précoce) chez des nouveau-nés prématurés à haut risque. La plupart des études évaluaient l'administration de dexaméthasone, mais nous avons également inclus des études qui évaluaient de l'hydrocortisone, même si celle-ci était utilisée à l'origine dans la prise en charge de l'hypotension.

Recueil et analyse des données

Nous avons extrait et analysé les données relatives aux résultats cliniques, y compris la mortalité, la maladie pulmonaire chronique, le décès ou la maladie pulmonaire chronique, l'échec de l'extubation, les complications au cours de l'hospitalisation primaire et les résultats de santé à long terme.

Résultats principaux

Vingt-neuf ECR recrutant un total de 3 750 participants étaient éligibles dans cette revue. Le risque de biais global était probablement faible, car tous étaient des essais contrôlés randomisés et la plupart avaient utilisé des méthodes rigoureuses. Des bénéfices significatifs ont été observés pour les résultats suivants : taux plus faibles d'échec de l'extubation et réduction des risques de maladie pulmonaire chronique à 28 jours et 36 semaines d'âge post-menstruel, de décès ou de maladie pulmonaire chronique à 28 jours et 36 semaines d'âge post-menstruel, de persistance du canal artériel et de rétinopathie du prématuré (RDP), y compris la RDP sévère. Aucune différence significative n'était observée en termes de taux de mortalité néonatale ou subséquente, d'infection, d'hémorragie intraventriculaire sévère, de leucomalacie périventriculaire, d'entérocolite nécrosante ou d'hémorragie pulmonaire. Le saignement gastro-intestinal et la perforation intestinale étaient des effets indésirables importants. Les risques d'hyperglycémie, d'hypertension, de myocardiopathie hypertrophique et de retard de croissance augmentaient également. Dans les 12 essais rapportant des résultats différés, plusieurs effets neurologiques indésirables étaient observés lors des examens de contrôle, notamment un retard de développement (non défini), une paralysie cérébrale et un examen neurologique anormal. Néanmoins, les troubles neurosensoriels majeurs ne présentaient pas d'augmentation significative, tant pour l'ensemble des sept études dans lesquelles ce critère de jugement pouvait être examiné que pour les deux études individuelles dans lesquelles les taux de paralysie cérébrale ou d'examen neurologique anormal présentaient une augmentation significative. Qui plus est, les taux des critères de jugement combinés de la mortalité et de la paralysie cérébrale, ou de la mortalité et des troubles neurosensoriels majeurs, ne présentaient pas d'augmentation significative. Le médicament utilisé dans la plupart des études (n = 20) était la dexaméthasone ; neuf études seulement utilisaient de l'hydrocortisone. Dans les analyses en sous-groupe par type de corticostéroïde, la plupart des effets bénéfiques et délétères étaient attribuables à la dexaméthasone ; l'hydrocortisone avait peu d'effet sur les différents critères de jugement, à l'exception d'une augmentation de la perforation intestinale et d'une réduction limite de la persistance du canal artériel.

Conclusions des auteurs

Les effets bénéfiques de la corticothérapie postnatale précoce (≤ 7 jours), en particulier de la dexaméthasone, pourraient ne pas compenser les effets indésirables du traitement. Bien que la corticothérapie précoce facilite l'extubation et réduise le risque de maladie pulmonaire chronique et de persistance du canal artériel, elle entraîne des effets indésirables à court terme, y compris un saignement gastro-intestinal, une perforation intestinale, une hyperglycémie, une hypertension, une myocardiopathie hypertrophique et un retard de croissance. Les études de suivi à long terme rapportent un risque accru d'examen neurologique anormal et de paralysie cérébrale. Néanmoins, la qualité méthodologique des études examinant les critères de jugement à long terme est limitée dans certains cas ; les enfants survivants avaient été principalement évalués avant l'âge scolaire, et aucune étude ne présentait de puissance statistique suffisante pour détecter des effets neurosensoriels indésirables importants à long terme. Il est absolument nécessaire de réaliser un suivi à long terme et de documenter les résultats différés, en particulier les résultats neurologiques et liés au développement des nourrissons survivants recrutés dans tous les essais randomisés portant sur une corticothérapie postnatale précoce. L'hydrocortisone, aux doses et schémas thérapeutiques utilisés dans les ECR identifiés, présente peu d'effets bénéfiques ou délétères et ne peut pas être recommandée pour la prévention de la maladie pulmonaire chronique.

Plain language summary

Early (up to seven days) postnatal corticosteroids for preventing chronic lung disease in preterm infants

Corticosteroids can reduce lung inflammation in newborns with chronic lung disease, but there are major adverse effects of the drugs. Chronic lung disease is a major problem for newborn babies in neonatal intensive care units. Persistent inflammation of the lungs is the most likely cause. Corticosteroid drugs have been used to either prevent or treat chronic lung disease because of their strong anti-inflammatory effects. This review of trials found that the benefits of giving corticosteroids to infants up to seven days of age may not outweigh the known adverse effects. The beneficial effects were a shorter time on the ventilator and less chronic lung disease, but the adverse effects included high blood pressure, bleeding from the stomach or bowel, perforation of the bowel, an excess of glucose in the bloodstream and an increased risk of cerebral palsy at follow-up. Use of early corticosteroids, especially dexamethasone, to treat or prevent chronic lung disease should be curtailed until more research has been performed.

Résumé simplifié

Corticothérapie postnatale précoce (jusqu'à 7 jours) pour prévenir la maladie pulmonaire chronique chez les nouveau-nés prématurés

Les corticostéroïdes peuvent réduire l'inflammation pulmonaire chez les nouveau-nés atteints de maladie pulmonaire chronique, mais ces médicaments présentent d'importants effets indésirables. La maladie pulmonaire chronique constitue un problème majeur chez les nouveau-nés placés en unités néonatales de soins intensifs. Une inflammation persistante des poumons en est probablement la cause. Les corticostéroïdes sont utilisés dans la prévention ou le traitement de la maladie pulmonaire chronique en raison de leurs puissants effets anti-inflammatoires. Cette revue des essais a observé que les effets bénéfiques de l'administration de corticostéroïdes chez les nourrissons âgés de jusqu'à 7 jours pourraient ne pas compenser les effets indésirables connus. Ces effets bénéfiques étaient une période de ventilation plus courte et une réduction de l'incidence de la maladie pulmonaire chronique, mais les effets indésirables incluaient une hypertension artérielle, un saignement de l'estomac ou de l'intestin, une perforation de l'intestin, un excès de glucose dans le courant sanguin et un risque accru de paralysie cérébrale lors du suivi. L'administration précoce de corticostéroïdes, en particulier de dexaméthasone, dans le traitement ou la prévention de la maladie pulmonaire chronique devrait être limitée tant que de nouvelles recherches n'auront pas été effectuées.

Notes de traduction

Traduit par: French Cochrane Centre 1st February, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Description of the condition

Advances in neonatal care, including the use of antenatal corticosteroids and surfactant therapy, have improved the outcome of preterm infants with respiratory distress syndrome, but the risk of chronic lung disease or bronchopulmonary dysplasia has been only modestly reduced (Egberts 1997). The terms chronic lung disease and bronchopulmonary dysplasia are often used interchangeably; for the purposes of this review we have decided to use chronic lung disease to describe infants with oxygen dependency at either 28 days of life or 36 weeks' postmenstrual age. More infants with chronic lung disease are being cared for in neonatal units and their management is both time-consuming and costly. Chronic lung disease describes injury and maldevelopment of the lung that follows preterm birth and is a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis.

Description of the intervention

Postnatal corticosteroid treatment has been shown to have some beneficial acute effects on lung function in infants with established chronic lung disease, especially those that are ventilator-dependent (Mammel 1983; CDTG 1991). Recently, there has been concern that the benefits of corticosteroids might not outweigh the adverse effects, which include hypertension, hyperglycaemia, intestinal perforation and extreme catabolism (Anonymous 1991; Ng 1993).

Corticosteroids have been used to try to prevent chronic lung disease by treating at-risk preterm infants within the first four days of life. They are given either parenterally or enterally. It is not clear if early use of corticosteroids provides long-term benefits; nor is it clear that adverse neurological outcomes found in animal studies do not apply to the immature human newborn infant.

How the intervention might work

Corticosteroids might prevent chronic lung disease because of their potent anti-inflammatory effects.

Why it is important to do this review

Multiple systematic reviews of the use of postnatal corticosteroids in infants with or at risk of chronic lung disease have been published (Halliday 1997; Bhuta 1998; Arias-Camison 1999; Halliday 1999; Tarnow-Mordi 1999; Doyle 2000b; Doyle 2010a; Doyle 2010b; Doyle 2010c). Other systematic reviews have addressed the use of early (Shah 2007b) or late (Onland 2012) use of inhaled corticosteroids in the prevention or treatment of chronic lung disease, as well as comparisons between the use of systemic steroids and inhaled steroids (Shah 2003; Shah 2007a).

There are three existing Cochrane reviews, which review separately the trials in which postnatal corticosteroids were started within 96 hours of birth (Halliday 2010), 7 to 14 days after birth (Halliday 2003a), or predominantly after three weeks (Doyle 2014). This review examines the outcome of trials where preterm infants have been treated with corticosteroids up to seven days after birth. It is an update of previous Cochrane reviews (Halliday 2000; Halliday 2010), and it includes long-term outcome data from 12 trials.

Objectives

To examine the relative benefits and adverse effects of postnatal corticosteroids commenced within the first seven days of life to preterm infants at risk of developing chronic lung disease.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials of postnatal corticosteroid therapy in preterm infants at risk of developing chronic lung disease, who were enrolled within the first seven days of life (early postnatal corticosteroids). We included trials using hydrocortisone in the first days of life even if it had been used primarily to treat or prevent hypotension.

Types of participants

Preterm infants at risk of developing chronic lung disease, including those who are ventilator-dependent.

Types of interventions

Intravenous or oral corticosteroids versus control (placebo or no treatment). Trials of inhaled corticosteroids were not included in this review.

Types of outcome measures

Primary outcomes
  • Mortality

  • Chronic lung disease (including at 28 days, at 36 weeks' postmenstrual age and at 36 weeks' postmenstrual age in survivors)

  • Death or chronic lung disease (at 28 days and 36 weeks' postmenstrual age)

  • Long-term outcomes (including blindness, deafness, cerebral palsy and major neurosensory disability)

Secondary outcomes
  • Failure to extubate

  • Late rescue with corticosteroids (all infants and in survivors)

  • Need for home oxygen therapy

  • Complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, pulmonary air leak, patent ductus arteriosus, severe intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleeding, intestinal perforation and severe retinopathy of prematurity)

Search methods for identification of studies

We sought randomised controlled trials of postnatal corticosteroid therapy from the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 8), MEDLINE (1966 to August 2013), handsearching paediatric and perinatal journals, and by examining previous review articles and information received from practising neonatologists. We searched MEDLINE using the terms: adrenal cortex hormones or dexamethasone or betamethasone or hydrocortisone or steroids or corticosteroids, limits randomised controlled trials, human, all infant: birth to 23 months. We contacted the authors of all studies, when possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.

Data collection and analysis

We used the methods of the Cochrane Neonatal Group for data collection and analysis.

Selection of studies

We included all randomised and quasi-randomised controlled trials that fulfilled the selection criteria described in the previous section. The authors independently reviewed the results of the updated search and selected studies for inclusion. We resolved any disagreement by discussion.

Data extraction and management

For each trial we sought information regarding the method of randomisation, blinding, stratification, reporting of the outcome of all the infants enrolled and whether the trial was single or multicentre. Information on the trial participants included birth weight, gestational age, severity of respiratory distress syndrome, need for mechanical ventilation and surfactant, and gender. We analysed information on clinical outcomes for mortality, survival without chronic lung disease, chronic lung disease defined at 28 days and 36 weeks' postmenstrual age, failure to extubate, pneumothorax, infection, hyperglycaemia, hypertension, severe retinopathy of prematurity, patent ductus arteriosus, severe intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleeding, intestinal perforation and need for late corticosteroid treatment, as well as long-term outcomes including blindness, deafness, cerebral palsy and major neurosensory disability.

For each study, one review author entered the final data into Review Manager (RevMan) 5 software (RevMan 2012) and then a second review author checked for accuracy. We resolved discrepancies through discussion or by involving a third assessor. 

We attempted to contact authors of the original reports to provide further details when information regarding any of the above was unclear.

Assessment of risk of bias in included studies

We used the standard method of the Cochrane Neonatal Group for assessing the methodological quality of the studies. The authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or by involving a third assessor. 

We assessed the risk of bias of the studies using the following criteria: 

Sequence generation (checking for possible selection bias)

For each included study, we categorised the method used to generate the allocation sequence as:

  • low risk (any truly random process, e.g. random number table; computer random number generator);

  • high risk (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk.

Allocation concealment (checking for possible selection bias)

For each included study, we categorised the method used to conceal the allocation sequence as:

  • low risk (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes);

  • high risk (open random allocation; unsealed or non-opaque envelopes; alternation; date of birth);

  • unclear risk.

Blinding (checking for possible performance bias)

For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes. We categorised the methods as:

  • low risk, high risk or unclear risk for participants;

  • low risk, high risk or unclear risk for personnel;

  • low risk, high risk or unclear risk for outcome assessors.

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised the methods as:

  • low risk (< 20% missing data);

  • high risk (≥ 20% missing data);

  • unclear risk.

Selective reporting bias

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:

  • low risk (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk.

Other sources of bias

For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

  • low risk;

  • high risk;

  • unclear risk.

Measures of treatment effect

We used the standard methods of the Cochrane Neonatal Group to analyse data.

We performed statistical analyses using RevMan 5. We analysed dichotomous data using risk ratio (RR), risk difference (RD) and the number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH). We reported 95% confidence intervals (CI) for all estimates.

No continuous outcomes were included in this review. If included, we planned to analyse continuous data using the mean difference (MD) or the standardised mean difference (SMD) to combine trials that measure the same outcome but use different methods.

Unit of analysis issues

For clinical outcomes such as episodes of sepsis, we analysed the data as proportion of neonates having one or more episodes.

Dealing with missing data

For included studies, we noted levels of attrition. If we had concerns regarding the impact of including studies with high levels of missing data in the overall assessment of treatment effect, we planned to explore this concern using sensitivity analysis.

All outcomes analyses were on an intention-to-treat basis; i.e. we included all participants randomised to each group in the analyses. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic. If noted, we planned to explore the possible causes of statistical heterogeneity using pre-specified subgroup analysis (for example, differences in study quality, participants, intervention regimens or outcome assessments).

Assessment of reporting biases

We assessed possible publication bias and other biases using symmetry/asymmetry of funnel plots.

For included trials that were recently performed (and therefore prospectively registered), we explored possible selective reporting of study outcomes by comparing the primary and secondary outcomes in the reports with the primary and secondary outcomes proposed at trial registration, using the websites www.clinicaltrials.gov and www.controlled-trials.com. If such discrepancies were found, we planned to contact the primary investigators to obtain missing outcome data on outcomes pre-specified at trial registration.

Data synthesis

Where we judged meta-analysis to be appropriate, we carried out the analysis using RevMan 5, supplied by The Cochrane Collaboration. We used the Mantel-Haenszel method for estimates of typical risk ratio and risk difference. No continuous outcomes were included in this review. We planned to analyse continuous measures using the inverse variance method, if included. 

We used the fixed-effect model for all meta-analyses.

Subgroup analysis and investigation of heterogeneity

We included subgroup analyses by the type of corticosteroid used (dexamethasone or hydrocortisone) where there were sufficient numbers of trials to make such subgroup analyses meaningful.

Sensitivity analysis

We planned sensitivity analyses for situations where this might affect the interpretation of significant results (for example, where there is risk of bias associated with the quality of some of the included trials or missing outcome data). We thought none were necessary in this review.

Results

Description of studies

Results of the search

Twenty-nine trials qualified for inclusion in this review. Most of the trials enrolled low birth weight infants with respiratory distress syndrome who were receiving mechanical ventilation.

Included studies

See Characteristics of included studies.

The corticosteroid administered was usually dexamethasone and the most common treatment regimen was 0.50 mg/kg/day for three days followed by 0.25 mg/kg/day for three days, 0.12 mg/kg/day for three days and 0.05 mg/kg/day for three days. There was, however, considerable variation in treatment regimens, including short courses of one to two days and longer courses of up to four weeks. Nine studies used hydrocortisone (Baden 1972; Watterberg 1999; Biswas 2003; Watterberg 2004; Efird 2005; Peltoniemi 2005; Ng 2006; Bonsante 2007; Batton 2012), and in some cases the indication was management of hypotension when low (almost physiological) doses were used (see under Description of studies).

Anttila 2005 was a multicentre, double-blind, placebo-controlled trial of infants with birth weight of 500 g to 999 g, gestation of less than 32 weeks and respiratory failure by four hours of age. One hundred and nine infants were randomised to receive either four doses of dexamethasone (0.25 mg/kg at 12-hour intervals) or saline placebo.

Baden 1972 included 44 infants with respiratory distress syndrome, mild hypoxia and hypercapnia and a chest radiograph compatible with respiratory distress syndrome. They were randomised to receive either hydrocortisone 15 mg/kg on admission and 12 hours later intravenously, or a placebo. Their birth weights ranged from 800 g to 2805 g and gestational ages from 26 to 36 weeks.

Batton 2012 was a pilot study of infants 23 to 26 weeks' gestation with low blood pressure in the first 24 hours of life. Dopamine and hydrocortisone were being compared with placebo in a factorial design. The dose of hydrocortisone was 1 mg/kg loading, then 0.5 mg/kg 12-hourly for six doses (total dose 3.5 mg/kg). The trial stopped early because of slow recruitment after only 10 infants were enrolled.

Biswas 2003 was a multicentre, randomised trial of 253 infants of less than 30 weeks' gestational age. The infants were mechanically ventilated and were entered within nine hours of birth. All were given surfactant in the first 24 hours of life. Those in the treatment group (n = 125) were randomised to receive an infusion of hydrocortisone of 1 mg/kg/day and tri-iodothyronine (T3) of 6 µg/kg/day for five days, then hydrocortisone 0.5 mg/kg/day and T3 3 µg/kg/day for two days. The placebo group (n = 128) received an equal volume of 5% dextrose.

Bonsante 2007 enrolled a total of 50 infants of either less than 1250 g birth weight or gestation 24 to 30 weeks who were less than 48 hours old and were ventilator-dependent after surfactant treatment. Exclusion criteria were cardiopulmonary malformations, perinatal asphyxia, death less than 12 hours after recruitment, or use of steroids for any reason less than 12 days after birth. No infants were excluded for these latter two reasons. Stratification was by birth weight (not specified), gestational age (not specified) and antenatal steroid exposure. Infants were randomly allocated to either a 12-day course of hydrocortisone (1.0 mg/kg for nine days, then 0.5 mg/kg/day for three days) (n = 25) or an equivalent volume of 0.9% saline placebo (n = 25). The sample size calculation was based on the results of Watterberg 1999, with an estimate of 138 infants to be recruited. The study was stopped early at 50 infants enrolled because of reports from other trials of spontaneous intestinal perforation with early hydrocortisone treatment.

Efird 2005 was a randomised controlled trial of hydrocortisone to prevent hypotension in infants of less than 1000 g birth weight and gestation of 24 to 28 weeks. Thirty-four infants were randomised to receive either 1 mg/kg of intravenous hydrocortisone 12-hourly for two days, followed by 0.3 mg/kg 12-hourly for three days or a normal saline placebo.

Garland 1999 was a prospective, multicentre, randomised trial comparing a three-day course of dexamethasone therapy, beginning at 24 to 48 hours of life, with placebo. Two hundred and forty-one preterm infants (dexamethasone n = 118, placebo n = 123) were enrolled, who weighed between 500 g and 1500 g, had received surfactant therapy and were at significant risk for chronic lung disease or death using a predictive model at 24 hours. Dexamethasone was given in a three-day tapering course at 12-hour intervals. The first two doses were 0.4 mg/kg, the 3rd and 4th doses were 0.2 mg/kg and the 5th and 6th doses were 0.1 mg/kg and 0.05 mg/kg respectively. A similar volume of normal saline was given to placebo-treated infants at similar time intervals.

Halac 1990 was a randomised trial to determine if prenatal corticosteroid therapy would reduce the incidence of necrotising enterocolitis. Women were randomised to prenatal betamethasone or placebo when they were admitted in preterm labour and expected to deliver within 24 hours. Infants of mothers who had received placebo were then randomised to postnatal dexamethasone or placebo; only the infants randomised to postnatal therapy are included in this review. Study infants were less than 1501 g birth weight or less than 34 weeks' gestation and had evidence of "birth asphyxia" (one-minute Apgar score below five, prolonged resuscitation and metabolic acidosis (bicarbonate < 15 mmol/L within one hour of birth)). Treatment group was assigned by a table of random numbers. The treatment group (n = 130) received 2 mg/kg/day of dexamethasone phosphate intravenously for seven days; the control group (n = 118) received an equal volume of 10% dextrose. The major endpoint of the study was necrotising enterocolitis.

Kopelman 1999 was a prospective, blinded, randomised controlled trial of 70 infants of less than 28 weeks' gestation who required mechanical ventilation. Thirty-seven infants received dexamethasone 0.20 mg/kg at delivery and 33 infants received a placebo of an equal volume of saline.

Lin 1999 was a randomised trial with a sequential design involving infants of 500 g to 1999 g. Infants were stratified by birth weight into three groups: 500 g to 999 g, 1000 g to 1500 g and 1501 g to 1999 g. Within each group equal numbers of dexamethasone-treated or control cards were placed in envelopes for random selection of the first infant of each pair. The next infant of the appropriate birth weight stratum was enrolled for the match. A pharmacist opened the envelope and the dexamethasone or saline placebo was administered blind. Entry criteria were: presence of severe radiographic respiratory distress syndrome, need for assisted ventilation within six hours of birth and given one dose of surfactant. Treated infants were given dexamethasone starting within 12 hours of birth at 0.25 mg/kg/dose 12-hourly for seven days, 0.12 mg/kg/dose 12-hourly for seven days, 0.05 mg/kg/dose 12-hourly for seven days and 0.02 mg/kg/dose 12-hourly for seven days, giving a total of 4 weeks' treatment. Results are presented for 20 treated and 20 control infants.

Mukhopadhyay 1998 was a randomised trial with untreated controls. The method of randomisation was not described. Treated infants received dexamethasone 0.5 mg/kg/dose 12-hourly for three days, beginning within six hours of birth. Nineteen infants of less than 34 weeks' gestation and less than 2000 g, who could be provided with mechanical ventilation, were included in the study. These infants had severe respiratory distress syndrome but were not given surfactant.

Ng 2006 was a double-blind, randomised controlled trial of a "stress dose" of hydrocortisone for treatment of refractory hypotension. Forty-eight infants of birth weight less than 1500 g were randomised to have either hydrocortisone 1 mg/kg eight-hourly for five days or an equivalent volume of isotonic saline.

Peltoniemi 2005 enrolled a total of 51 infants either less than 1251 g birth weight or less than 31 weeks' gestation, who were under 36 hours old and who were ventilator-dependent. There were three collaborating centres in Finland. Stratification was by centre and birth weight (501 g to 749 g, 750 g to 999 g and 1000 g to 1250 g). Infants were randomly allocated to either a 10-day tapering course of hydrocortisone (2 mg/kg/day for two days, 1.5 mg/kg/day for two days, 0.75 mg/kg/day for six days) (n = 25) or an equivalent volume of 0.9% saline placebo (n = 26). The sample size calculation was based on detecting an increase in survival without chronic lung disease from 50% to 70% and required 160 patients per study arm (alpha and beta error 0.05 and 0.20 respectively). The study was stopped early at 51 infants because two of the hydrocortisone-treated infants had intestinal perforation and because of reports from other RCTs of early hydrocortisone of the same complication.

Rastogi 1996 recruited 70 infants with birth weights of 700 g to 1500 g who had severe respiratory distress syndrome (assisted ventilation with at least 40% oxygen and/or 7 cm H2O mean airway pressure, a/A PO2 ratio of 0.24 or less) and had been treated with surfactant before entry. The infants were less than 12 hours old. Infants were excluded if they had major malformations, chromosome abnormalities, five-minute Apgar scores of under three or severe infection. The intervention group had dexamethasone intravenously every 12 hours according to the following schedule: 0.50 mg/kg/day on days one to three, 0.30 mg/kg/day on days four to six, 0.20 mg/kg/day on days seven to nine and finally 0.10 mg/kg/day on days 10 to 12. A saline placebo was given intravenously to the control group.

Romagnoli 1999 was a randomised trial using numbered, sealed envelopes involving 25 dexamethasone-treated infants and 25 untreated controls. Entry criteria were: birth weight less than 1251 g, gestational age less than 33 weeks, ventilator and oxygen-dependent at 72 hours and at high risk of chronic lung disease using a local scoring system that predicted a 90% risk. Treated infants were given dexamethasone beginning on the 4th day at a dose of 0.5 mg/kg/day for three days, 0.25 mg/kg/day for three days and 0.125 mg/kg/day for one day.

Sanders 1994 enrolled 40 infants of less than 30 weeks' gestation who had respiratory distress syndrome diagnosed by clinical and radiographic signs, required mechanical ventilation at 12 to 18 hours of age, and had received at least one dose of surfactant. Exclusion criteria at entry included a strong suspicion of sepsis or pneumonia, congenital heart disease, chromosome abnormalities and those infants who received an exchange transfusion. The infants were randomised to receive either dexamethasone 0.50 mg/kg between 12 and 18 hours of age and a second dose 12 hours later, or a saline placebo. Both treatments were given intravenously.

Shinwell 1996 was a multicentre trial that randomised 248 infants of birth weight 500 g to 2000 g if they had clinical and radiographic evidence of respiratory distress syndrome, required mechanical ventilation with more than 40% oxygen, were less than 12 hours old and had no contraindications to corticosteroid treatment, such as a bleeding tendency, hypertension, hyperglycaemia or active infection. Infants with lethal congenital malformations were also excluded. The intervention group received dexamethasone 0.25 mg/kg intravenously every 12 hours for a total of six doses. The control group received intravenous saline.

Sinkin 2000 was a multicentre, randomised, double-blind trial of 384 infants of less than 30 weeks' gestation with respiratory distress syndrome. One hundred and eighty-nine infants received dexamethasone 0.50 mg/kg at 12 to 18 hours of age and with a second dose 12 hours later, and 195 infants had an equal volume of saline placebo.

Soll 1999 was a multicentre, randomised, double-blinded, controlled trial comparing dexamethasone given at 12 hours of age with selective late dexamethasone therapy in premature infants weighing 501 g to 1000 g (early dexamethasone n = 272, late selective therapy n = 270). The infants required assisted ventilation, had received surfactant therapy, were physiologically stable, had no obvious life-threatening congenital anomaly, had blood cultures obtained and had antibiotic therapy started. Infants were randomly assigned to early dexamethasone therapy or saline placebo. Intravenous dexamethasone was administered for 12 days according to the following schedule: 0.5 mg/kg/day for three days, 0.25 mg/kg/day for three days, 0.1 mg/kg/day for three days and 0.05 mg/kg/day for three days. Infants in either group could receive late postnatal corticosteroids beginning on day 14 if they needed assisted ventilation with supplemental oxygen greater than 30%.

Stark 2001 was a randomised, multicentre, controlled trial to compare a tapering course of stress-dose corticosteroid started on the first day with placebo. Infants with birth weight 501 g to 1000 g needing mechanical ventilation before 12 hours of age were eligible for the study. Infants with birth weight over 750 g also needed to have received surfactant and required an oxygen concentration of 30% or greater. The initial dose of dexamethasone was 0.15 mg/kg/day for three days, then tapered over seven days. After enrolling 220 infants (sample size was 1200), the trial was halted because of an excess of intestinal perforations in the dexamethasone-treated group. One hundred and eleven infants were randomised to receive dexamethasone and 109 placebo.

Subhedar 1997 was a randomised trial that enrolled infants into one of four treatment groups using a factorial design. Both inhaled nitric oxide (iNO) and early dexamethasone were compared separately with controls. Forty-two infants were randomised: 10 receiving iNO alone, 11 dexamethasone alone, 10 both treatments and 11 neither treatment. The 21 infants receiving dexamethasone were compared with 21 controls. Infants were eligible for entry into the trial at 96 hours of age if they met the following criteria: gestational age less than 32 weeks, mechanical ventilation from birth, had received surfactant therapy and were thought to be at high risk of developing chronic lung disease using a scoring system (Ryan 1996). Exclusion criteria included major congenital anomaly, structural cardiac defect, significant ductus shunting, culture-positive sepsis, intraventricular haemorrhage with parenchymal involvement, pulmonary or gastrointestinal haemorrhage, disordered coagulation or platelet count less than 50,000. Dexamethasone was given intravenously at 12-hourly intervals for six days: 0.50 mg/kg/dose for six doses and 0.25 mg/kg/dose for a further six doses. Control infants were not given a placebo.

Suske 1996 randomised 26 infants with gestational ages of 24 to 34 weeks, who had respiratory distress syndrome that had been treated with surfactant. Infants with known septicaemia during the first week of life, haemodynamically relevant cardiac anomalies except for patent ductus arteriosus, or malformations of the lung or central nervous system (CNS) were excluded. Randomisation was by drawing lots prior to the age of two hours. The intervention group received dexamethasone 0.50 mg/kg intravenously in two divided doses for five days and the controls received no placebo.

Tapia 1998 was a multicentre, double-blind, placebo-controlled trial of 109 preterm infants with respiratory distress syndrome and birth weights between 700 g and 1600 g, who were treated with mechanical ventilation and surfactant. Fifty-five infants were randomised to receive dexamethasone 0.50 mg/kg/day for three days, followed by 0.25 mg/kg/day for three days, followed by 0.12 mg/kg/day for three days and then 0.06 mg/kg/day for three days. Fifty-four control infants received an equal volume of saline.

Vento 2004 enrolled 20 neonates with birth weight less than 1251 g and gestation less than 33 weeks who were oxygen and ventilator-dependent on the fourth day of life, who were randomised to receive either dexamethasone 0.50 mg/kg/day for three days, 0.25 mg/kg/day for three days and 0.125 mg/kg/day for one day (total dose 2.375 mg/kg) or no corticosteroid treatment.

Wang 1996 was a randomised trial of a 21-day course of either dexamethasone or saline placebo given in a double-blind fashion. The method of randomisation was not stated. The entry criteria were: birth weight 1000 g to 1999 g, appropriate for gestational age, clinical and radiological severe respiratory distress syndrome, mechanical ventilation and age less than 12 hours. Surfactant was not given as it was not commercially available in Taiwan at the time of the study. Treated infants were given dexamethasone 0.25 mg/kg/dose 12-hourly for seven days, 0.125 mg/kg/dose 12-hourly for seven days and 0.05 mg/kg/dose 12-hourly for seven days making a total course of 21 days. The first dose of dexamethasone was given during the first 12 hours of life. There were 34 infants in the dexamethasone group and 29 in the placebo control group.

Watterberg 1999 was a randomised, double-masked, placebo-controlled pilot study to compare early treatment with low-dose hydrocortisone (1.0 mg/kg/day for nine days, then 0.5 mg/kg/day for three days), begun before 48 hours of age, with placebo. Forty infants weighing between 500 g and 999 g and who were mechanically ventilated were enrolled at two centres: 20 hydrocortisone-treated and 20 placebo controls.

Watterberg 2004 was a multicentre, masked, randomised trial of hydrocortisone to prevent early adrenal insufficiency. Three hundred and sixty infants with birth weights of 500 g to 999 g who were mechanically ventilated were randomised to receive either hydrocortisone 1 mg/kg/day for 12 days, then 0.5 mg/kg/day for three days or saline placebo. Infants were enrolled between 12 and 48 hours of life. The trial was stopped because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone group.

Yeh 1990 enrolled 57 infants whose birth weights were less than 2000 g and who had severe respiratory distress syndrome based upon the appearance of a chest radiograph and the need for mechanical ventilation within four hours after birth. The absence of infection was also required for inclusion. The infants were randomly assigned to receive dexamethasone 0.50 mg/kg per dose every 12 hours from days one to three, then 0.25 mg/kg per dose 12-hourly from days four to six, then 0.12 mg/kg per dose 12-hourly from days seven to nine and finally 0.05 mg/kg per dose 12-hourly from days 10 to 12. All doses were given intravenously. A saline solution was used in the placebo group.

Yeh 1997 was a multicentre, randomised, double-blind clinical trial of 262 preterm infants (< 2000 g) who had respiratory distress syndrome and required mechanical ventilation from shortly after birth. The treated group had dexamethasone 0.25 mg/kg/dose every 12 hours intravenously from day one to seven; 0.12 mg/kg/dose every 12 hours intravenously from day 8 to 14; 0.05 mg/kg/dose every 12 hours intravenously from days 15 to 21; and 0.02 mg/kg/dose every 12 hours intravenously from day 22 to 28. Control infants had a saline placebo.

Excluded studies

We excluded 25 studies. See Characteristics of excluded studies.

We excluded studies for several reasons. In Gaissmaier 1999, the primary outcome was need for an epinephrine infusion 12 hours after treatment. No long-term outcomes were reported. Tsukahara 1999 was not a RCT; there were 26 study infants and 12 historical controls.

Studies of late postnatal corticosteroids are included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014). These studies are excluded from this review and include: Avery 1985; Ariagno 1987; Cummings 1989; Harkavy 1989; Noble-Jamieson 1989; Kazzi 1990; CDTG 1991; Ohlsson 1992; Kari 1993; Brozanski 1995; Durand 1995; Scott 1997; Kovacs 1998; Papile 1998; Romagnoli 1998; Vincer 1998; Kothadia 1999; Walther 2003; Vento 2004; Doyle 2006 and Parikh 2013.

In Dobryansky 2012, 120 very low birth weight infants were randomised to both hydrocortisone and caffeine as active treatments, compared with "standard guidelines", which presumably meant no hydrocortisone or caffeine. The major outcomes reported included bronchopulmonary dysplasia and bronchopulmonary dysplasia combined with death. As caffeine alone reduces bronchopulmonary dysplasia (Schmidt 2006), the independent effect of hydrocortisone cannot be determined.

In Yaseen 1999, although 29 very low birth weight infants were randomly allocated to either dexamethasone or placebo before six hours of age, none of the outcomes reported were applicable to this review. The outcomes reported comprised only changes in mean values over the first five days for oxygenation, blood pressure and serum creatinine, urea and glucose, and not rates of chronic lung disease, hypertension or hypoglycaemia, for example.

There are no studies currently awaiting further assessment.

Risk of bias in included studies

Overall the risk of bias was low for most studies. They were all randomised controlled trials, although the method of random allocation was not always clear. Allocation concealment applied to most studies. Blinding of investigators and others was mostly achieved through use of placebos, usually saline solution. Follow-up reporting for short-term outcomes was mostly complete, but was more variable for long-term outcomes beyond discharge and later into childhood.

In Anttila 2005, randomisation was carried out in the pharmacy of the co-ordinating centre using coded vials, with blinding of the study investigators. Open-label dexamethasone was allowed when deemed necessary by the attending neonatologist but its use was discouraged. Intention-to-treat analysis was performed. There was no follow-up component.

Randomisation in Baden 1972 was by vials and a table of random numbers. The clinical personnel were not aware of the content of any vial. Outcomes were given for all of the infants enrolled.

The follow-up component was as follows (Fitzhardinge 1974): survivors were seen at 12 months of age, corrected for prematurity, by one paediatrician and one psychologist. A neurologist saw all children with abnormal neurological signs. Observers were blind to treatment group allocation. The follow-up rate of survivors was 93% (25/27). Criteria for the diagnosis of cerebral palsy were not specified, nor were there specific criteria for blindness or deafness (children were tested by free-field pure-tone audiometry). Psychological assessment included the Griffiths scales. Major neurosensory disability was not specified.

The method of randomisation in Batton 2012 was not stated. An identical placebo was used. There was no follow-up component.

In Biswas 2003, randomisation was conducted by the Perinatal Trials Unit in Oxford, with stratification for centre and gender, and the code was held by the study pharmacist. Controls received an equal infusion rate of 5% dextrose. Syringes were made in one pharmacy and transported to individual study centres. Short-term outcomes were reported for all infants enrolled. There was no follow-up component.

Randomisation in Bonsante 2007 was centralised using a computer-generated random number sequence. There was stratification into six risk groups to ensure a homogeneous number of infants with regard to birth weight, gestation and antenatal corticosteroid administration. The drugs were prepared each day in the pharmacy and the care team, parents and the personnel collecting the data had no knowledge of the random assignment at any time.

Results of follow-up at two years of age are reported (follow-up component) in conjunction with data from another study (Peltoniemi 2009), but clinical criteria for various outcomes were not described. Follow-up data were reported for 92% (33/36) of survivors up to hospital discharge.

In Efird 2005, randomisation was by opening sequentially numbered, opaque envelopes containing pre-assigned treatment designations. Infants of multiple gestations were randomised as separate participants. Clinicians were blinded to treatment identity. If hypotension persisted the randomisation assignment could be unblinded and hydrocortisone administered if the infant had been assigned to the placebo group. There was no follow-up component.

Infants in Garland 1999 were randomised at each centre within each of four strata based on birth weight (≤ 1000 g, > 1000 g) and arterial/alveolar (a/A) ratio before surfactant (≤ 0.15, > 0.15). Randomisation codes were maintained by the study pharmacists at each centre. Investigators, caregivers and parents were blinded to treatment allocation. At the first interim analysis (n = 75), an increased risk of gastrointestinal perforation was noted in the dexamethasone group. After adjusting for severity of illness the difference was not sufficiently statistically significant to stop enrolment. However, to ensure patient safety the data monitoring committee recommended reducing the dexamethasone dose. The dosing schedule was changed to four doses of 0.25 mg/kg/dose every 12 hours, begun at 24 to 48 hours, followed by doses of 0.125 mg/kg and 0.05 mg/kg at the next two 12-hour periods respectively. After the first interim analysis, all enrolled infants received ranitidine therapy during the first three days of the study. Outcome measures appear to have been reported for all 241 infants enrolled in the study. There was no follow-up component.

Randomisation in Halac 1990 was by means of a table of random numbers, with placebo blinding. It was stated that deaths before 10 days of age were excluded from the study; there were a total of five early deaths from sepsis, but it was not clear how often this occurred in each group. Apart from these infants, outcome data were provided for all remaining infants enrolled. There was limited follow-up to six months of age, but no results were given (apart from a statement that "growth and development were not hampered in any of these patients").

In Kopelman 1999, randomisation was performed in the pharmacy after stratification for treatment with antenatal corticosteroids. The blinded clinical team provided care. Outcome data were provided for all infants enrolled. There was no follow-up component.

Randomisation in Lin 1999 was by opening sealed envelopes in the pharmacy. The study had a sequential analysis design with 12 infants being paired successfully. Outcome measures were given for all 40 infants enrolled including those who remained unpaired. There was no follow-up component.

For Mukhopadhyay 1998, the method of randomisation is not stated. Only 28 of 43 eligible infants could be provided with ventilation. Eight infants were subsequently excluded due to non-availability of blood gases due to a technical fault and one baby was excluded because of congenital heart block. This left 19 infants for study; 10 received intravenous dexamethasone and nine were not treated with any drug. There is no mention of placebo. Outcome measures were reported for these 19 infants. There was no follow-up component.

Randomisation in Ng 2006 was achieved using computer-generated random numbers and opening of sequentially numbered, sealed, opaque envelopes in the pharmacy. Assignment was in blocks of six and once an envelope was opened an infant would be irrevocably entered into the trial. To ensure effective blinding of the medications both types of trial drug were colourless, odourless and made up to the same volume before being sent to the ward. There was no follow-up component.

In Peltoniemi 2005, randomisation was performed centrally by non-clinical staff independent of the chief investigators, with random variation in block sizes of two to eight, and separately for each centre. Syringes were prepared and labelled identically in the pharmacy department of the centre, concealing allocation from the study site's investigators and the infant's caregivers. Open-label corticosteroids were discouraged after randomisation, but not prohibited; some infants may have received both a second course of their initially allocated study drug and open-label corticosteroids. No one apart from the pharmacist at study sites had access to the treatment codes. Short-term outcomes were reported for all infants enrolled.

The follow-up component was as follows (Peltoniemi 2009): surviving children were assessed at 24 months of age, corrected for prematurity, by paediatricians, paediatric neurologists and psychologists at individual study sites who were blinded to treatment group allocation. Children were considered to have a major neurosensory impairment if they had cerebral palsy, blindness (inability to see any objects, with the exception of light), deafness (failure to pass an evoked otoacoustic emission test during the neonatal period and no response in brainstem auditory evoked potentials) or developmental delay (defined as a Mental Developmental Index (MDI) on the Bayley Scales of Infant Development < 70 (<-2 standard deviation (SD)) or a developmental quotient < 70 on the Griffiths Cognitive Scales). The follow-up rate of survivors at two years was 98% (45/46).

Randomisation in Rastogi 1996 occurred in the pharmacy using a random number list after stratifying for birth weight into three groups: 700 g to 999 g, 1000 g to 1249 g and 1250 g to 1500 g. The clinical team and other study personnel were blinded to the assignments until the study was completed and all outcome variables were recorded for all infants. There was no follow-up component.

In Romagnoli 1999, randomisation, obtained by random number allocation, was achieved by opening numbered, sealed envelopes. Infants with prenatal infections, congenital malformations and evidence of sepsis at randomisation were excluded. There is no mention of placebo. Outcome measures were reported for all 50 infants enrolled.

The follow-up component was as follows (Romagnoli 2002): survivors were seen at 34 to 42 months of age, corrected for prematurity, by one paediatrician and one neurologist, with observers blinded to treatment group allocation. The follow-up rate of survivors was 100% (45/45). Cerebral palsy was diagnosed by the neurologist, but the criteria were not specified, neither were there specific criteria for blindness or deafness. Psychological assessment included the Stanford-Binet - 3rd Revision and intellectual impairment comprised an IQ < 70. Major neurosensory impairment comprised either blindness or deafness.

In Sanders 1994, randomisation occurred in the pharmacy after opening sealed envelopes. Dexamethasone or placebo were dispensed in labelled syringes. Clinical personnel were not aware of the assignment of the intervention. Outcomes are given for all 40 infants enrolled.

The follow-up component was as follows (Sinkin 2002): survivors were seen at mean ages of 64 (SD 8) months (dexamethasone) and 61 (SD 4) months (controls), not corrected for prematurity, by a paediatrician, a neurologist and a psychologist, with observers blinded to treatment group allocation. Additional data were sought from parents and teachers. The follow-up rate of survivors was 100% (31/31). The criterion for the diagnosis of cerebral palsy was a fixed motor deficit diagnosed by the neurologist. Blindness comprised visual acuity < 6/60 in the better eye. Deafness was defined as the need for a hearing aid. Psychological assessment included the Wechsler Scales (WISC and WPPSI) - intellectual impairment comprised a Full Scale IQ < 70. Major neurosensory disability was not specified. Further follow-up at 15 years of age is planned.

In Shinwell 1996, each participating unit was supplied with numbered sets of syringes containing either dexamethasone or physiological saline. Syringes containing dexamethasone were not distinguishable from those containing saline. Syringe sets were numbered according to a random number list and randomisation was stratified by centre and by two birth weight groups: 500 g to 1000 g and 1001 g to 2000 g. The drug assignment was not known to any of the investigators until after the three-month observation period of the last enrolled infant. Outcomes are reported for 248 of the 255 infants who were enrolled. The seven infants subsequently excluded from analysis included three with major congenital abnormalities (two with myotonic dystrophy and one with cyanotic congenital heart disease), three with errors in drug administration and one randomised after the age of 12 hours.

The follow-up component was as follows (Shinwell 2002): survivors were seen at a mean age of 53 (SD 18; range 24 to 71) months, presumably not corrected for prematurity. These children were seen in multiple follow-up clinics by multiple paediatricians, with observers blinded to treatment group allocation. The follow-up rate of survivors was 83% (159/190). Criteria for the diagnosis of cerebral palsy were not specified, but the diagnosis was made by neurologists in all cases. There were no specified criteria for blindness. Deafness comprised the need for hearing aids. There were no formal psychological assessments; developmental delay was assigned by judgement of the multiple assessors. Major neurosensory disability comprised any of non-ambulant cerebral palsy, global retardation (not specified), blindness or deafness. Further follow-up is planned at school age.

Randomisation in Sinkin 2000, with stratification by centre, was performed using a set of sealed envelopes in the pharmacy. Outcome data appear to have been provided for all infants enrolled.

The follow-up component was as follows (Sinkin 2002): data were obtained from one of the four original centres in the study, from follow-up clinic appointments, and from questionnaires to parents and paediatricians. Survivors were seen at approximately 12 months of age, corrected for prematurity, by a paediatrician, a neurologist and a psychologist, with observers blinded to treatment group allocation. The follow-up rate of survivors was 13% (41/311) of survivors at 36 weeks' postmenstrual age overall, but was confined to one of four individual study centres, within which the follow-up rate was 100% (41/41). The criterion for the diagnosis of cerebral palsy was a fixed motor deficit diagnosed by the neurologist. Blindness comprised visual acuity < 6/60 in the better eye. Deafness comprised the need for a hearing aid. Psychological assessment included the Bayley Scales of Infant Development. Major neurosensory disability was not specified.

Randomisation in Soll 1999 was in hospital pharmacies after opening opaque, sealed envelopes supplied by the Vermont Oxford Neonatal Network. The study was stopped prior to completion of sample size goals due to concern regarding adverse effects in the early corticosteroid therapy group. Outcome measures appear to have been reported for most of the 542 infants enrolled. There was no follow-up component.

In Stark 2001, random allocation was performed in hospital pharmacies using a random number scheme. The study had a factorial design so that infants were also randomised to routine ventilator management or a strategy of minimal ventilator support aimed at reducing mechanical lung injury. After enrolling 220 infants from a sample size estimate of 1200 the trial was halted. Outcome measures seem to have been reported for all 220 patients enrolled in the trial.

The follow-up component was as follows: survivors were seen at 18 to 22 months of age, corrected for prematurity, by trained developmental observers blinded to treatment group allocation. The follow-up rate of survivors was 88% (144/164). Criteria for the diagnosis of cerebral palsy included non-progressive abnormalities of tone in at least one limb and abnormal control of movement and posture. Blindness was defined as no useful vision in either eye. Deafness was defined as disability with bilateral hearing amplification. Psychological assessment included the MDI and the Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development-II (Bayley 1993). Major neurosensory disability comprised any of moderate or severe cerebral palsy (sit independently with support or worse), blindness, deafness or an MDI or PDI <-2 SD.

In Subhedar 1997, block randomisation was performed using computer-generated random numbers and sealed envelopes. No placebo was used. There was no evidence of blinding of clinicians. Outcome measures were reported for all infants enrolled.

The follow-up component was as follows (Subhedar 2002): survivors were seen at 30 months of age, corrected for prematurity, by one developmental paediatrician who was blinded to treatment group allocation. The follow-up rate of survivors was 95% (21/22). Criteria for the diagnosis of cerebral palsy were specified, but not for deafness; blindness was diagnosed by an ophthalmologist. Psychological assessment included the MDI and the PDI of the Bayley Scales of Infant Development. Major neurosensory disability comprised any of cerebral palsy, an MDI or PDI < 71, blindness or deafness.

In Suske 1996, randomisation was by drawing lots; the lot numbers corresponded to numbers on non-transparent envelopes. The random lots and the envelopes were drawn by a neutral, uninvolved person. This was considered a pilot trial before starting a multicentre study and it was planned that the trial would be stopped if a statistically significant difference was found between the groups. The inclusion criteria were met by 41 infants. Due to lack of co-operation and co-ordination at the beginning of the study, nine infants were not randomised. Four infants were excluded after randomisation because of definite signs of septicaemia. Results are given for 26 of the 28 remaining infants. There was no follow-up component.

Random assignment in Tapia 1998 was at each centre using ampoules of dexamethasone and saline prepared in the hospital pharmacy of one of the centres. Outcomes were reported for 109 of the 113 infants enrolled. Two infants from the dexamethasone group were excluded, one because of congenital cystic adenomatoid malformation and one because of early sepsis. Two patients from the placebo group were excluded, one because of early sepsis and the other was transferred to another hospital at two weeks of age and further data on outcome could not be obtained. There was no follow-up component.

The method of randomisation in Vento 2004 was not stated. It is not clear if the clinicians caring for the infants were blinded to treatment allocation. Control infants did not receive a placebo. There was no follow-up component.

In Wang 1996, random allocation was said to have been double-blind but the exact method was not described. Outcome measures were reported for all 63 infants enrolled in the study. There was no follow-up component.

Infants in Watterberg 1999 were randomised at each centre by constant block design with four patients per block to minimise imbalance over time. Separate randomisation tables were used for infants exposed to antenatal corticosteroids. The hydrocortisone doses and the placebo of normal saline were prepared by the hospital pharmacies. Outcome measures were reported for all of the 40 infants enrolled in the trial.

The follow-up component was as follows (Watterberg 2002): survivors were seen in a regular follow-up clinic for one of the two study sites at a mean age of 11 (SD 2) months, corrected for prematurity, by a neonatologist and a physiotherapist, with observers blinded to treatment group allocation. The follow-up rate of survivors was 53% (18/34) for the study overall, but 86% (18/21) for the study centre with follow-up data. Criteria for the diagnosis of cerebral palsy were specified and comprised abnormal tone and movement. Blindness was diagnosed by an ophthalmologist, and deafness was screened for in early infancy and at follow-up. There was no formal psychological testing. Major neurosensory disability was not defined.

In Watterberg 2004, randomisation was performed centrally, stratified for birth weight (500 g to 749 g and 750 g to 999 g) and centre, with permuted block sizes of six within each stratum. Only the pharmacists at individual sites preparing the drug were aware of the group assignment. All other personnel were masked. Twins were randomised together to the same study arm. Mortality was reported for all infants enrolled, but other short-term outcomes were reported for all but three infants who were withdrawn from the study.

The follow-up component was as follows (Watterberg 2007): surviving children were assessed at 18 to 22 months of age, corrected for prematurity, by assessors at individual study sites who were blinded to treatment group allocation.  Children were considered to have a neurodevelopmental (neurosensory) impairment if they had cerebral palsy (criteria included abnormalities of tone, movement and posture), functional blindness (inability to complete the Bayley Scales of Infant Development - Second Edition (BSID-II) (Bayley 1993) because of visual impairment), functional deafness (inability to complete BSID-II because of hearing impairment), developmental delay (defined as a MDI on the BSID-II < 70 (<-2 SD), (Bayley 1993) or motor delay (defined as a Psychomotor Developmental Index on the BSID-II < 70 (<-2 SD)).  The follow-up rate of survivors at 18 to 22 months was 86% (252/294), or 87% (252/291) excluding three children whose families had withdrawn consent.

In Yeh 1990, randomisation was performed in the pharmacy using balanced blocks of 10. The vials were labelled in the pharmacy and the clinical staff were unaware of the assignment. Sixty infants were included in the study and three were subsequently withdrawn: one because of death from Haemophilus influenzae septicaemia six hours after enrolment, and two because of an error in the measurement of birth weight (581 g and 2200 g). Outcomes for these three infants are not given. There was no follow-up component.

The method of randomisation in Yeh 1997 was by an assignment list in the central pharmacy. The sample size was calculated on the basis of an expected 50% reduction in the incidence of chronic lung disease with early dexamethasone, allowing a 5% chance of a type I error and a 10% chance of a type II error. Short-term outcome data are presented for all 262 infants enrolled. The study is described as double-blind.

The follow-up components were as follows: a) (Yeh 1998) survivors were seen at a mean age of 25 months, corrected for prematurity, by one neurologist and one psychologist, with observers blinded to treatment group allocation. The follow-up rate of survivors was 81% (133/164). Criteria for the diagnosis of cerebral palsy, blindness or deafness were not specified. Psychological assessment included the MDI and the PDI of the Bayley Scales of Infant Development. Major neurosensory disability comprised severe motor dysfunction (child non-ambulant), or an MDI or PDI <-2 SD. b). (Yeh 2004) Survivors were reassessed at seven to nine years of age. The follow-up rate of survivors was 92% (146/159). Assessors were blind to treatment allocation. A paediatric neurologist assessed the children for cerebral palsy. Motor skills were assessed with the Movement ABC. IQ was measured with the WISC-III. Vision and hearing were formally evaluated. Major neurological disability comprised any of cerebral palsy, vision worse than 20/60, deafness requiring hearing aids, or an IQ < 5th centile. It was unclear if age was corrected for prematurity. We used data for cerebral palsy at eight years in the meta-analysis as the diagnosis of cerebral palsy is more certain at eight years than at two years of age, and because the follow-up rate was higher when the participants were eight years of age. Blood pressure, height, weight and head circumference were measured at eight years of age but not reported as standardised scores (SD or Z-scores) to enable pooling of data for meta-analysis.

Effects of interventions

Results of meta-analysis

Meta-analysis of these 29 studies of early postnatal corticosteroid treatment shows the following results.

Mortality

There was no evidence that early postnatal corticosteroid treatment reduced mortality either at 28 days (typical risk ratio (RR) 1.02, 95% CI 0.88, 1.19; 19 studies and 2950 infants) (Analysis 1.1), before discharge (typical RR 1.00, 95% CI 0.88 to 1.12; 28 studies and 3730 infants) (Analysis 1.2) or at the latest age possible to determine the outcome (typical RR 0.99, 95% CI 0.88 to 1.11; 28 studies and 3730 infants) (Analysis 1.3). There was little evidence of publication bias for mortality at latest age (Figure 1).

Figure 1.

Funnel plot of comparison: 1 Mortality, outcome: 1.3 Mortality at latest reported age.

Chronic lung disease

Early corticosteroids reduced the incidence of chronic lung disease, defined as needing oxygen supplementation at either 28 days (typical RR 0.87, 95% CI 0.81 to 0.93; typical RD (RD) -0.07, 95% CI -0.10 to -0.03; 17 studies and 2874 infants) (Analysis 2.1) or 36 weeks' postmenstrual age (typical RR 0.79, 95% CI 0.71 to 0.88; typical RD -0.07, 95% CI -0.10 to -0.04; 21 studies and 3286 infants) (Analysis 2.2). There was little evidence of publication bias for oxygen supplementatation at 36 weeks (Figure 2).There was also a reduction in chronic lung disease at 36 weeks' postmenstrual age in survivors (typical RR 0.82, 95% CI 0.74 to 0.90; typical RD -0.08, 95% CI -0.11 to -0.04; 18 studies and 2462 infants) (Analysis 2.3). Early corticosteroids reduced the need for later corticosteroid treatment overall (typical RR 0.75, 95% CI 0.68 to 0.82; typical RD -0.11, 95% CI -0.15 to -0.07; 14 studies and 2483 infants) (Analysis 2.4) and in survivors (typical RR 0.77, 95% CI 0.67 to 0.89; typical RD -0.11, 95% CI -0.77 to -0.05; seven studies and 895 infants) (Analysis 2.5). There was no significant reduction in the proportion of survivors discharged home on oxygen, although there were fewer studies where this outcome could be determined (typical RR 0.72, 95% CI 0.51 to 1.03; six studies and 691 infants) (Analysis 2.6).

Figure 2.

Funnel plot of comparison: 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), outcome: 2.2 CLD (36 weeks).

Death or chronic lung disease

Early corticosteroids reduced the incidence of death or chronic lung disease, defined as needing oxygen supplementation at either 28 days (typical RR 0.92, 95% CI 0.88 to 0.96; typical RD -0.06, 95% CI -0.09 to -0.03; 15 studies and 2546 infants) (Analysis 3.1) or 36 weeks' postmenstrual age (typical RR 0.89, 95% CI 0.84 to 0.95; typical RD -0.06, 95% CI -0.09 to -0.02; 22 studies and 3317 infants) (Analysis 3.2). There was little evidence of publication bias for mortality or chronic lung disease at 36 weeks (Figure 3).

Figure 3.

Funnel plot of comparison: 3 Death or chronic lung disease (CLD), outcome: 3.2 Death or CLD at 36 weeks.

Failure to extubate

Early corticosteroids reduced the rates of failure to extubate at three days (typical RR 0.73, 95% CI 0.62 to 0.86; typical RD -0.19, 95% CI -0.28 to -0.10; three studies and 381 infants) (Analysis 4.1), seven days (typical RR 0.75, 95% CI 0.65 to 0.86; typical RD -0.13, 95% CI - 0.19 to -0.07; seven studies and 956 infants) (Analysis 4.2), 14 days (typical RR 0.77, 95% CI 0.62 to 0.97; typical RD -0.10, 95% CI -0.19 to -0.02; four studies and 443 infants) (Analysis 4.3) and at 28 days (typical RR 0.84, 95% CI 0.72 to 0.98; typical RD -0.07, 95% CI -0.13 to -0.01, seven studies and 902 infants) (Analysis 4.4).

Complications during the primary hospitalisation
Metabolic complications

Early corticosteroids increased the risk of hyperglycaemia (typical RR 1.33, 95% CI 1.20 to 1.47; typical RD 0.11, 95% CI 0.07 to 0.15; 13 studies and 2167 infants) (Analysis 5.2) and hypertension (typical RR 1.85, 95% CI 1.54 to 2.22; typical RD 0.10, 95% CI 0.07 to 0.13; 11 studies and 1993 infants) (Analysis 5.3).

Gastrointestinal complications

Early corticosteroids increased the risks of gastrointestinal bleeding (typical RR 1.86, 95% CI 1.35 to 2.55; typical RD 0.05, 95% CI 0.03 to 0.08; 12 studies and 1816 infants) (Analysis 5.14) and gastrointestinal perforation (typical RR 1.81, 95% CI 1.33 to 2.48, typical RD 0.04, 95% CI 0.02 to 0.06; 15 studies and 2519 infants) (Analysis 5.15), but there was no evidence of effect on the incidence of necrotising enterocolitis (typical RR 0.87, 95% CI 0.70 to 1.08; 23 studies and 3507 infants) (Analysis 5.13).

Other effects

Early corticosteroids increased the risk of hypertrophic cardiomyopathy (RR 4.33, 95% CI 1.40 to 13.4; RD 0.40, 95% CI 0.17 to 0.63; one study and 50 infants) (Analysis 5.4) and growth failure (RR 6.67, 95% CI 2.27 to 19.6; RD 0.68, 95% CI 0.48 to 0.88; one study and 50 infants) (Analysis 5.5) in one study where these were reported. Early corticosteroids reduced the risk of patent ductus arteriosus (typical RR 0.79, 95% CI 0.72 to 0.85; typical RD -0.09, 95% CI -0.12 to -0.06; 23 studies and 3492 infants) (Analysis 5.7). There were no significant effects on infection (typical RR 1.02, 95% CI 0.93 to 1.13; 23 studies and 3558 infants) (Analysis 5.1), pulmonary air leaks (typical RR 0.93, 95% CI 0.75 to 1.15; 14 studies and 2604 infants) (Analysis 5.6), severe intraventricular haemorrhage (typical RR 0.95, 95% CI 0.82 to 1.10; 25 studies and 3582 infants) (Analysis 5.8), periventricular leukomalacia (typical RR 1.18, 95% CI 0.84 to 1.65; 13 studies and 2186 infants) (Analysis 5.10), or pulmonary haemorrhage (typical RR 1.16, 95% CI 0.85 to 1.59; nine studies and 1299 infants) (Analysis 5.16). Any retinopathy of prematurity (typical RR 0.88, 95% CI 0.80 to 0.97; 10 studies and 1345 infants) (Analysis 5.17) and both severe retinopathy of prematurity (typical RR 0.79, 95% CI 0.65 to 0.97; RD -0.04, 95% CI -0.07 to -0.01; 13 studies and 2056 infants) (Analysis 5.18) and severe retinopathy of prematurity in survivors (typical RR 0.77, 95% CI 0.64 to 0.94; RD -0.05, 95% CI -0.09 to 0.01; 12 studies and 1575 infants) (Analysis 5.19) were reduced by early corticosteroids.

Follow-up data

Follow-up studies are limited in number compared to the total number of studies: there are 12 with follow-up data out of a total of 29.

Developmental delay

Developmental delay was increased with corticosteroids in one study with the criteria for the diagnosis not explicit (RR 1.68, 95% CI 1.08 to 2.61; RD 0.14, 95% CI 0.03 to 0.24; one study and 248 infants) (Analysis 6.5), but there were no significant differences seen when developmental delay was determined by formal develpmental assessments (Analysis 6.1; Analysis 6.2; Analysis 6.3; Analysis 6.4) .

Cerebral palsy

Cerebral palsy was increased with corticosteroids (typical RR 1.45, 95% CI 1.06 to 1.98; typical RD 0.03, 95% CI 0.00 to 0.06; 12 studies and 1452 infants) (Analysis 6.11), but there was a non-significant increase in the combined outcome, death or cerebral palsy (typical RR 1.09, 95% CI 0.95 to 1.25; 12 studies and 1452 infants) (Analysis 6.13). There was little evidence of publication bias for the outcome of cerebral palsy (Figure 4).

Figure 4.

Funnel plot of comparison: 6 Long-term follow-up, outcome: 6.11 Cerebral palsy.

Major neurosensory disability

There were non-significant effects on major neurosensory disability (typical RR 1.16, 95% CI 0.94 to 1.43; seven studies and 1233 infants) (Analysis 6.15) and the combined outcome of death or major neurosensory disability (typical RR 1.05, 95% CI 0.93 to 1.17; seven studies and 1233 infants) (Analysis 6.17).

Abnormal neurological examination

There was a significant increase in the rate of abnormal neurological examination (typical RR 1.81, 95% CI 1.33 to 2.47; typical RD 0.10, 95% CI 0.05 to 0.15; five studies and 829 infants) (Analysis 6.19) and in the combined outcome of death or abnormal neurological examination (typical RR 1.23, 95% CI 1.06 to 1.42; typical RD 0.10, 95% CI 0.03 to 0.16; five studies and 829 infants) (Analysis 6.21). Although the criteria for this diagnosis were vague and varied between studies, the size of the difference in this outcome in the trials where data were available was similar to the size of the difference in cerebral palsy in the corresponding study. In the study of Yeh et al (Yeh 1997), the data for cerebral palsy were obtained at age eight to nine years, whereas the abnormal examination data were obtained from earlier in childhood, at two years of age.

Other long-term outcomes

There were no significant effects on other long-term outcomes of blindness, deafness, formal psychometric testing, abnormal electroencephalogram (EEG), behaviour problems or rehospitalisation in infancy.

Subgroup analysis by type of corticosteroid used

Mortality

There was little difference in the effects of either dexamethasone or hydrocortisone on mortality at 28 days (typical RR dexamethasone 1.06, 95% CI 0.90 to 1.24; 16 studies and 2603 infants; hydrocortisone 0.78, 95% CI 0.50 to 1.23; three studies and 347 infants) (Analysis 1.1), before discharge (typical RR dexamethasone 1.03, 95% CI 0.90 to 1.18; 19 studies and 2840 infants; hydrocortisone 0.87, 95% CI 0.66 to 1.14; nine studies and 890 infants) (Analysis 1.2) or at the latest age possible to determine the outcome (typical RR dexamethasone 1.02, 95% CI 0.90 to 1.17; 19 studies and 2840 infants; hydrocortisone 0.87, 95% CI 0.64 to 1.14; nine studies and 890 infants) (Analysis 1.3).

Chronic lung disease

Most of the benefit of early corticosteroids in reducing the incidence of chronic lung disease came from dexamethasone, with little effect of hydrocortisone, regardless of the definition of chronic lung disease: needing oxygen supplementation at 28 days (typical RR dexamethasone 0.85, 95% CI 0.79 to 0.92; typical RD -0.07, 95% CI -0.11 to -0.04; 16 studies and 2621 infants; hydrocortisone 1.00, 95% CI 0.85 to 1.18; one study and 253 infants) (Analysis 2.1), needing oxygen at 36 weeks' postmenstrual age (typical RR dexamethasone 0.70, 95% CI 0.61 to 0.81; typical RD -0.08, 95% CI -0.12 to -0.05; 15 studies and 2484 infants; hydrocortisone 0.96, 95% CI 0.82 to 1.12; six studies and 802 infants) (Analysis 2.2). There was a significant difference in the test for subgroup differences for the outcome of needing oxygen at 36 weeks (chi-square = 8.79, P=0.003). The benefit in reducing the need for late rescue with postnatal corticosteroids was also largely confined to the dexamethasone group (typical RR dexamethasone 0.72, 95% CI 0.65 to 0.80; typical RD -0.14, 95% CI -0.18 to -0.10; 10 studies and 1974 infants; hydrocortisone 1.01, 95% CI 0.73 to 1.40; four studies and 509 infants) (Analysis 2.4). There was significant heterogeneity for some of these comparisons (2.1, 2.3, and 2.4), suggesting caution when interpreting the results.

Death or chronic lung disease

Most of the benefit of early corticosteroids in reducing the incidence of the combined outcome of death or chronic lung disease came from dexamethasone, with little effect of hydrocortisone: death or chronic lung disease, defined as needing oxygen supplementation at 28 days (typical RR dexamethasone 0.91, 95% CI 0.86 to 0.96; typical RD -0.07, 95% CI -0.10 to -0.03; 14 studies and 2293 infants; hydrocortisone 1.00, 95% CI 0.90 to 1.12; one study and 253 infants) (Analysis 3.1) or 36 weeks' postmenstrual age (typical RR dexamethasone 0.87, 95% CI 0.80 to 0.94; typical RD -0.07, 95% CI -0.10 to -0.03; 15 studies and 2483 infants; hydrocortisone 0.95, 95% CI 0.86 to 1.06; seven studies and 836 infants) (Analysis 3.2). There was significant heterogeneity for one of these comparisons (3.1), suggesting caution when interpreting the results.

Complications during the primary hospitalisation

Some of the short-term complications observed with corticosteroids were related more to dexamethasone than to hydrocortisone, including hyperglycaemia (typical RR dexamethasone 1.35, 95% CI 1.21 to 1.49; typical RD 0.11, 95% CI 0.08 to 0.15; 12 studies and 2117 infants; hydrocortisone 0.92, 95% CI 0.50 to 1.67; one study and 50 infants) (Analysis 5.2), hypertension (typical RR dexamethasone 1.84, 95% CI 1.53 to 2.21; typical RD 0.10, 95% CI 0.07 to 0.13; 10 studies and 1943 infants; hydrocortisone RR 3.00, 95% CI 0.33 to 26.92; one study and 50 infants) (Analysis 5.3) and gastrointestinal haemorrhage (typical RR dexamethasone 1.87, 95% CI 1.35 to 2.58; typical RD 0.05, 95% CI 0.03 to 0.08; 10 studies and 1725 infants; hydrocortisone 1.53, 95% CI 0.27 to 8.74; two studies and 91 infants) (Analysis 5.14). However, both types of corticosteroid were associated with more gastrointestinal perforation (typical RR dexamethasone 1.73, 95% CI 1.20 to 2.51; typical RD 0.03, 95% CI 0.01 to 0.05; nine studies and 1936 infants; hydrocortisone 2.02, 95% CI 1.13 to 3.59; typical RD 0.06, 95% CI 0.01 to 0.10; six studies and 583 infants) (Analysis 5.15) and lower rates of patent ductus arteriosus (typical RR dexamethasone 0.76, 95% CI 0.69 to 0.84; typical RD -0.10, 95% CI -0.13 to -0.06; 17 studies and 2706 infants; hydrocortisone 0.85, 95% CI 0.73 to 0,99; typical RD -0.09, 95% CI -0.12 to -0.06; six studies and 786 infants) (Analysis 5.7).

Follow-up data

Cerebral palsy and the combined outcome of death or cerebral palsy were more common with dexamethasone but not hydrocortisone (cerebral palsy typical RR dexamethasone 1.75, 95% CI 1.20 to 2.55; typical RD 0.05, 95% CI 0.01 to 0.09; seven studies and 921 infants; hydrocortisone 0.97, 95% CI 0.55 to 1.69; five studies and 531 infants) (Analysis 6.11); death or cerebral palsy typical RR dexamethasone 1.17, 95% CI 1.00 to 1.37; typical RD 0.07, 95% CI 0.00 to 0.13; seven studies and 921 infants; hydrocortisone 0.91, 95% CI 0.70 to 1.19; five studies and 531 infants) (Analysis 6.13).

We noted that in some of the subgroup analyses there were few studies and small sample sizes for the hydrocortisone subgroup; hence the power to detect either beneficial or harmful effects of hydrocortisone was limited under these circumstances.

Results of individual trials

Anttila 2005: The primary outcome was survival without bronchopulmonary dysplasia, intraventricular haemorrhage (grade 3 or 4) or periventricular leukomalacia and although this tended to be greater in the dexamethasone group the differences compared with controls were not statistically significant. The relative risk for death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 0.78 (95% confidence interval (CI) 0.54 to 1.13) overall and 0.61 (95% CI 0.33 to 1.11) in the subgroup with birth weight 750 g to 999 g. There were no detectable trends in mortality, severe intraventricular haemorrhage or periventricular leukomalacia. The rates of patent ductus arteriosus, retinopathy of prematurity or sepsis did not differ between groups. Mean arterial blood pressures were increased in the dexamethasone group during the first week (P = 0.015) and the dexamethasone group tended to need more insulin therapy (49% versus 39%; P = 0.25).

Baden 1972: No significant effect on blood gases, pH, oxygen requirement, need for assisted ventilation or survival was demonstrated in this study. There were no significant differences in the rates of cerebral palsy or deafness in survivors, or in mean scores on the Griffiths scales, or in the combined rate of death or cerebral palsy (Fitzhardinge 1974).

Batton 2012: There were minimal effects on rates of death during the primary hospitalisation, bronchopulmonary dysplasia (undefined), intraventricular haemorrhage, periventricular leukomalacia or necrotising enterocolitis.

Biswas 2003: There were no significant effects of the infusion of hydrocortisone and T3 on the primary endpoint of death or failure to extubate by seven days, or death or oxygen dependency at 14 days. Patent ductus arteriosus was significantly reduced in the treatment group (41/125 versus 60/128; risk ratio 0.70, 95% CI 0.51 to 0.96), but there were no other significant differences in secondary outcomes.

Bonsante 2007: Oxygen-free survival was significantly greater in the hydrocortisone group than in controls (64% versus 32%; P = 0.023). The effect of hydrocortisone was particularly evident in the subgroup not exposed to prenatal corticosteroids. Four infants in the hydrocortisone group died compared to 10 in the control group (16% versus 40%; P = 0.05). Duration of ventilation, patent ductus arteriosus, severe retinopathy of prematurity, severe intraventricular haemorrhage and periventricular leukomalacia were not different between groups.

Efird 2005: Vasopressor use was lower in the hydrocortisone-treated group, significantly so on the second day of life. There were no significant differences in cortisol levels between groups at any time point. There were no significant differences in mortality, duration of ventilation, bronchopulmonary dysplasia (oxygen at 36 weeks' postmenstrual age), nosocomial infections, necrotising enterocolitis, spontaneous intestinal perforations or intraventricular haemorrhage. No infants were treated or removed from the study as a result of hypertension. There was no difference in rate of glucose intolerance between groups but two infants in the hydrocortisone group received insulin for five days.

Garland 1999: Early dexamethasone-treated infants were more likely to survive without chronic lung disease (83/118 versus 71/123; P = 0.03) than placebo-treated controls. They were also less likely to develop chronic lung disease if they survived to 28 days (16/99 versus 27/98; P = 0.042). Mortality rates were not significantly different. Subsequent dexamethasone therapy was used less often in the early dexamethasone-treated infants who survived (68/99 versus 81/98; P = 0.01). Intestinal perforation was more common, but not significantly so, in the dexamethasone-treated infants (12/118 versus 7/122; P = 0.20); during the first week of life the difference was significant (9/118 versus 1/122; P = 0.009). Infants in the dexamethasone group also spent less time in oxygen (median days 43 versus 50; P = 0.04). Any grade of intraventricular haemorrhage (36% versus 52%; P = 0.02) and patent ductus arteriosus ligation (14% versus 28%; P = 0.01) were also less common in the dexamethasone group. Hypertension and insulin therapy occurred more often in the dexamethasone-treated infants (P = 0.007).

Halac 1990: There were no substantial or statistically significant effects of dexamethasone on neonatal mortality, mortality to hospital discharge, necrotising enterocolitis, sepsis, patent ductus arteriosus or severe intraventricular haemorrhage.

Kopelman 1999: Intermittent mandatory ventilation (IMV) rate and ventilation index improved more rapidly in the dexamethasone-treated group. Mean blood pressure was higher after the first day in the dexamethasone group. Patent ductus arteriosus was less common in dexamethasone-treated infants (13/37 versus 19/33; P = 0.08) and fewer received indomethacin (8/37 versus 15/33; P = 0.03). At the study hospital where early extubation was practised, more dexamethasone-treated infants were extubated during the first week (10/22 versus 2/16, P < 0.03). There was no difference in intraventricular haemorrhage. No adverse effects occurred.

Lin 1999: For the endpoint of chronic lung disease at 28 days statistical significance favouring dexamethasone was reached when analysis of 12 consecutive pairs in which one infant had chronic lung disease and the other did not showed that 10 pairs favoured dexamethasone and two pairs favoured control. Data presented for 40 infants (20 in each group) show a lower incidence of chronic lung disease at 28 days in the dexamethasone group (n = 3) compared with nine in the control group (P < 0.05). Duration of oxygen therapy was also shorter in the dexamethasone group: 7 +/- 6 days versus 13 +/- 12 days (P < 0.05). Among survivors, 12/15 were extubated in the dexamethasone group compared to 9/16 in the control group at the end of the study. Infants in the treated group had transient hyperglycaemia and hypertension, but there were no differences between the groups for mortality, incidence of sepsis or intraventricular haemorrhage.

Mukhopadhyay 1998: Oxygen requirement was lower in the treated group on days three, four and five compared to the control group, although the differences were not statistically significant. Mean duration of ventilation was shorter in the dexamethasone group (87 +/- 42 hours) versus control group (120+/- 46 hours); P value not given. There was one case of culture-positive sepsis in the dexamethasone group and two in the control group. None of the infants developed bronchopulmonary dysplasia (definition not given). Four infants in the dexamethasone group developed a pneumothorax versus three in the control group. Survival was 60% in the treated group and 55% in the control group.

Ng 2006: Nineteen infants (79%) in the hydrocortisone group were weaned from vasopressor support within 72 hours compared with eight controls (33%) (P < 0.001). The cumulative doses of dopamine and dobutamine after randomisation were significantly lower in the hydrocortisone group. Duration of ventilation, duration of oxygen and incidence of bronchopulmonary dysplasia (oxygen at 36 weeks' postmenstrual age) were not significantly different between groups. There were no differences between groups for highest serum glucose, culture-proven sepsis, necrotising enterocolitis, intestinal perforation, duration of hospitalisation and mortality. However, significantly more hydrocortisone-treated infants had glycosuria (P = 0.029).

Peltoniemi 2005: Hydrocortisone-treated infants did not have a significant increase in survival without bronchopulmonary dysplasia (64% versus 54% placebo) or a significant decrease in bronchopulmonary dysplasia in survivors (odds ratio (OR) 0.53, 95% CI 0.17 to 1.71). However, the study enrolled only 16% of its intended sample size. Two infants in the hydrocortisone group died and three in the placebo group. During the first week of life, infants in the hydrocortisone group needed lower mean airway pressures compared to the placebo group (P = 0.03). Patent ductus arteriosus (36% versus 73%; P = 0.01) and duration of oxygen therapy (34 versus 62 days; P = 0.02) were lower in the hydrocortisone group but intraventricular haemorrhage, cystic periventricular leukomalacia, retinopathy of prematurity, sepsis, necrotising enterocolitis, gastrointestinal haemorrhage, open corticosteroid treatment and durations of intubation and hospitalisation were not different between groups. There was an increased risk of gastrointestinal perforation in the hydrocortisone group (16% versus 0%; P = 0.05). There were no differences in the rate of hyperglycaemia needing insulin or blood pressures (diastolic and systolic).

Rastogi 1996: Ventilator variables at 5 to 14 days were significantly improved in those infants who received dexamethasone compared to those who received placebo. The effect seemed to be more marked in infants weighing less than 1250 g at birth. Significantly more infants could be extubated by 14 days in the dexamethasone group (26/32 versus 14/32; P = 0.004). Dexamethasone therapy reduced the incidence of chronic lung disease at 28 days (OR 0.10, 95% CI 0.03 to 0.30) and eliminated chronic lung disease at 36 weeks' postmenstrual age. Dexamethasone-treated infants were more likely to show weight loss at 14 days (12.9% versus 3.7%; P = 0.01) and higher blood pressures from days 3 to 10. However, no differences were seen in time to regain birth weight, hypertension (one infant in each group) or incidence of intraventricular haemorrhage.

Romagnoli 1999: The incidences of chronic lung disease at 28 days and 36 weeks' postmenstrual age were significantly lower in the dexamethasone group than the control group (P < 0.001). Infants in the dexamethasone group remained intubated and required oxygen therapy for a shorter period than those in the control group (P < 0.001). Hyperglycaemia, hypertension, growth failure and hypertrophy of the left ventricle were transient side effects of early corticosteroid administration. There were no significant differences in the rates of cerebral palsy, blindness, deafness, intellectual impairment or mean IQ, or in the combined rate of death or cerebral palsy (Romagnoli 2002).

Sanders 1994: The dexamethasone group required less ventilatory support (mean airway, peak inspiratory and end-expiratory pressures, and IMV) and supplemental oxygen after study day four (all P < 0.05). Improved tidal volume in the dexamethasone group, as assessed by pulmonary function testing of infants who remained intubated, was seen on study day seven (P = 0.02). The dexamethasone group required a shorter time in hospital (median 95 days versus 106 days, P = 0.01). Survival in the dexamethasone group was 89% versus 67% in the placebo group (P = 0.08). Survival without chronic lung disease was 68% in the dexamethasone versus 43% in the placebo group (P = 0.14). Mean blood pressure was elevated on study day four to seven. No differences in the rate of hyperglycaemia, incidence or severity of intraventricular haemorrhage or days to regain birth weight were seen. There were no significant differences in the rates of cerebral palsy, blindness, deafness or intellectual impairment, or in the combined rate of death or cerebral palsy (Sinkin 2002).

Shinwell 1996: No differences were found in any outcome variable except for a reduction in the need for mechanical ventilation at three days in dexamethasone-treated infants (54/122, 44% versus 71/106, 67%; P = 0.001). Gastrointestinal haemorrhage, hypertension and hyperglycaemia were more common in treated infants, but no life-threatening complications, such as gastrointestinal perforation, were encountered. Follow-up of survivors at two to six years showed no significant differences in the rates of blindness, deafness, major neurosensory disability, or in the combined rate of death or major neurosensory disability. However, there were significant increases in the rates of abnormal neurological examination, developmental delay and cerebral palsy. There was also a significant increase in the combined rate of death or cerebral palsy (Shinwell 2002).

Sinkin 2000: No differences were found in the dexamethasone and placebo groups, respectively, for the primary outcomes of survival (79% versus 83%), survival without oxygen at 36 weeks' postmenstrual age (both 59%), and survival without oxygen at 36 weeks' postmenstrual age and without late corticosteroids (46% versus 44%). No significant differences between the groups were found for median time in oxygen (50 versus 56 days), ventilation (20 versus 27 days), time to regain birth weight (15.5 versus 15.0 days) nor length or stay (88 versus 89 days). Infants given early dexamethasone were less likely to receive late corticosteroids for bronchopulmonary dysplasia during their hospital stay (25% versus 35%, P = 0.042). No clinically significant side effects were noted in the dexamethasone group, although there were transient elevations in blood glucose and blood pressure with return to baseline by study day 10. Among infants who died (40 versus 33), there were no differences in the median days on oxygen, ventilation or length of hospital stay. However, in survivors (149 versus 162), the following were observed: median days on oxygen 37 versus 45, ventilation 14 versus 19 days, and length of stay 79 versus 81 days, for the dexamethasone versus placebo groups, respectively. There were no significant differences in the rates of cerebral palsy, or in the combined rate of death or cerebral palsy, or in mean Bayley scores (Sinkin 2002).

Soll 1999: There were no differences in the primary outcome of chronic lung disease or death at 36 weeks' postmenstrual age (early therapy 135/272 versus 143/267; risk ratio (RR) 0.93, 95% CI 0.79 to 1.09). Infants who received early corticosteroid therapy were less likely to need late treatment (114/270 versus 164/267; RR 0.69, 95% CI 0.58 to 0.81). They also had a lower risk of patent ductus arteriosus: 92/272 versus 117/269; RR 0.78, 95% 0.63 to 0.96) and were less likely to receive indomethacin therapy (132/273 versus 176/269; RR 0.74, 95% CI 0.64 to 0.86). However, infants who received early corticosteroid therapy were more likely to have complications such as hyperglycaemia (200/271 versus 151/263; RR 1.29, 95% CI 1.13 to 1.46) and use of insulin therapy (168/271 versus 102/267; RR 1.62, 95% CI 1.36 to 1.94). There were trends toward increased gastrointestinal haemorrhage (33/271 versus 21/267; RR 2.55, 95% CI 0.92 to 2.61) and gastrointestinal perforation (31/271 versus 20/267; RR 1.53, 95% CI 0.89 to 2.61). In infants who had cranial ultrasound scans there was a trend towards an increase in periventricular leukomalacia in the early corticosteroid group (18/252 versus 8/250; RR 2.23, 95% CI 0.99 to 5.04). Infants who received early corticosteroid therapy had fewer days in supplemental oxygen but they experienced poorer weight gain.

Stark 2001: Corticosteroid-treated infants had a lower incidence of the primary outcome, death or chronic lung disease at 36 weeks' postmenstrual age (63% versus 69%; P < 0.05). Fewer infants in the corticosteroid group had pulmonary interstitial emphysema (9% versus 23%; P < 0.05), required oxygen at 28 days (78% versus 94%; P < 0.05) or had subsequent corticosteroid treatment (34% versus 51%; P < 0.05). The rates of severe intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity and nosocomial infection were similar. Hypertension and hyperglycaemia were more frequent in the corticosteroid group (27% versus 4% and 23% versus 12% respectively with both P < 0.05). During the first 14 days, 14/111 (13%) infants in the corticosteroid group and 3/109 (3%) infants in the placebo group had spontaneous gastrointestinal perforation without necrotising enterocolitis (P < 0.05). Spontaneous perforation was also associated with indomethacin treatment (P = 0.005) and there was an interaction between indomethacin and corticosteroid therapy (P = 0.04). There were no significant differences in the rates of cerebral palsy, developmental delay, major neurosensory disability, the combined rate of death or cerebral palsy, or the combined rate of death or major neurosensory disability (Stark 2001).

Subhedar 1997: There was no difference in the combined incidence of chronic lung disease and/or death before discharge from hospital between either infants treated with dexamethasone and controls (RR 0.95, 95% CI 0.79 to -1.18) or those treated with inhaled nitric oxide and controls (RR 1.05, 95% CI 0.84 to 1.25). There were no significant differences in the rates of cerebral palsy, blindness, deafness, developmental delay, the combined rate of death or cerebral palsy, or the combined rate of death or major neurosensory disability (Subhedar 2002).

Suske 1996: Infants in the dexamethasone group were extubated earlier (6.6 days versus 14.2 days; P < 0.02) and required less time in supplemental oxygen (4.2 days versus 12.5 days; P < 0.02). Pulmonary complications tended to be lower in the dexamethasone group (1/14 versus 4/12), as was the frequency of retinopathy of prematurity (2/14 versus 6/12; P < 0.05).

Tapia 1998: There were no significant differences in mortality and/or chronic lung disease between the groups. There was a significant reduction in the number of infants requiring oxygen at 36 weeks' postmenstrual age in the dexamethasone group (8% versus 33%; P < 0.05). Stepwise logistic regression analysis with oxygen dependency at 36 weeks as the dependent variable and birth weight, gestational age, gender, prenatal corticosteroids and study treatment as the independent variables showed that study treatment was the only variable significantly associated with oxygen dependency at 36 weeks. There were no differences in the number of days of mechanical ventilation and oxygen treatment between the groups. There were no differences in the incidences of major morbidity and possible complications related to corticosteroid administration, except for a lower incidence of necrotising enterocolitis in the dexamethasone group.

Vento 2004: Seven dexamethasone-treated infants and two control infants were extubated during the study period of seven days. There were no differences between groups for respiratory distress syndrome, patent ductus arteriosus or severe intraventricular haemorrhage (grade 3 or 4). Dexamethasone-treated infants had lower absolute cell count and proportion of polymorphs in tracheal aspirate fluid compared with control infants as early as day one of treatment. They also had significantly higher dynamic compliance values compared to control infants (P < 0.01) as early as day two of treatment. There were also significantly lower inspired oxygen concentrations on day two (0.24 versus 0.31; P < 0.05) and mean airway pressure on day five (4.8 versus 7.2 cm H2O; P < 0.05).

Wang 1996: Dexamethasone treatment decreased fractional inspired oxygen concentration, arterial carbon dioxide tension and mean airway pressure, and facilitated successful weaning from mechanical ventilation. SP-A concentrations in tracheal aspirates were increased at day seven and 14, and SP-D concentrations were increased during the period from days 3 to 14 in the dexamethasone-treated group, compared with the control group.

Watterberg 1999: More infants treated with hydrocortisone survived without supplemental oxygen at 36 weeks' postmenstrual age (12/20 versus 7/20; P = 0.023). Hydrocortisone treatment was also associated with a reduction in the duration of oxygen > 40% (7 versus 28 days; P = 0.06), duration of oxygen > 25% (48 versus 69 days; P = 0.02) and duration of mechanical ventilation (25 versus 32 days; P = 0.03). There were no differences in the rates of death, sepsis, patent ductus arteriosus, necrotising enterocolitis, gastrointestinal perforation, intraventricular haemorrhage or retinopathy of prematurity. There were no significant differences in the rates of cerebral palsy, blindness, deafness, or the combined rate of death or cerebral palsy (Watterberg 2002).

Watterberg 2004: There were no differences in primary outcomes between groups (hydrocortisone versus placebo): survival without bronchopulmonary dysplasia (35% versus 34%), death before 36 weeks' postmenstrual age (15% versus 16%) and death before discharge (16% versus 17%). In a subgroup of infants exposed to chorioamnionitis, the hydrocortisone-treated group had significantly improved survival without bronchopulmonary dysplasia (38% versus 24%; P = 0.005) and lower mortality at 36 weeks' postmenstrual age (10% versus 18%; P = 0.02) and before discharge (12% versus 21%; P = 0.02). During treatment the rates of hyponatraemia, hypernatraemia, hyperkalaemia, hyperglycaemia, hypertension and gastrointestinal bleeding were similar between groups. Seventy-four infants (41%) in the hydrocortisone group were treated with insulin versus 62 (34%) in the placebo group (P = 0.19). Serum sodium and mean arterial blood pressure were significantly higher in hydrocortisone-treated infants (P < 0.001 and P = 0.022, respectively). Other outcomes included no differences in weight gain or head circumference, durations of oxygen and ventilation, pulmonary air leaks, pulmonary haemorrhage, patent ductus arteriosus, sepsis, intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity and necrotising enterocolitis. However, hydrocortisone-treated infants were less likely to receive open-label corticosteroids during the treatment period (18% versus 28%; P = 0.02) and more likely to have a spontaneous gastrointestinal perforation (9% versus 2%; P = 0.01). At follow-up there were no significant differences in the rates of cerebral palsy, major neurological disability, developmental delay, rehospitalisation, or the combined rates of death or cerebral palsy, or death or major neurological disability (Watterberg 2007).

Yeh 1990: Infants in the dexamethasone group had significantly higher pulmonary compliance, tidal volume and minute ventilation, and required lower mean airway pressure for ventilation than infants in the placebo group. The endotracheal tube was successfully removed from more infants in the dexamethasone group (16/28 versus 8/29; P < 0.025) at two weeks of age. Nineteen infants (65%) in the placebo group and 11 (39%) in the dexamethasone group (P < 0.05) had lung injuries characterised by: 1. surviving infants with chronic lung disease; 2. infants who died of intractable respiratory failure and had evidence of chronic lung disease at autopsy; and 3. infants who died of intractable respiratory failure with clinical evidence of chronic lung disease. Dexamethasone therapy was associated with a temporary increase in blood pressure and plasma glucose concentration and a delay in somatic growth.

Yeh 1997: Infants in the dexamethasone group had a significantly lower incidence of chronic lung disease than those in the placebo group, judged either at 28 postnatal days (21/132 versus 40/130, P < 0.05) or at 36 weeks' postmenstrual age (20/132 versus 37/130, P < 0.05). More infants in the dexamethasone group were extubated during the study. There was no difference in mortality between the groups (39/130 versus 44/132); however, a higher proportion of infants in the dexamethasone group died in the late study period, probably attributable to infection. There was no difference between the groups in the duration of oxygen therapy and hospitalisation. Significantly more infants in the dexamethasone group had either bacteraemia or clinical sepsis (44/132 versus 27/130, P < 0.05). Other immediate but transient side effects observed in the dexamethasone group were hyperglycaemia, hypertension, cardiac hypertrophy, hyperparathyroidism and delay in growth rate. At 25 months of age there were no significant differences in the rates of blindness, developmental delay, major neurosensory disability, the combined rate of death or cerebral palsy, or the combined rate of death or major neurosensory disability. However, there were significant increases in the rates of abnormal neurological examination and cerebral palsy among survivors (Yeh 1998). The follow-up rate of survivors at eight years was 92% (146/159). Although rates of cerebral palsy were not significantly higher in the dexamethasone group, their overall motor performance on the Movement ABC was worse than in controls. IQ and other cognitive performance was significantly worse in the dexamethasone group. Overall, the survivors in the dexamethasone group had more major neurological disability.

Discussion

Corticosteroids are potent drugs which may improve lung function in infants with chronic lung disease by a number of different mechanisms. It has been suggested that they might have a role to play in the prevention of chronic lung disease by suppressing the inflammatory response in the lungs of infants at risk (Groneck 1995). It has also been shown that infants who develop chronic lung disease have low cortisol levels following adrenocorticotrophic hormone (ACTH) stimulation during the first week of life (Watterberg 1999). To be effective in preventing chronic lung disease corticosteroids may have to be given within the first few days of life.

This review has demonstrated that early corticosteroid treatment facilitates weaning from the ventilator. Additional advantages are increased survival without chronic lung disease at 28 days and 36 weeks' postmenstrual age, and reductions in the risk of chronic lung disease at 28 days and at 36 weeks' postmenstrual age, the need for late treatment with corticosteroids and patent ductus arteriosus. On the other hand, there are increases in the risks of gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure.

There are other potential hazards of corticosteroid treatment in the neonate including restriction of growth (Gibson 1993), protein breakdown (van Goudoever 1994), cardiac hypertrophy (Werner 1992) and possible adverse effects on development of the central nervous system (Weichsel 1977; Gramsbergen 1998) and lungs (Tschanz 1995). One study has shown a significant decline in the growth of head circumference with early corticosteroid treatment (Papile 1996). Long-term follow-up results show that early corticosteroid treatment is associated with a significant increase in the risk of developmental delay and cerebral palsy, but no significant effects on the combined outcome of death or cerebral palsy, except in the subgroup of infants treated with dexamethasone. One study where the rate of cerebral palsy was significantly higher at two years of age used a four-week tapering course of dexamethasone (Yeh 1997), so is similar in duration to the six-week tapering course of late corticosteroids reported by O'Shea 1999 and included in the systematic review of late corticosteroids (Doyle 2014). However, in the Yeh study (Yeh 1997), the numbers of surviving children with cerebral palsy declined between two and eight to nine years of age, and the difference became statistically non-significant. In the follow-up study of Shinwell 1996 (Shinwell 2002), adverse long-term neurological outcomes were reported in children treated with only a three-day course of early dexamethasone starting within 12 hours of birth. This finding is of extreme importance and concern as there was about a three-fold increased risk of cerebral palsy in survivors, including children with spastic diplegia, spastic quadriplegia and hemiplegia. Why dexamethasone given early for a short course should have such devastating effects is unknown. Certainly some infants would have been treated with repeat courses of dexamethasone but this would have been more likely in the control infants. Periventricular leukomalacia is an obvious cause of cerebral palsy, but studies have shown no excess of this in corticosteroid-treated infants compared with controls. Despite the increase in the diagnosis of cerebral palsy, it is important to note that this does not necessarily translate into major functional disability for the children concerned.

This systematic review found that early (≤ 7 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants, in the regimens used, have significant short and long-term effects, both beneficial and harmful. A significant problem in interpreting the late follow-up data is that only 12 of the 28 trials of early postnatal corticosteroids have reported follow-up results; therefore, the possibility of follow-up bias and publication bias must be considered. Potential limitations of the study with a significant increase in the rate of cerebral palsy are that only 84% of surviving infants were examined and the age of assessment was in early childhood (Shinwell 1996). It is important to remember that cerebral palsy had been diagnosed before the children were five years of age in most cases; diagnosing cerebral palsy with certainty before five years of age is problematic (Stanley 1982). In the other study where the rate of cerebral palsy was significantly worse at two years of age, with 81% follow-up, the difference became non-significant at eight to nine years, an age when the diagnosis of cerebral palsy is more certain, and where the follow-up rate was much better (92%) (Yeh 1997), illustrating the importance of age of assessment and high follow-up rates. No study was designed primarily to test the effect of postnatal corticosteroids on adverse long-term neurosensory outcome and all were underpowered to detect clinically important differences in long-term neurosensory outcome.

In the subgroup analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone, with hydrocortisone having little effect, but the power to detect beneficial or harmful effects of hydrocortisone was low in most comparisons.

In an observational study of infants born after antenatal corticosteroid therapy there appeared to be an excess of periventricular leukomalacia in those whose mothers had received dexamethasone rather than betamethasone (Baud 1999). Most studies of postnatal corticosteroids used dexamethasone in high doses of 0.5 to 1.0 mg/kg/day. Other corticosteroids or lower doses of dexamethasone may prove to be safer, but there is little evidence to support the use of hydrocortisone as prophylaxis for chronic lung disease in the dose regimes employed in the studies reviewed. Further studies are needed comparing lower doses of corticosteroids, other corticosteroids and alternative routes of administration, e.g. inhalation (see Cochrane Review by Shah 2007b).

Authors' conclusions

Implications for practice

The benefits of early postnatal corticosteroids in preterm infants at risk of developing chronic lung disease may not outweigh the real or potential adverse effects. Early postnatal corticosteroid treatment resulted in short-term benefits, including earlier extubation and decreased risks of chronic lung disease and of 'death or chronic lung disease' at 28 days and 36 weeks' postmenstrual age, but was also associated with significant short and long-term adverse effects. Adverse effects included the short-term risk of gastrointestinal bleeding, intestinal perforation, hyperglycaemia and hypertension, and the long-term risks of abnormal neurological examination and cerebral palsy. However, the methodological quality of the studies determining the long-term outcomes was limited in some cases; the children were assessed predominantly before school age and no study was sufficiently powered to detect important adverse long-term neurosensory outcomes. Therefore, given the risks of potential short-term and long-term adverse effects versus the potential short-term benefits, it appears appropriate to curtail early corticosteroid treatment for the prevention of chronic lung disease.

Implications for research

There is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. Tests of gross motor function, cognitive functioning, hearing and visual acuity should be included in these follow-up studies.

Future studies are also needed to identify accurately those infants most at risk of developing chronic lung disease. Any future placebo-controlled trials of postnatal corticosteroids in preterm infants should include long-term neurological follow-up. Studies comparing different types, doses and durations of corticosteroid treatment, and examining the effects of inhaled corticosteroids, are urgently needed.

Acknowledgements

None noted.

Data and analyses

Download statistical data

Comparison 1. Mortality
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Neonatal mortality (up to 28 days)192950Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.88, 1.19]
1.1 Dexamethasone162603Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.90, 1.24]
1.2 Hydrocortisone3347Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.50, 1.23]
2 Mortality to hospital discharge283730Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.88, 1.12]
2.1 Dexamethasone192840Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.90, 1.18]
2.2 Hydrocortisone9890Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.66, 1.14]
3 Mortality at latest reported age283730Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.88, 1.11]
3.1 Dexamethasone192840Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.90, 1.17]
3.2 Hydrocortisone9890Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.67, 1.14]
Analysis 1.1.

Comparison 1 Mortality, Outcome 1 Neonatal mortality (up to 28 days).

Analysis 1.2.

Comparison 1 Mortality, Outcome 2 Mortality to hospital discharge.

Analysis 1.3.

Comparison 1 Mortality, Outcome 3 Mortality at latest reported age.

Comparison 2. Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 CLD (28 days)172874Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.81, 0.93]
1.1 Dexamethasone162621Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.79, 0.92]
1.2 Hydrocortisone1253Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.85, 1.18]
2 CLD (36 weeks)213286Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.71, 0.88]
2.1 Dexamethasone152484Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.61, 0.81]
2.2 Hydrocortisone6802Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.82, 1.12]
3 CLD at 36 weeks in survivors182462Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.74, 0.90]
3.1 Dexamethasone131841Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.64, 0.84]
3.2 Hydrocortisone5621Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.85, 1.12]
4 Late rescue with corticosteroids142483Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.68, 0.82]
4.1 Dexamethasone101974Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.65, 0.80]
4.2 Hydrocortisone4509Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.73, 1.40]
5 Survivors who had late rescue with corticosteroids7895Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.67, 0.89]
5.1 Dexamethasone6853Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.68, 0.91]
5.2 Hydrocortisone142Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.24, 0.98]
6 Survivors discharged home on oxygen6691Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.51, 1.03]
6.1 Dexamethasone3406Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.48, 1.26]
6.2 Hydrocortisone3285Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.40, 1.11]
Analysis 2.1.

Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 1 CLD (28 days).

Analysis 2.2.

Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 2 CLD (36 weeks).

Analysis 2.3.

Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 3 CLD at 36 weeks in survivors.

Analysis 2.4.

Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 4 Late rescue with corticosteroids.

Analysis 2.5.

Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 5 Survivors who had late rescue with corticosteroids.

Analysis 2.6.

Comparison 2 Chronic lung disease (CLD)/bronchopulmonary dysplasia (BPD), Outcome 6 Survivors discharged home on oxygen.

Comparison 3. Death or chronic lung disease (CLD)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death or CLD at 28 days152546Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.88, 0.96]
1.1 Dexamethasone142293Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.86, 0.96]
1.2 Hydrocortisone1253Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.90, 1.12]
2 Death or CLD at 36 weeks223317Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.84, 0.95]
2.1 Dexamethasone152481Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.80, 0.94]
2.2 Hydrocortisone7836Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.86, 1.06]
Analysis 3.1.

Comparison 3 Death or chronic lung disease (CLD), Outcome 1 Death or CLD at 28 days.

Analysis 3.2.

Comparison 3 Death or chronic lung disease (CLD), Outcome 2 Death or CLD at 36 weeks.

Comparison 4. Failure to extubate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to extubate by 3rd day3381Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.62, 0.86]
2 Failure to extubate by 7th day7956Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.65, 0.86]
3 Failure to extubate by 14th day4443Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.62, 0.97]
4 Failure to extubate by 28th day7902Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.72, 0.98]
Analysis 4.1.

Comparison 4 Failure to extubate, Outcome 1 Failure to extubate by 3rd day.

Analysis 4.2.

Comparison 4 Failure to extubate, Outcome 2 Failure to extubate by 7th day.

Analysis 4.3.

Comparison 4 Failure to extubate, Outcome 3 Failure to extubate by 14th day.

Analysis 4.4.

Comparison 4 Failure to extubate, Outcome 4 Failure to extubate by 28th day.

Comparison 5. Complications during primary hospitalisation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Infection233558Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.93, 1.13]
1.1 Dexamethasone182821Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.91, 1.15]
1.2 Hydrocortisone5737Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.87, 1.21]
2 Hyperglycaemia132167Risk Ratio (M-H, Fixed, 95% CI)1.33 [1.20, 1.47]
2.1 Dexamethasone122117Risk Ratio (M-H, Fixed, 95% CI)1.35 [1.21, 1.49]
2.2 Hydrocortisone150Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.50, 1.67]
3 Hypertension111993Risk Ratio (M-H, Fixed, 95% CI)1.85 [1.54, 2.22]
3.1 Dexamethasone101943Risk Ratio (M-H, Fixed, 95% CI)1.84 [1.53, 2.21]
3.2 Hydrocortisone150Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.33, 26.92]
4 Hypertrophic cardiomyopathy150Risk Ratio (M-H, Fixed, 95% CI)4.33 [1.40, 13.37]
5 Growth failure150Risk Ratio (M-H, Fixed, 95% CI)6.67 [2.27, 19.62]
6 Pulmonary air leak142604Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.75, 1.15]
6.1 Dexamethasone111941Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.67, 1.09]
6.2 Hydrocortisone3663Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.77, 1.81]
7 Patent ductus arteriosus (PDA)233492Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.72, 0.85]
7.1 Dexamethasone172706Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.69, 0.84]
7.2 Hydrocortisone6786Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.73, 0.99]
8 Severe IVH253582Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.82, 1.10]
8.1 Dexamethasone172736Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.81, 1.14]
8.2 Hydrocortisone8846Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.65, 1.24]
9 Severe intraventricular haemorrhage (IVH) in infants examined61388Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.68, 1.09]
10 Periventricular leukomalacia (PVL)132186Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.84, 1.65]
10.1 Dexamethasone71414Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.84, 1.84]
10.2 Hydrocortisone6772Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.54, 1.96]
11 PVL in infants with cranial ultrasound scans61320Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.88, 1.88]
12 PVL in survivors seen at follow-up2183Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.60, 2.48]
13 Necrotising enterocolitis (NEC)233507Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.70, 1.08]
13.1 Dexamethasone152661Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.69, 1.13]
13.2 Hydrocortisone8846Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.30]
14 Gastrointestinal bleeding121816Risk Ratio (M-H, Fixed, 95% CI)1.86 [1.35, 2.55]
14.1 Dexamethasone101725Risk Ratio (M-H, Fixed, 95% CI)1.87 [1.35, 2.58]
14.2 Hydrocortisone291Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.27, 8.74]
15 Gastrointestinal perforation152519Risk Ratio (M-H, Fixed, 95% CI)1.81 [1.33, 2.48]
15.1 Dexamethasone91936Risk Ratio (M-H, Fixed, 95% CI)1.73 [1.20, 2.51]
15.2 Hydrocortisone6583Risk Ratio (M-H, Fixed, 95% CI)2.02 [1.13, 3.59]
16 Pulmonary haemorrhage91299Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.85, 1.59]
16.1 Dexamethasone7686Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.65, 1.45]
16.2 Hydrocortisone2613Risk Ratio (M-H, Fixed, 95% CI)1.52 [0.90, 2.54]
17 Any retinopathy of prematurity (ROP)91345Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.80, 0.97]
17.1 Dexamethasone81042Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.72, 0.99]
17.2 Hydrocortisone1303Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.84, 1.04]
18 Severe ROP132056Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.65, 0.97]
18.1 Dexamethasone81507Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.60, 0.99]
18.2 Hydrocortisone5549Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.60, 1.16]
19 Severe ROP in survivors121575Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.64, 0.94]
19.1 Dexamethasone101238Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.59, 0.95]
19.2 Hydrocortisone2337Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.60, 1.17]
Analysis 5.1.

Comparison 5 Complications during primary hospitalisation, Outcome 1 Infection.

Analysis 5.2.

Comparison 5 Complications during primary hospitalisation, Outcome 2 Hyperglycaemia.

Analysis 5.3.

Comparison 5 Complications during primary hospitalisation, Outcome 3 Hypertension.

Analysis 5.4.

Comparison 5 Complications during primary hospitalisation, Outcome 4 Hypertrophic cardiomyopathy.

Analysis 5.5.

Comparison 5 Complications during primary hospitalisation, Outcome 5 Growth failure.

Analysis 5.6.

Comparison 5 Complications during primary hospitalisation, Outcome 6 Pulmonary air leak.

Analysis 5.7.

Comparison 5 Complications during primary hospitalisation, Outcome 7 Patent ductus arteriosus (PDA).

Analysis 5.8.

Comparison 5 Complications during primary hospitalisation, Outcome 8 Severe IVH.

Analysis 5.9.

Comparison 5 Complications during primary hospitalisation, Outcome 9 Severe intraventricular haemorrhage (IVH) in infants examined.

Analysis 5.10.

Comparison 5 Complications during primary hospitalisation, Outcome 10 Periventricular leukomalacia (PVL).

Analysis 5.11.

Comparison 5 Complications during primary hospitalisation, Outcome 11 PVL in infants with cranial ultrasound scans.

Analysis 5.12.

Comparison 5 Complications during primary hospitalisation, Outcome 12 PVL in survivors seen at follow-up.

Analysis 5.13.

Comparison 5 Complications during primary hospitalisation, Outcome 13 Necrotising enterocolitis (NEC).

Analysis 5.14.

Comparison 5 Complications during primary hospitalisation, Outcome 14 Gastrointestinal bleeding.

Analysis 5.15.

Comparison 5 Complications during primary hospitalisation, Outcome 15 Gastrointestinal perforation.

Analysis 5.16.

Comparison 5 Complications during primary hospitalisation, Outcome 16 Pulmonary haemorrhage.

Analysis 5.17.

Comparison 5 Complications during primary hospitalisation, Outcome 17 Any retinopathy of prematurity (ROP).

Analysis 5.18.

Comparison 5 Complications during primary hospitalisation, Outcome 18 Severe ROP.

Analysis 5.19.

Comparison 5 Complications during primary hospitalisation, Outcome 19 Severe ROP in survivors.

Comparison 6. Long-term follow-up
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Bayley Mental Developmental Index (MDI) <-2SD3842Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.78, 1.29]
2 Bayley MDI <-2SD in tested survivors3528Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.79, 1.25]
3 Bayley Psychomotor Developmental Index (PDI) <-2SD3842Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.85, 1.60]
4 Bayley PDI <-2SD in tested survivors3528Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.87, 1.57]
5 Developmental delay (criteria not specified)1248Risk Ratio (M-H, Fixed, 95% CI)1.68 [1.08, 2.61]
6 Developmental delay (criteria not specified) in tested survivors1159Risk Ratio (M-H, Fixed, 95% CI)1.94 [1.30, 2.88]
7 Blindness7888Risk Ratio (M-H, Fixed, 95% CI)2.01 [0.74, 5.50]
8 Blindness in survivors assessed7550Risk Ratio (M-H, Fixed, 95% CI)2.16 [0.80, 5.86]
9 Deafness7670Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.30, 3.14]
10 Deafness in survivors assessed7441Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.31, 3.06]
11 Cerebral palsy121452Risk Ratio (IV, Fixed, 95% CI)1.45 [1.06, 1.98]
11.1 Dexamethasone7921Risk Ratio (IV, Fixed, 95% CI)1.75 [1.20, 2.55]
11.2 Hydrocortisone5531Risk Ratio (IV, Fixed, 95% CI)0.97 [0.55, 1.69]
12 Death before follow-up in trials assessing cerebral palsy121452Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.81, 1.14]
12.1 Dexamethasone81281Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.83, 1.19]
12.2 Hydrocortisone4171Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.42, 1.21]
13 Death or cerebral palsy121452Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]
13.1 Dexamethasone7921Risk Ratio (M-H, Fixed, 95% CI)1.17 [1.00, 1.37]
13.2 Hydrocortisone5531Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.70, 1.19]
14 Cerebral palsy in survivors assessed12959Risk Ratio (M-H, Fixed, 95% CI)1.50 [1.13, 2.00]
14.1 Dexamethasone7586Risk Ratio (M-H, Fixed, 95% CI)1.82 [1.29, 2.57]
14.2 Hydrocortisone5373Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.56, 1.63]
15 Major neurosensory disability (variable criteria - see individual studies)71233Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.94, 1.43]
15.1 Dexamethasone4772Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.03, 1.83]
15.2 Hydrocortisone3461Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.69, 1.28]
16 Death before follow-up in trials assessing major neurosensory disability (variable criteria)71233Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.81, 1.17]
16.1 Dexamethasone4772Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.82, 1.25]
16.2 Hydrocortisone3461Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.58, 1.25]
17 Death or major neurosensory disability (variable criteria)71233Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.93, 1.17]
17.1 Dexamethasone4772Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.99, 1.30]
17.2 Hydrocortisone3461Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.73, 1.10]
18 Major neurosensory disability (variable criteria) in survivors examined7799Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.94, 1.38]
18.1 Dexamethasone4469Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.05, 1.77]
18.2 Hydrocortisone3330Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.69, 1.22]
19 Abnormal neurological exam (variable criteria - see individual studies)5829Risk Ratio (M-H, Fixed, 95% CI)1.81 [1.33, 2.47]
20 Death before follow-up in trials assessing abnormal neurological exam (variable criteria)5829Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.79, 1.21]
21 Death or abnormal neurological exam (variable criteria)5829Risk Ratio (M-H, Fixed, 95% CI)1.23 [1.06, 1.42]
22 Abnormal neurological exam (variable criteria) in tested survivors5508Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.41, 2.52]
23 Intellectual impairment (IQ < 70)290Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.57, 3.31]
24 Intellectual impairment (IQ < 70) in survivors assessed276Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.47, 2.65]
25 "Major neurosensory impairment" - blindness or deafness150Risk Ratio (M-H, Fixed, 95% CI)0.6 [0.16, 2.25]
26 "Major neurosensory impairment" - blindness or deafness - in survivors assessed145Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.16, 2.12]
27 Behaviour abnormalities150Risk Ratio (M-H, Fixed, 95% CI)0.6 [0.16, 2.25]
28 Behaviour abnormalities in 3-year old survivors assessed146Risk Ratio (M-H, Fixed, 95% CI)0.6 [0.16, 2.22]
29 Abnormal EEG2306Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.66, 2.33]
30 Abnormal EEG in tested survivors2146Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.61, 2.08]
31 Re-hospitalisation in infancy3672Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.68, 1.08]
32 Re-hospitalisation in infancy in survivors3430Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.71, 1.07]
Analysis 6.1.

Comparison 6 Long-term follow-up, Outcome 1 Bayley Mental Developmental Index (MDI) <-2SD.

Analysis 6.2.

Comparison 6 Long-term follow-up, Outcome 2 Bayley MDI <-2SD in tested survivors.

Analysis 6.3.

Comparison 6 Long-term follow-up, Outcome 3 Bayley Psychomotor Developmental Index (PDI) <-2SD.

Analysis 6.4.

Comparison 6 Long-term follow-up, Outcome 4 Bayley PDI <-2SD in tested survivors.

Analysis 6.5.

Comparison 6 Long-term follow-up, Outcome 5 Developmental delay (criteria not specified).

Analysis 6.6.

Comparison 6 Long-term follow-up, Outcome 6 Developmental delay (criteria not specified) in tested survivors.

Analysis 6.7.

Comparison 6 Long-term follow-up, Outcome 7 Blindness.

Analysis 6.8.

Comparison 6 Long-term follow-up, Outcome 8 Blindness in survivors assessed.

Analysis 6.9.

Comparison 6 Long-term follow-up, Outcome 9 Deafness.

Analysis 6.10.

Comparison 6 Long-term follow-up, Outcome 10 Deafness in survivors assessed.

Analysis 6.11.

Comparison 6 Long-term follow-up, Outcome 11 Cerebral palsy.

Analysis 6.12.

Comparison 6 Long-term follow-up, Outcome 12 Death before follow-up in trials assessing cerebral palsy.

Analysis 6.13.

Comparison 6 Long-term follow-up, Outcome 13 Death or cerebral palsy.

Analysis 6.14.

Comparison 6 Long-term follow-up, Outcome 14 Cerebral palsy in survivors assessed.

Analysis 6.15.

Comparison 6 Long-term follow-up, Outcome 15 Major neurosensory disability (variable criteria - see individual studies).

Analysis 6.16.

Comparison 6 Long-term follow-up, Outcome 16 Death before follow-up in trials assessing major neurosensory disability (variable criteria).

Analysis 6.17.

Comparison 6 Long-term follow-up, Outcome 17 Death or major neurosensory disability (variable criteria).

Analysis 6.18.

Comparison 6 Long-term follow-up, Outcome 18 Major neurosensory disability (variable criteria) in survivors examined.

Analysis 6.19.

Comparison 6 Long-term follow-up, Outcome 19 Abnormal neurological exam (variable criteria - see individual studies).

Analysis 6.20.

Comparison 6 Long-term follow-up, Outcome 20 Death before follow-up in trials assessing abnormal neurological exam (variable criteria).

Analysis 6.21.

Comparison 6 Long-term follow-up, Outcome 21 Death or abnormal neurological exam (variable criteria).

Analysis 6.22.

Comparison 6 Long-term follow-up, Outcome 22 Abnormal neurological exam (variable criteria) in tested survivors.

Analysis 6.23.

Comparison 6 Long-term follow-up, Outcome 23 Intellectual impairment (IQ < 70).

Analysis 6.24.

Comparison 6 Long-term follow-up, Outcome 24 Intellectual impairment (IQ < 70) in survivors assessed.

Analysis 6.25.

Comparison 6 Long-term follow-up, Outcome 25 "Major neurosensory impairment" - blindness or deafness.

Analysis 6.26.

Comparison 6 Long-term follow-up, Outcome 26 "Major neurosensory impairment" - blindness or deafness - in survivors assessed.

Analysis 6.27.

Comparison 6 Long-term follow-up, Outcome 27 Behaviour abnormalities.

Analysis 6.28.

Comparison 6 Long-term follow-up, Outcome 28 Behaviour abnormalities in 3-year old survivors assessed.

Analysis 6.29.

Comparison 6 Long-term follow-up, Outcome 29 Abnormal EEG.

Analysis 6.30.

Comparison 6 Long-term follow-up, Outcome 30 Abnormal EEG in tested survivors.

Analysis 6.31.

Comparison 6 Long-term follow-up, Outcome 31 Re-hospitalisation in infancy.

Analysis 6.32.

Comparison 6 Long-term follow-up, Outcome 32 Re-hospitalisation in infancy in survivors.

What's new

DateEventDescription
8 January 2014New citation required but conclusions have not changedAdded data from Batton 2012: pilot study of hydrocortisone for blood pressure support. Minor changes to Stark 2001, with full publication of follow-up data (2013).
7 September 2013New search has been performedSearches updated 22 August 2013.

History

Protocol first published: Issue 3, 1998
Review first published: Issue 3, 1998

DateEventDescription
5 November 2009Amended Peltoniemi 2005 reference citation edit.
10 November 2008New citation required but conclusions have not changedSubstantive update.
10 September 2008New search has been performed

This review updates the existing review of 'Early postnatal (< 96 hours) corticosteroids for preventing chronic lung disease in preterm infants' published in The Cochrane Library, Issue 1, 2003.

This update contains data from a total of 28 trials, 12 of which have long-term follow-up data.

10 April 2008AmendedConverted to new review format.
11 November 2002New search has been performedThe review updates the existing review of 'Early postnatal (< 96 hours) corticosteroids for preventing chronic lung disease in preterm infants' published in The Cochrane Library, Issue 1, 2001.

Additional long-term neurodevelopmental follow-up data have been included in this update from seven trials: data for Baden 1972 and Romagnoli 1999 were published in full reports; data for Subhedar 1997 were published as a letter to the editor; data for Stark 2001 were obtained from a presented and published abstract; and data for Sanders 1994, Sinkin 2000 and Watterberg 1999 were provided by the investigators. Two trials reporting short-term outcome data are also newly included: Halac 1990 and Biswas 2003.

Although early steroid treatment facilitates extubation and reduces the risk of chronic lung disease, long-term follow-up studies indicate a possible increased risk of adverse neurosensory outcome. Furthermore, short-term complications such as gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure are increased by early steroid treatment.
11 November 2002New citation required and conclusions have changedSubstantive amendment.

Contributions of authors

Lex Doyle collated the data concerning long-term neurosensory outcomes; he assisted Henry Halliday and Richard Ehrenkranz in identfying all of the studies, synthesising the data, and writing some of the earlier versions of the review. Richard Ehrenkranz assisted Henry Halliday in identfying all of the studies, synthesising the data, and writing the earlier versions of the review. Henry Halliday identified all of the studies, synthesised the data, and wrote the earlier versions of this review.

Declarations of interest

Lex Doyle was Chief Investigator of the DART study, a randomised controlled trial of low-dose, short-course dexamethasone in ventilator-dependent infants, funded by the National Health and Medical Research Council of Australia.

Henry Halliday (HLH) is a retired neonatologist. He is joint Editor-in-Chief of the journal Neonatology and sits on many Data Monitoring and Trial Steering Committees for various neonatal/perinatal trials. He has received support in the past for co-ordinating the OSECT study (2000) when Astra Zeneca (Sweden) supplied the metered dose inhalers of budesonide and placebo. HLH also acts as a consultant for Chiesi Farmiceutici (Italy), a company that sells two neonatal drugs - Curosurf (a surfactant to treat respiratory distress syndrome) and Peyona (a caffeine preparation to treat apnea of prematurity).

Sources of support

Internal sources

  • Action Research UK Grant to study the effects of postnatal steroids, UK.

  • Action Research UK Grant to study long-term follow-up, UK.

External sources

  • National Health and Medical Research Council, Australia.

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anttila 2005

MethodsMulticentre, double-blind, placebo-controlled, randomised trial
Participants109 infants with birth weight 500g to 999 g, gestation < 32 weeks, need for mechanical ventilation and supplemental oxygen by 4 hours of age. Stratified by weight (500 g to 749 g versus 750g to 999 g)
Exclusions: life-threatening congenital anomalies or known chromosomal anomaly
Interventions4 doses of dexamethasone 0.25 mg/kg each at 12-hourly intervals or normal saline as placebo. First dose was given before 6 hours. Open-label dexamethasone was allowed when deemed necessary by attending physician, but its use was discouraged
OutcomesSurvival to 36 weeks without IVH (grade III-IV), PVL (echodensities after 1st week or periventricular cysts on ultrasound) or BPD (oxygen at 36 weeks), growth, duration of assisted ventilation and oxygen, late corticosteroid treatment, infection, hyperglycaemia, hypertension, ROP, PDA, GI bleeding and perforation and NEC
NotesThis paper also reported a meta-analysis of early short versus early prolonged dexamethasone treatment
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation by use of coded vials prepared in the pharmacy of each centre
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Baden 1972

MethodsDouble-blind, placebo-controlled, randomised trial
Participants44 preterm infants < 24 hours old with respiratory distress confirmed both clinically and radiologically
InterventionsHydrocortisone 25 mg/kg on admission and 12 hours later intravenously
Control group given placebo
OutcomesDeath, FiO2, cortisol levels and blood gases
NotesThe oldest study, carried out 1972. Used hydrocortisone in a very short course of treatment
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation using random numbers and sealed envelopes
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Batton 2012

MethodsMulticentre, randomised, placebo-controlled trial
ParticipantsInfants 23 to 26 completed weeks' gestation with study-defined low blood pressure
InterventionsHydrocortisone 1 mg/kg loading, then 0.5 mg/kg at 12-hourly intervals for 6 doses
OutcomesShort-term outcomes during the primary hospitalisation of death, BPD (not defined), IVH grade III or IV, PVL and NEC requiring surgery
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEnrolled infants were randomised from a pre-specified sequence allocated by centre and administered by an investigational pharmacist.
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Biswas 2003

MethodsMulti-centre, placebo-controlled, randomised trial
Participants253 infants < 30 weeks' gestation, within 9 hours of birth at entry; all mechanically ventilated
InterventionsHydrocortisone 1 mg/kg/day as continuous infusion for 5 days, then 0.5 mg/kg/day for 2 days. Also given tri-iodothyronine 6 µg/kg/day for 5 days, halving to 3 µg/kg/day for 2 days
Controls given equal volume infusion of 5% dextrose
OutcomesThe primary outcome was death or ventilator dependence at 7 days, or death or oxygen dependence at 14 days
Secondary outcomes included durations of ventilation, oxygen dependence and hospitalisation, oxygen dependency at 36 weeks, IVH, PVL, PDA and NEC
NotesHydrocortisone combined with T3 infusion
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by Oxford Perinatal Trials Unit.
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Bonsante 2007

MethodsTwo-centre, randomised, double-blind, placebo-controlled trial
Participants70 infants either < 1000 g birth weight or < 28 weeks' gestation, ventilator-dependent after 7 days of age and considered to be a candidate for corticosteroids
Exclusions: major anomaly likely to affect long-term neurological outcome
InterventionsActive treatment – total dose of hydrocortisone 10.5 mg/kg over 10 days
Placebo group - equal volume of 0.9% saline
OutcomesPrimary outcomes: survival free of disability at 2 years of age, mortality up to 2 years of age and neurological outcome after discharge
Secondary outcomes: rate of CLD, death or CLD, failure to extubate, other complications during primary hospital stay including GI perforation, severe IVH (grade 3 or 4) and cystic PVL, long-term neurosensory impairment (blindness, deafness, developmental delay assessed by MDI on Bayley scales, cerebral palsy) and disabilities (severe - any of severe cerebral palsy (not likely to walk), blindness or severe developmental delay (MDI < 55), moderate - moderate cerebral palsy (not walking at 2 years but likely to do so), deafness, moderate developmental delay (MDI 55 to < 70), mild - mild cerebral palsy (walking at 2 years) or mild developmental delay (MDI 70 to < 85)
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation centrally
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessment blind: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up reporting: yes for outcomes during primary hospital stay - 98% of surviving infants traced to 2 years of age

Efird 2005

MethodsRandomised, double-blind, placebo-controlled trial
Participants34 infants of gestation > 23 weeks and < 29 weeks, and birth weight > 500 g and < 1000 g enrolled by 2 hours of age Exclusions: major malformations, chromosomal abnormalities and congenital heart disease
InterventionsHydrocortisone intravenously at dose of 1 mg/kg every 12 hours for 2 days, followed by 0.3 mg/kg every 12 hours for 3 days Control infants received an equivalent volume of normal saline as placebo
OutcomesBlood pressure, urine output, hyperglycaemia, mortality, durations of mechanical ventilation and hospital stay, CLD (oxygen at 36 weeks), infection, NEC, intestinal perforation, PDA, IVH, PVL and cortisol levels
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation using sequentially numbered, oreassigned treatment designations in sealed, opaque envelopes
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Garland 1999

MethodsMulti-centre, placebo-controlled, randomised trial
Participants241 infants weighing between 500 g and 1500 g, received surfactant, at significant risk for CLD or death using a model to predict at 24 hours
Interventions3-day course of dexamethasone beginning at 24 to 48 hours. The first 2 doses were 0.4 mg/kg, 3rd and 4th doses 0.2 mg/kg and the 5th and 6th doses 0.1 mg/kg and 0.05 mg/kg respectively. Dexamethasone dose reduced slightly after first interim analysis (see Notes)
A similar volume of normal saline was given to control infants
OutcomesThe primary outcomes were survival without CLD defined as oxygen therapy at 36 weeks to maintain SaO2 above 91% and mortality
Secondary outcomes included duration of ventilation and supplemental oxygen, respiratory support at 28 days, length of stay for survivors, use of subsequent dexamethasone therapy and usual complications of prematurity
NotesAt the first interim analysis (n = 75) an increased risk of GI perforation was noted in the dexamethasone group. The data monitoring committee recommended reducing the dexamethasone dose to: 4 doses of 0.25 mg/kg/dose every 12 hours begun at 24 to 48 hours followed by doses of 0.125 mg/kg and 0.05 mg/kg at the next two 12-hour periods respectively
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by study pharmacists at each centre
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Halac 1990

MethodsPlacebo-controlled, randomised trial
Participants248 infants, birth weight ≤ 1500 g, gestation < 34 weeks, with evidence of "birth asphyxia" (1-minute Apgar score < 5, prolonged resuscitation and metabolic acidosis (HCO3 < 15 mmol/l within 1 hour of birth))
Interventions7-day course of dexamethasone 1 mg/kg 12-hourly beginning on first day of life
OutcomesNeonatal mortality, mortality to discharge, NEC, PDA, sepsis and severe IVH
NotesPossible exclusion of 5 deaths after randomisation but not clear which group they came from
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation using list of random numbers
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Kopelman 1999

MethodsTwo-centre, randomised, placebo-controlled trial
Participants70 infants of < 28 weeks' gestation requiring intermittent mandatory ventilation and arterial catheterisation
InterventionsDexamethasone 0.2 mg/kg within 2 hours of delivery
Control infants given an equal volume of saline
OutcomesVentilation Index (VI), IMV rate, mean blood pressure, incidence of PDA, need for indomethacin and number extubated during the first week and usual complications of RDS
NotesAfter an interim analysis showed that the incidence of IVH was much lower than expected, enrolment was stopped and the analysis was limited to a comparison of ventilator settings, blood pressure and pressor use during the first 7 days
The outcome of successful extubation was available at only 1 hospital where 38 infants were enrolled
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in the hospital pharmacy stratified by use of antenatal corticosteroids; exact method of randomisation not stated
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Lin 1999

MethodsPlacebo-controlled, randomised trial
Participants40 infants of 500 g to 1999 g with severe RDS, needing IPPV within 6 hours of birth
InterventionsDexamethasone 0.25 mg/kg 12-hourly from 1 to 7 days, 0.12 mg/kg 12-hourly from 8 to 14 days, 0.05 mg/kg 12-hourly from 15 to 21 days, 0.02 mg/kg 12-hourly from 22 to 28 days
Saline placebo was given to controls
OutcomesMortality at 28 days and discharge, failure to extubate (during study), death or CLD (36 weeks), CLD (28 days and 36 weeks), infection (clinical), severe IVH, plasma glucose and mean blood pressure on days 2, 5, 7 and 16, weight at 2 weeks
NotesSequential analysis for 12 pairs. Data given for 40 infants as randomised into the 2 groups
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in a paired sequential trial. Assignment determined by pharmacist and groups stratified by birth weight: 500 g to 999 g, 1000 g to 1500 g and 1501 g to 1999 g. Allocation by drawing lots
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Mukhopadhyay 1998

MethodsSingle centre randomised controlled trial
Participants19 infants < 34 weeks and < 2000 g who could be provided with ventilation. Clinical and radiographic evidence of RDS, IPPV with oxygen > 30%
InterventionsDexamethasone 0.5 mg/kg per dose 12-hourly for 3 days starting within 6 hours of birth
The control group did not receive any drug
OutcomesChanges in oxygen requirements, mean duration of ventilation, culture-positive sepsis, PDA, BPD (not defined), pneumothorax, mortality
NotesInfants were only entered into the trial if a ventilator was available. Surfactant was not given
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation, method not stated
Allocation concealment (selection bias)Unclear riskAllocation concealment: not sure
Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of intervention: no
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome measurement: no
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Ng 2006

MethodsDouble-blind, randomised controlled trial
Participants48 infants of gestation < 32 weeks and birth weight < 1500 g who had systemic hypotension despite treatment with volume expanders and dopamine within the first 7 days of life. Infants also had to have an indwelling arterial catheter for continuous BP monitoring
Exclusions: major or lethal congenital or chromosomal abnormalities, congenital heart defects, previous postnatal systemic or inhaled corticosteroids, proven infection or NEC
InterventionsHydrocortisone 1 mg/kg every 8 hours for 5 days
Control infants received isotonic saline as a placebo for 5 days
OutcomesBP, use of vasopressors, durations of ventilation, oxygen and hospital stay, PIE, pulmonary haemorrhage, pneumothorax, hyperglycaemia, glycosuria, IVH (grades III or IV), PVL, NEC, GI perforation, sepsis, ROP (> stage II) and mortality
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation in blocks of 6 by computer-generated random numbers and opening numbered, sealed, opaque envelopes
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Peltoniemi 2005

MethodsMulti-centre, double-blind, randomised controlled trial
Participants51 infants with birth weight 501 g to 1250 g, gestation 23 to 29 weeks, needing mechanical ventilation before age of 24 hours. The subgroup 1000 g to 1250 g had to need supplemental oxygen and mechanical ventilation > 24 hours despite surfactant Exclusions: lethal malformations or suspected chromosomal abnormalities
InterventionsHydrocortisone 2.0 mg/kg/day intravenously 8-hourly for 2 days, 1.5 mg/kg/day 8-hourly for 2 days, 0.75 mg/kg/day 12-hourly for 6 days
Control infants received isotonic saline as placebo. The first dose was given before 36 hours. Use of open-label corticosteroids was discouraged
OutcomesSurvival without BPD (oxygen at 36 weeks), IVH (grades III or IV), cystic PVL, durations of ventilation, oxygen and hospital stay, sepsis, hyperglycaemia, hypertension, PDA, GI bleeding, GI perforation, NEC, ROP and cortisol levels. Long-term outcomes: neurosensory impairments (blindness, deafness, developmental delay assessed by MDI on Bayley scales, cerebral palsy) and disabilities (severe - any of severe cerebral palsy (not likely to walk), blindness or severe developmental delay (MDI < 55, moderate - moderate cerebral palsy (not walking at 2 years but likely to do so), deafness, moderate developmental delay (MDI 55 to < 70), mild - mild cerebral palsy (walking at 2 years) or mild developmental delay (MDI 70 to < 85)
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in each centre using identical coded syringes. Stratified by birth weight (501 g to 750 g versus 750 g to 999 g versus 1000 g to 1250 g)
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Rastogi 1996

MethodsDouble-blind, randomised controlled trial
Participants70 preterm infants < 12 hours old, weighing 700 g to 1500 g with respiratory distress syndrome (RDS) confirmed clinically and radiologically, infants needed mechanical ventilation > 30% O2 and/or MAP 7 cmH2O a/A < 0.25 after surfactant treatment
Exclusions for major malformations, chromosome abnormalities, severe infection, Apgar < 3 at 5 minutes
InterventionsIntravenous dexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days, 0.15 mg/kg/day for 3 days, 0.05 mg/kg/day for 3 days
Control group given saline placebo
OutcomesFiO2, MAP, BPD (28 days and CXR), severe BPD (36 weeks), duration O2, infections, deaths, pneumothorax, pulmonary haemorrhage, PDA, IVH, NEC, hyperglycaemia, insulin use, hypertension, ROP
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation: using a pharmacy list, stratified for birth weight
Allocation concealment (selection bias)Low riskAllocation concealment yes
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComplete follow-up: yes

Romagnoli 1999

MethodsRandomised, non-blinded, controlled trial
Participants50 infants < 1251 g or < 33 weeks, oxygen-dependent at 72 hours and at high risk of CLD according to a scoring system predicting 90% risk of CLD
InterventionsDexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days and 0.125 mg/kg/day for 1 day
Control group: no mention of placebo
OutcomesSurvival to 28 days, survival to discharge, PDA, IVH (grades 3 and 4), PVL, sepsis, NEC, ROP (stages III and above), requiring ventilation at 28 days, CLD at 28 days and 36 weeks, hyperglycaemia, hypertension, needed late corticosteroids, growth failure and left ventricular hypertrophy
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation using random numbers, concealed in numbered sealed envelopes
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of intervention: no
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome measurements: no
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Sanders 1994

MethodsRandomised, double-blinded, controlled trial
Participants40 infants < 30 weeks' gestation and 12 to 18 hours old with RDS, both clinical and radiological. The infants were being treated with mechanical ventilation and surfactant
Exclusions comprised sepsis, congenital heart disease, chromosome abnormalities or need for exchange transfusion
InterventionsDexamethasone 0.5 mg/kg twice intravenously
Control group given saline placebo
OutcomesMAP, FiO2, mortality, extubation < 7 days, pulmonary function tests, duration IPPV, O2, hospital, mortality, BPD (36 weeks O2), late corticosteroids
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in the pharmacy using sealed envelopes. Method for randoisation not described.
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Shinwell 1996

MethodsMulti-centre, double-blind, randomised controlled trial
Participants248 preterm infants with birth weight 500 g to 2000 g, 1 to 3 days old, requiring mechanical ventilation with more than 40% oxygen
Exclusions for active bleeding, hypertension, hyperglycaemia, active infection and lethal congenital anomalies
InterventionsIntravenous dexamethasone 0.25 mg/kg every 12 hours 6 times
Controls given saline placebo
OutcomesMortality, survival with no O2, mechanical ventilation at 3 and 7 days, CLD, duration in hospital, IVH, PVL, pneumothorax, PIE, PDA, sepsis, hypertension, hyperglycaemia
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation, stratified by centre and birth weight, from random numbers list in the pharmacy
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes for short-term; 84% for long-term

Sinkin 2000

MethodsMulticentre, randomised, double-blind trial
Participants384 infants < 30 weeks' gestation with RDS by clinical and radiographic signs, needing IPPV at 12 to 18 hours of age and had received at least 1 dose of surfactant
InterventionsDexamethasone 0.5 mg/kg at 12 to 18 hours of age and second dose 12 hours later
Control group given an equal volume of placebo
OutcomesPrimary outcomes were survival, survival without oxygen at 28 days or 36 weeks, and survival without oxygen at 28 days or 36 weeks and without late corticosteroids
Length of time in oxygen, on ventilation, to regain birth weight and in hospital Hyperglycaemia, hypertension, IVH, PDA, sepsis, NEC, isolated GI perforation, ROP, air leak, discharged home on oxygen
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in the pharmacy with labelled syringes. Stratification by centre. Exact method of randomisation not stated
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Soll 1999

MethodsMulticentre, randomised, double-blind trial
Participants542 infants weighing 501 g to 1000 g who required assisted ventilation < 12 hours, had received surfactant by 12 hours, were physiologically stable and had no life-threatening congenital anomalies
InterventionsDexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days, 0.10 mg/kg/day for 3 days and 0.05 mg/kg/day for 3 days Control infants received a similar volume of normal saline
Infants in either group could receive late postnatal corticosteroids beginning on day 14 if they were on assisted ventilation with supplemental oxygen > 30%
OutcomesPrimary outcome was CLD or death at 36 weeks adjusted age
Secondary outcome measures included clinical status at 14 days and 28 days, duration of assisted ventilation, supplemental oxygen and hospital stay, treatment with late postnatal corticosteroids, proven sepsis, hypertension and hyperglycaemia requiring therapy, weight at 36 weeks and the usual complications of prematurity
NotesPublished as an extended abstract and presented at a clinical meeting
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in hospital pharmacies by opening opaque, sealed envelopes. Precise method of randomisation not stated.
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Stark 2001

MethodsMulticentre, randomised, double-blind trial
Participants220 infants with birth weight 501 g to 1000 g, mechanically ventilated < 12 hours. Infants > 750 g also needed to receive surfactant and have FiO2 > 0.29
InterventionsDexamethasone 0.15 mg/kg/day for 3 days, then tapered over 7 days
Saline placebo
OutcomesDeath or CLD, oxygen at 28 days, PIE, late corticosteroid treatment, hypertension, hyperglycaemia, GI perforation
NotesFactorial design, infants also randomised to routine ventilator management or a strategy of minimal ventilator support to reduce mechanical lung injury. After enrolling 220 infants (sample size estimate was 1200) the trial was halted due to unanticipated adverse events
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation using numbers generated by a random, permuted block algorithm, stratified by birth weight
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Subhedar 1997

MethodsRandomised controlled trial - factorial design
Participants42 preterm infants, entry at 96 hours if gestation < 32 weeks, mechanical ventilation from birth, surfactant treatment and high risk of developing CLD by a score (Ryan 1996)
Exclusion criteria: major congenital anomaly, structural cardiac defect, significant ductus shunting, culture-positive sepsis, IVH with parenchymal involvement, pulmonary or GI haemorrhage, abnormal coagulation or thrombocytopenia (platelets < 50,000)
InterventionsIntravenous dexamethasone at 12-hourly intervals for 6 days; 0.5 mg/kg/dose for 6 doses and 0.25 mg/kg/dose for a further 6 doses. Inhaled NO 5 to 20 ppm for 72 hours
Control groups were not given a placebo
OutcomesMortality, CLD at 28 days and > 36 weeks with abnormal chest radiograph
Duration of ventilation, time to extubation, duration of hospitalisation, maximum grade of IVH, pulmonary haemorrhage, pneumothorax, severe PDA, NEC, ROP (stages 3 or 4)
Complications including ileal perforation, upper GI haemorrhage, hyperglycaemia, hypertension, septicaemia
NotesNote factorial design which means that half of the treated and half of the control infants also received 72 hours of inhaled NO
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation by computer-generated random numbers and sealed envelopes. Factorial design provided 4 groups: early dexamethasone, inhaled NO, both drugs together and neither drug
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of intervention: no
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome measurements: no
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Suske 1996

MethodsRandomised controlled trial
Participants26 preterm infants < 2 hours old, with birth weight < 1500 g if FiO2 > 0.50, or > 1500 g birth weight with FiO2 >0.70, exclusion for known sepsis, cardiac anomalies, malformations of lung or CNS
InterventionsIntravenous dexamethasone 0.5 mg/kg/day for 5 days
Controls were not given a placebo
OutcomesBlood gases, ventilator settings, mortality IVH, BPD (O2 28 days), NEC, late sepsis, PDA, ROP, air leak, duration in hospital
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation using sealed envelopes. Randomisation achieved by drawing lots.
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of intervention: no
Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome measurement: no
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Tapia 1998

MethodsMulticentre, double-blind, placebo-controlled, randomised trial
Participants113 (4 exclusions for congenital abnormality, early sepsis and failure to obtain follow-up data) infants with birth weight between 700 and 1600 g, clinical and radiological diagnosis of RDS, needing mechanical ventilation and < 36 hours of age
Exclusion criteria were life-threatening congenital malformation or chromosome abnormality, a strong suspicion of infection at birth (maternal chorioamnionitis) or early sepsis (positive blood culture in the first 36 hours of life)
InterventionsIntravenous dexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg for 3 days, 0.12 mg/kg/day for 3 days and 0.06 mg/kg/day for 3 days
The placebo group received an equivalent volume of saline solution
OutcomesThe primary outcomes were death before hospital discharge, BPD (oxygen need at 28 days and X-ray changes), death or BPD and oxygen need at 36 weeks
Other outcomes included time on ventilator, time in over 40% oxygen and time in oxygen
Major morbidity and complications included pneumothorax, PIE, PDA, pulmonary haemorrhage, pneumonia, sepsis, NEC, ROP, hypertension, hyperglycaemia and IVH (grades I-II and III-IV)
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation using ampoules of dexamethasone and saline prepared in the hospital pharmacy. Exact method of randomisation not described
Allocation concealment (selection bias)Low riskBlinding of randomisation: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: almost (109/113)

Vento 2004

MethodsRandomised controlled trial
Participants20 infants with birth weight < 1251 g and gestation < 33 weeks who were oxygen- and ventilator-dependent on 4th day of life and who were at high risk of CLD by authors' own scoring system
Exclusions: none stated
InterventionsIntravenous dexamethasone 0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days and 0.125 mg/kg/day for 1 day (total dose 2.375 mg/kg)
The control group received no corticosteroid treatment
OutcomesTracheal aspirates for cell counts, pulmonary mechanics, PDA, IVH (grades III and IV), extubation during study period
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation but method not stated
Allocation concealment (selection bias)Unclear riskAllocation concealment: uncertain
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of intervention: uncertain
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome measurement: uncertain
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Wang 1996

MethodsDouble-blind, randomised controlled trial
Participants63 infants with birth weight from 1000 g to 1999 g, AGA, clinical and radiographic RDS, IPPV (0 to 12 age after birth)
InterventionsDexamethasone 0.25 mg/kg 12-hourly from 1 to 7 days, 0.125 mg/kg 12-hourly from 8 to 14 days, 0.05 mg/kg, 12-hourly from 15 to 21 days. First dose administered < 12 hours
Controls received saline placebo
OutcomesOxygen requirements, PCO2, MAP, SP-A and SP-D in tracheal aspirate, failure to extubate by 3rd day, 7th day, 14th day and 28th day, mortality before discharge, sepsis, CLD at 28 days
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in a double-blind fashion, method not stated
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Watterberg 1999

MethodsTwo-centre, double-blind, randomised controlled trial
Participants40 infants weighing between 500 g and 999 g who were AGA and needed mechanical ventilation < 48 hours of age
Exclusion criteria included maternal diabetes, congenital sepsis and SGA
InterventionsHydrocortisone 1.0 mg/kg/day every 12 hours for 9 days, 0.5 mg/kg/day for 3 days
Control infants were given an equal volume of normal saline
OutcomesThe primary outcome was survival without supplemental oxygen at 36 weeks' post-conception
Secondary outcomes included in survivors: CLD at 36 weeks, duration of mechanical ventilation, > 40% oxygen, > 25% oxygen, hospital stay, and weight and head circumference at 36 weeks
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation at each centre by constant block design with 4 patients per block to minimise bias over time. Separate randomisation tables were used for infants exposed to antenatal corticosteroids.
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Watterberg 2004

MethodsMulti-centre, double-blind, randomised controlled trial
Participants360 infants of 500 g to 999 g birth weight, needing mechanical ventilation and aged 12 to 48 hours
Exclusions: major congenital anomaly, congenital sepsis, postnatal corticosteroids, triplet or higher order gestation
InterventionsHydrocortisone 1 mg/kg/day 12-hourly for 12 days, then 0.5 mg/kg/day for 3 days
Control group infants received an equal volume of normal saline placebo
OutcomesSurvival without BPD (oxygen at 36 weeks), physiological BPD, death before 36 weeks, death before discharge, BPD in survivors, durations of mechanical ventilation, oxygen and hospital stay, weight and OFC at 36 weeks, PDA, infection, NEC, GI perforation, major IVH (grades 3 or 4), cystic PVL, ROP and open-label corticosteroid therapy
Longer-term outcomes included neurosensory impairments (any of cerebral palsy, blindness, deafness, or developmental or motor delay assessed by the Bayley Scales (MDI or PDI, respectively))
NotesThe sample size estimate was 712 but the study was stopped early because on an increased incidence of apparently spontaneous GI perforation in the hydrocortisone group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation, stratified by centre and birth weight (500 g to 749 g versus 750 g to 999 g) using a permuted-blocks scheme with blocks of 6 in each stratum. Randomisation lists in each pharmacy in a sealed envelope
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: yes

Yeh 1990

MethodsDouble-blind, randomised controlled trial
Participants57 preterm infants weighing between 700 g and 1999 g, < 13 hours old with severe RDS both clinically and radiologically. They needed mechanical ventilation < 4 hours and were excluded if they had infection
InterventionsIntravenous dexamethasone 0.50 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days, 0.12 mg/kg/day for 3 days, 0.05 mg/kg/day for 3 days
Control infants were given saline placebo
OutcomesMAP, FiO2, pulmonary function tests, BP, glucose, mortality, CLD, duration O2, hospital, weight loss, sepsis, PDA, IVH (> grade I), ROP
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation in blocks of 10 using a pharmacy list. Exact method of randomisation not described
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurements: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: almost

Yeh 1997

  1. a

    ACTH: adrenocorticotrophic hormone

    AGA: appropriate for gestational age

    BP: blood pressure
    BPD: bronchopulmonary dysplasia
    CLD: chronic lung disease
    CNS: central nervous system
    CXR: chest X-ray
    FiO2: fraction of inspired oxygen
    GI: gastrointestinal

    HCO3: bicarbonate
    IVH: intraventricular haemorrhage

    IMV: intermittent mandatory ventilation

    IPPV: intermittnet positive airway pressure
    MAP: mean airway pressure
    MDI: Mental Developmental Index
    NEC: necrotising enterocolitis
    NO: nitric oxide

    NRN: Neonatal Research Network
    O2: oxygen

    OFC: occipito-frontal circumference
    PDA: patent ductus arteriosus
    PDI: Psychomotor Developmental Index

    PIE: pulmonary interstitial emphysema

    ppm: parts per million
    PVL: periventricular leukomalacia
    RDS: respiratory distress syndrome
    ROP: retinopathy of prematurity
    SaO2: oxygen saturation

    SGA: small for gestational age

    SP-A: surfactant protein-A

    SP-D: surfactant protein-D

MethodsMulti-centre, double-blind, randomised controlled trial
Participants262 infants of birth weight < 2000 g with RDS and requiring mechanical ventilation after birth
InterventionsDexamethasone 0.25 mg/kg/dose every 12 hours intravenously on days 1 to 7; 0.12 mg/kg/dose every 12 hours intravenously from 8 to 14 days; 0.05 mg/kg/dose every 12 hours intravenously from day 15 to 21; and 0.02 mg/kg/dose every 12 hours intravenously from days 22 to 28
Control infants were given saline placebo
OutcomesCLD either judged at 28 days or at 36 weeks
Extubation during the study, mortality, bacteraemia or clinical sepsis, and side effects of hyperglycaemia, hypertension, cardiac hypertrophy, hyperparathyroidism and growth failure
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom allocation by central pharmacy random number list; exact method of randomisation not described
Allocation concealment (selection bias)Low riskAllocation concealment: yes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of intervention: yes
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome measurement: yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up: almost for short-term; 81% for long-term

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    BPD: bronchopulmonary dysplasia
    RCT: randomised controlled trial
    VLBW: very low birth weight

Ariagno 1987Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Avery 1985Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Brozanski 1995Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
CDTG 1991Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Cummings 1989Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Dobryansky 201220 VLBW infants were randomised to both hydrocortisone and caffeine as active treatments, compared with "standard guidelines", which presumably meant no hydrocortisone or caffeine. The major outcomes reported included BPD, and BPD combined with death. As caffeine reduces BPD (Schmidt 2006), the independent effect of hydrocortisone cannot be determined
Doyle 2006Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Durand 1995Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Gaissmaier 1999Primary outcome was need for an epinephrine infusion 12 hours after treatment. No long-term outcomes reported
Gross 2005Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Harkavy 1989Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Kari 1993Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Kazzi 1990Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Kothadia 1999Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Kovacs 1998Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Noble-Jamieson 1989Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Ohlsson 1992Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Papile 1998Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Parikh 2013Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Romagnoli 1998Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Scott 1997Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Tsukahara 1999Not a RCT; 26 study infants and 12 historical controls
Vincer 1998Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Walther 2003Study of late postnatal corticosteroids included in the review 'Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants' (Doyle 2014)
Yaseen 1999Study of early dexamethasone but no outcomes relevant to this review were reported

Ancillary