Results of the search

Thirty‐two studies qualified for inclusion in this review (Figure 1). Most of these trials enrolled low birth weight infants with respiratory distress syndrome who were receiving mechanical ventilation.

Figure 1

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Study flow diagram: review update.

Included studies

See Characteristics of included studies.

The corticosteroid that was usually administered was dexamethasone, and the most common treatment regimen consisted of 0.50 mg/kg/d for three days followed by 0.25 mg/kg/d for three days, then 0.12 mg/kg/d for three days followed by 0.05 mg/kg/d for three days. However, trialists described considerable variation in treatment regimens, including short courses of one to two days and longer courses of up to four weeks. Eleven studies used hydrocortisone (Baden 1972; Batton 2012; Baud 2016; Biswas 2003; Bonsante 2007; Efird 2005; Hochwald 2014; Ng 2006; Peltoniemi 2005; Watterberg 1999; Watterberg 2004). In some cases, when low (almost physiological) doses were used, the indication was management of hypotension (see under Description of studies).

Anttila 2005 was a multi‐centre, double‐blind, placebo‐controlled trial of infants with birth weight of 500 grams to 999 grams, gestation less than 32 weeks, and respiratory failure by four hours of age. Investigators randomised 109 infants to receive 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. Researchers randomised infants to receive hydrocortisone 15 mg/kg on admission and 12 hours later intravenously, or placebo. Birth weights ranged from 800 grams to 2805 grams, and gestational ages from 26 to 36 weeks.

Batton 2012 was a pilot study of infants at 23 to 26 weeks' gestation with low blood pressure in the first 24 hours of life. Investigators compared dopamine and hydrocortisone versus placebo using 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 was stopped early because of slow recruitment after only 10 infants were enrolled.

Baud 2016 was a multi‐centre double‐blind randomised controlled trial of 523 infants at 24 to 27 weeks’ gestational age who were recruited from 21 French centres with NICU facilities in the first 24 hours after birth between 25 May 2008 and 31 January 2014. The treatment group received hydrocortisone hemisuccinate 1 mg/kg/d divided into two doses for seven days, then 0.5 mg/kg/d once per day for three days (total dose, 8.5 mg/kg). Control infants were given an equivalent volume of 5% glucose placebo. The trial was halted early because of lack of funding.

Biswas 2003 was a multi‐centre randomised trial of 253 infants of less than 30 weeks' gestational age. Investigators mechanically ventilated infants and entered them into the study within nine hours of birth. They gave all infants surfactant during the first 24 hours of life. Trialists randomised those in the treatment group (n = 125) to receive an infusion of hydrocortisone 1 mg/kg/d and tri‐iodothyronine (T3) 6 µg/kg/d for five days, then hydrocortisone 0.5 mg/kg/d and T3 3 µg/kg/d for two days. The placebo group (n = 128) received an equal volume of 5% dextrose.

Bonsante 2007 enrolled a total of 50 infants of birth weight less than 1250 grams or at 24 to 30 weeks' gestation who were less than 48 hours old and were ventilator‐dependent after surfactant treatment. Exclusion criteria were cardiopulmonary malformations, perinatal asphyxia, death within 12 hours after recruitment, or use of steroids for any reason within 12 days after birth. Researchers excluded no infants for these latter two reasons. They stratified infants by birth weight (not specified), gestational age (not specified), and antenatal steroid exposure, then randomly allocated infants to a 12‐day course of hydrocortisone (1.0 mg/kg for nine days, then 0.5 mg/kg/d for three days) (n = 25) or an equivalent volume of 0.9% saline placebo (n = 25). Study authors based the sample size calculation on the results of Watterberg 1999, resulting in an estimate of 138 infants to be recruited. The study was stopped early when 50 infants had been 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 birth weight less than 1000 grams and gestation of 24 to 28 weeks. Trialists randomised 34 infants to receive 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 reported a prospective, multi‐centre, randomised trial comparing a three‐day course of dexamethasone therapy, beginning at 24 to 48 hours of life, versus placebo. Researchers enrolled 241 preterm infants (dexamethasone n = 118, placebo n = 123) who weighed between 500 grams and 1500 grams, had received surfactant therapy, and were at significant risk for BPD or death, using a predictive model at 24 hours. Trial authors gave dexamethasone to infants in a three‐day tapering course at 12‐hour intervals. The first two doses were 0.4 mg/kg, the third and fourth doses were 0.2 mg/kg, and the fifth and sixth doses were 0.1 mg/kg and 0.05 mg/kg, respectively. They gave a similar volume of normal saline to placebo‐treated infants at similar time intervals.

Halac 1990 was a randomised trial undertaken to determine if prenatal corticosteroid therapy would reduce the incidence of necrotising enterocolitis. Investigators randomised women to prenatal betamethasone or placebo when they were admitted in preterm labour and were expected to deliver within 24 hours. They then randomised infants of mothers who had received placebo to postnatal dexamethasone or placebo; we included in this review only infants who were randomised to postnatal therapy. Study infants weighed less than 1501 grams at birth or were born at less than 34 weeks' gestation and had evidence of "birth asphyxia" (one‐minute Apgar score < 5, prolonged resuscitation, and metabolic acidosis (bicarbonate < 15 mmol/L within one hour of birth)). Trialists assigned study groups via a table of random numbers. The treatment group (n = 130) received 2 mg/kg/d of dexamethasone phosphate intravenously for seven days; the control group (n = 118) received an equal volume of 10% dextrose. The major endpoint of this study was necrotising enterocolitis.

Hochwald 2014 reported a single‐centre randomised trial conducted to determine the effects of hydrocortisone on vasopressor dosing in hypotensive infants at < 31 weeks' gestation or with birth weight < 1251 grams during the first 48 hours after birth. Researchers randomly allocated 22 infants to hydrocortisone 2 mg/kg for one dose and 1 mg/kg for three doses, six hours apart, then 0.5 mg/kg for four doses, six hours apart (total dose, 7 mg/kg), or an equal volume of saline placebo.

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

Lauterbach 2006 presented a single‐centre randomised trial to determine the effects of two active drugs on occurrence of BPD at 36 weeks. The two active drugs were nebulised pentoxifylline diluted in distilled water and intravenous dexamethasone. Infants weighing < 1251 grams at birth who were receiving supplemental oxygen on the fourth day after birth were eligible if they did not have a grade 3 or 4 intraventricular haemorrhage. Study authors randomly allocated a total of 150 infants to nebulised pentoxifylline every six hours for three days, intravenous dexamethasone 0.25 mg/kg/12‐hourly for three days, or nebulised saline placebo every six hours for three days. Study drugs could be repeated every seven days if the infant was still ventilator‐ or oxygen‐dependent and a diagnosis of BPD had not been established. Trialists did not report the number of repeat doses for any group. Researchers entered only data from the dexamethasone group and the control group into the meta‐analysis.

Lin 1999 was a randomised trial with a sequential design involving infants weighing 500 grams to 1999 grams. Investigators stratified infants by birth weight into three groups: 500 grams to 999 grams, 1000 grams to 1500 grams, and 1501 grams to 1999 grams. Within each group, equal numbers of dexamethasone‐treated or control cards were placed into 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 investigators administered dexamethasone or saline placebo blind. Entry criteria included the presence of severe radiographic respiratory distress syndrome, the need for assisted ventilation within six hours of birth, and receipt of 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, resulting in a total of four weeks of treatment. Trialists presented results for 20 treated and 20 control infants.

Mukhopadhyay 1998 reported a randomised trial that included untreated controls. Study authors did not describe the method of randomisation used. Treated infants received dexamethasone 0.5 mg/kg/dose 12‐hourly for three days, beginning within six hours of birth. Researchers included 19 infants at less than 34 weeks' gestation and weighing less than 2000 grams who could be provided with mechanical ventilation. 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. Investigators randomised 48 infants of birth weight less than 1500 grams to receive hydrocortisone 1 mg/kg eight‐hourly for five days, or an equivalent volume of isotonic saline.

Peltoniemi 2005 enrolled a total of 51 infants weighing less than 1251 grams at birth or born at less than 31 weeks' gestation, who were under 36 hours old and were ventilator‐dependent. Investigators conducted this trial at three collaborating centres in Finland. They stratified infants by centre and by birth weight (501 grams to 749 grams, 750 grams to 999 grams, and 1000 grams to 1250 grams) and randomly allocated them to a 10‐day tapering course of hydrocortisone (2 mg/kg/d for two days, 1.5 mg/kg/d for two days, 0.75 mg/kg/d for six days) (n = 25) or an equivalent volume of 0.9% saline placebo (n = 26). Researchers based the sample size calculation on detecting an increase in survival without BPD from 50% to 70% and required inclusion of 160 participants per study arm (alpha and beta error 0.05 and 0.20, respectively). This study was stopped early at 51 infants because two of the hydrocortisone‐treated infants had intestinal perforation and other RCTs of early hydrocortisone had reported the same complication. Trialists followed up with children at two years and at five to seven years of age. Long‐term outcomes included in the meta‐analysis pertain to the five‐ to seven‐year follow‐up study only.

Rastogi 1996 recruited 70 infants with birth weight of 700 grams to 1500 grams who had severe respiratory distress syndrome (assisted ventilation with at least 40% oxygen and/or 7 cmH₂O mean airway pressure, alveolar/arterial (a/A) partial pressure of oxygen (PO₂) ratio ≤ 0.24) and had been treated with surfactant before entry. Infants were less than 12 hours old, and trialists excluded them if they had major malformations, chromosome abnormalities, five‐minute Apgar scores < 3, or severe infection. The intervention group received dexamethasone intravenously every 12 hours according to the following schedule: 0.50 mg/kg/d on days one to three, 0.30 mg/kg/d on days four to six, 0.20 mg/kg/d on days seven to nine, and finally 0.10 mg/kg/d on days 10 to 12. The control group received a saline placebo intravenously.

Romagnoli 1999 was a randomised trial that used numbered, sealed envelopes involving 25 dexamethasone‐treated infants and 25 untreated controls. Entry criteria were birth weight < 1251 grams, gestational age < 33 weeks, ventilator‐ and oxygen‐dependent at 72 hours, and high risk of BPD based on a local scoring system that predicted 90% risk. Treated infants were given dexamethasone beginning on the fourth day at a dose of 0.5 mg/kg/d for three days, 0.25 mg/kg/d for three days, and 0.125 mg/kg/d for one day.

Sanders 1994 enrolled 40 infants at 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 receipt of an exchange transfusion. Trialists randomised infants to receive dexamethasone 0.50 mg/kg at between 12 and 18 hours of age and a second dose 12 hours later, or a saline placebo. They administered both treatments intravenously.

Shinwell 1996 reported a multi‐centre trial that randomised 248 infants of birth weight 500 grams to 2000 grams 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. Investigators excluded infants with lethal congenital malformations. 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 multi‐centre randomised double‐blind trial that included 384 infants of less than 30 weeks' gestation with respiratory distress syndrome. A total of 189 infants received dexamethasone 0.50 mg/kg at 12 to 18 hours of age and a second dose 12 hours later, and 195 infants received an equal volume of saline placebo.

Soll 1999 described a multi‐centre randomised double‐blind controlled trial that compared dexamethasone given at 12 hours of age versus selective late dexamethasone therapy in premature infants weighing 501 grams to 1000 grams (early dexamethasone n = 272, late selective therapy n = 270). Infants required assisted ventilation, had received surfactant therapy, were physiologically stable, had no obvious life‐threatening congenital anomaly, had blood cultures obtained, and had started antibiotic therapy. Trialists randomly assigned infants to early dexamethasone therapy or saline placebo. They administered intravenous dexamethasone for 12 days according to the following schedule: 0.5 mg/kg/d for three days, 0.25 mg/kg/d for three days, 0.1 mg/kg/d for three days, and 0.05 mg/kg/d 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 multi‐centre controlled trial conducted to compare a tapering course of stress‐dose corticosteroid started on the first day versus placebo. Infants with birth weight 501 grams to 1000 grams needing mechanical ventilation before 12 hours of age were eligible for the study. Infants with birth weight over 750 grams 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/d 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. Researchers randomised 111 infants to receive dexamethasone and 109 to receive placebo.

Subhedar 1997 reported a randomised trial that enrolled infants into one of four treatment groups using a factorial design. Investigators compared both inhaled nitric oxide (iNO) and early dexamethasone separately versus controls. They randomised 42 infants: 10 to receive iNO alone, 11 dexamethasone alone, 10 both treatments, and 11 neither treatment. Researchers compared 21 infants receiving dexamethasone versus 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 BPD based on a scoring system (Ryan 1996). Exclusion criteria were major congenital anomaly, structural cardiac defect, significant ductus shunting, culture‐positive sepsis, intraventricular haemorrhage with parenchymal involvement, pulmonary or gastrointestinal haemorrhage, disordered coagulation, and platelet count < 50,000. Infants received dexamethasone 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 did not receive a placebo.

Suske 1996 randomised 26 infants with gestational age of 24 to 34 weeks who had respiratory distress syndrome and had been treated with surfactant. Trialists excluded 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). They performed randomisation by drawing lots before the age of two hours. The intervention group received dexamethasone 0.50 mg/kg intravenously in two divided doses for five days, and controls received no placebo.

Tapia 1998 was a multi‐centre double‐blind placebo‐controlled trial of 109 preterm infants with respiratory distress syndrome and birth weight between 700 grams and 1600 grams who were treated with mechanical ventilation and surfactant. Researchers randomised 55 infants to receive dexamethasone 0.50 mg/kg/d for three days, followed by 0.25 mg/kg/d for three days, followed by 0.12 mg/kg/d for three days, then 0.06 mg/kg/d for three days. A total of 54 control infants received an equal volume of saline.

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

Wang 1996 reported a randomised trial of a 21‐day course of dexamethasone or saline placebo given in a double‐blind fashion. Study authors did not state the method of randomisation used. Entry criteria were birth weight 1000 grams to 1999 grams, 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, for a total course of 21 days. The first dose of dexamethasone was given during the first 12 hours of life. Participants included 34 infants in the dexamethasone group and 29 in the placebo control group.

Watterberg 1999 described a randomised double‐masked placebo‐controlled pilot study conducted to compare early treatment with low‐dose hydrocortisone (1.0 mg/kg/d for nine days, then 0.5 mg/kg/d for three days), begun before 48 hours of age, versus placebo. Researchers enrolled at two centres 40 infants weighing between 500 grams and 999 grams who were mechanically ventilated: 20 hydrocortisone‐treated infants and 20 placebo controls.

Watterberg 2004 was a multi‐centre masked randomised trial of hydrocortisone to prevent early adrenal insufficiency. Investigators randomised 360 infants with birth weight of 500 grams to 999 grams who were mechanically ventilated to receive hydrocortisone 1 mg/kg/d for 12 days, then 0.5 mg/kg/d for three days, or saline placebo. They enrolled infants at 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 weight was < 2000 grams and who had severe respiratory distress syndrome diagnosed on the basis of a chest radiograph and the need for mechanical ventilation within four hours after birth. Absence of infection was also required for inclusion. Trialists randomly assigned infants to receive dexamethasone 0.50 mg/kg/dose 12‐hourly from days one to three, then 0.25 mg/kg/dose 12‐hourly from days four to six, then 0.12 mg/kg/dose 12‐hourly from days seven to nine, and finally 0.05 mg/kg/dose 12‐hourly from days 10 to 12. Researchers administered all doses intravenously and gave a saline solution to infants in the placebo group.

Yeh 1997 reported a multi‐centre randomised double‐blind clinical trial of 262 preterm infants (< 2000 grams) who had respiratory distress syndrome and required mechanical ventilation from shortly after birth. The treated group received dexamethasone 0.25 mg/kg/dose 12‐hourly intravenously from day one to day seven; 0.12 mg/kg/dose 12‐hourly intravenously from day 8 to day 14; 0.05 mg/kg/dose 12‐hourly intravenously from day 15 to day 21; and 0.02 mg/kg/dose 12‐hourly intravenously from day 22 to day 28. Control infants received a saline placebo.

Excluded studies

We excluded 25 studies. See Characteristics of excluded studies.

We excluded studies for several reasons. In one study, the primary outcome was the need for an epinephrine infusion 12 hours after treatment (Gaissmaier 1999). Study authors reported no long‐term outcomes. Another study was not an RCT (Tsukahara 1999). This study included 26 study infants and 12 historical controls.

We included studies of late postnatal corticosteroids in the review titled "Late (> 7 days) systemic postnatal corticosteroids for bronchopulmonary dysplasia in preterm infants." We excluded these studies from this review and included the following studies: Ariagno 1987; Avery 1985; Brozanski 1995; CDTG 1991; Cummings 1989; Doyle 2006; Durand 1995; Harkavy 1989; Kari 1993; Kazzi 1990; Kothadia 1999; Kovacs 1998; Noble‐Jamieson 1989; Ohlsson 1992; Papile 1998; Parikh 2013; Romagnoli 1997; Scott 1997; Vento 2004; Vincer 1998; and Walther 2003.

Investigators in one trial randomised 120 very low birth weight infants to both hydrocortisone and caffeine as active treatments, compared with treatment described in "standard guidelines", which presumably meant no hydrocortisone or caffeine (Dobryansky 2012). Major outcomes reported were BPD and BPD combined with death. As caffeine alone reduces BPD, the independent effect of hydrocortisone cannot be determined (Schmidt 2006).

Although researchers in another trial randomly allocated 29 very low birth weight infants to dexamethasone or placebo before six hours of age, they reported none of the outcomes that are applicable to this review (Yaseen 1999). Outcomes reported comprised only changes in mean values over the first five days for oxygenation, blood pressure and serum creatinine, and urea and glucose ‐ not rates of BPD, hypertension, or hypoglycaemia, for example.

We found no studies that are currently awaiting further assessment.

Results of meta‐analysis

Meta‐analysis of these 32 studies of early postnatal corticosteroid treatment yielded the following results.

Mortality

No evidence suggests that early postnatal corticosteroid treatment reduced mortality at 28 days of life (typical risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.19, 19 studies, 2950 infants; Analysis 1.1), at 36 weeks' gestational age (OR 1.01, 95% CI 0.89 to 1.14, 20 studies, 3733 infants; Analysis 1.2), before discharge (typical RR 0.95, 95% CI 0.85 to 1.07, 30 studies, 4273 infants; Analysis 1.3), or at the latest age possible to determine the outcome (typical RR 0.95, 95% CI 0.85 to 1.06, 31 studies, 4373 infants; Analysis 1.4). We found weak evidence of publication bias for mortality at latest age, particularly for studies examining treatment with hydrocortisone (Figure 2).

Figure 2

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Funnel plot of comparison: 1 Mortality, outcome: 1.4 Mortality at latest reported age.

Bronchopulmonary dysplasia

Early corticosteroids reduced the incidence of BPD, defined as needing oxygen supplementation at 28 days of life (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, 2874 infants; Analysis 2.1) or at 36 weeks' postmenstrual age (typical RR 0.79, 95% CI 0.72 to 0.87; typical RD ‐0.07, 95% CI ‐0.09 to ‐0.04; 24 studies, 3929 infants; Analysis 2.2). We found weak evidence of publication bias for oxygen supplementation at 36 weeks (Figure 3) and a reduction in BPD at 36 weeks' postmenstrual age among survivors (typical RR 0.81, 95% CI 0.74 to 0.88; typical RD ‐0.08, 95% CI ‐0.11 to ‐0.05; 21 studies, 2970 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, 2483 infants; Analysis 2.4) and among 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, 895 infants; Analysis 2.5). Results of analysis showed no significant reduction in the proportion of survivors discharged home on oxygen, although fewer studies were able to determine this outcome (typical RR 0.72, 95% CI 0.51 to 1.03, six studies, 691 infants; Analysis 2.6).

Figure 3

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Funnel plot of comparison: 2 Bronchopulmonary dysplasia (BPD), outcome: 2.2 BPD (36 weeks' postmenstrual age).

Death or bronchopulmonary dysplasia

Early corticosteroids reduced the incidence of death or BPD, defined as needing oxygen supplementation at 28 days of life (typical RR 0.92, 95% CI 0.88 to 0.96; typical RD ‐0.06, 95% CI ‐0.09 to ‐0.03; 15 studies, 2546 infants; Analysis 3.1) or at 36 weeks' postmenstrual age (typical RR 0.88, 95% CI 0.83 to 0.93; typical RD ‐0.06, 95% CI ‐0.09 to ‐0.03; 25 studies, 3960 infants; Analysis 3.2). We found weak evidence of publication bias for mortality or BPD at 36 weeks (Figure 4).

Figure 4

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Funnel plot of comparison: 3 Death or bronchopulmonary dysplasia (BPD), outcome: 3.2 Death or BPD at 36 weeks' postmenstrual age.

Follow‐up data

Follow‐up studies are few compared with the total number of studies: Of 32 studies, 13 provided follow‐up data.

Cerebral palsy

Corticosteroids increased cerebral palsy (typical RR 1.42, 95% CI 1.06 to 1.91; typical RD 0.02, 95% CI 0.00 to 0.05; 13 studies, 1973 infants; Analysis 6.11), but results showed little difference in the combined outcome, death or cerebral palsy (typical RR 1.03, 95% CI 0.91 to 1.16; 13 studies, 1973 infants; Analysis 6.13). We noted moderate heterogeneity (I² = 52%) for the combined outcome, death or cerebral palsy, among the dexamethasone studies and little evidence of publication bias for the outcome of cerebral palsy (Figure 5).

Figure 5

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

Subgroup analysis by type of corticosteroid used

Results of individual trials

Anttila 2005: The primary outcome was survival without BPD, intraventricular haemorrhage (grade 3 or 4), or periventricular leukomalacia, and although this tended to be greater in the dexamethasone group, differences compared with controls were not statistically significant. The risk ratio for death or BPD at 36 weeks' postmenstrual age was 0.78 (95% CI 0.54 to 1.13) overall, and 0.61 (95% CI 0.33 to 1.11) in the subgroup with birth weight 750 grams to 999 grams. We noted no detectable trends in mortality, severe intraventricular haemorrhage, or periventricular leukomalacia. 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% vs 39%; P = 0.25).

Baden 1972: Results of this study showed no significant effects on blood gases, pH, oxygen requirement, need for assisted ventilation, or survival. Data indicate no significant differences in rates of cerebral palsy or deafness among survivors, in mean scores on Griffiths Scales, or in the combined rate of death or cerebral palsy (Fitzhardinge 1974).

Batton 2012: Data show minimal effects on rates of death during primary hospitalisation, BPD (undefined), intraventricular haemorrhage, periventricular leukomalacia, or necrotising enterocolitis.

Baud 2016: Death or BPD at 36 weeks' gestational age occurred in 40% (102/255) of the hydrocortisone group compared with 49% (130/266) of the placebo group (OR 0.82, 95% CI 0.67 to 0.99). Rates of any neurodevelopmental impairment (NDI) among assessed survivors were similar in the two groups (hydrocortisone 27% (53/194); placebo 30% (55/185)), as were rates of moderate to severe impairment (hydrocortisone 7% (14/194); placebo 11% (21/185)). The combined outcome of death or moderate severe impairment in all randomised infants was lower in the hydrocortisone group than in the control group (hydrocortisone 24% (62/255); placebo 33% (88/266); OR 0.73, 95% CI 0.56 to 0.97).

Biswas 2003: Results showed no significant effects of 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 vs 60/128; RR 0.70, 95% CI 0.51 to 0.96), but data show no other significant differences in secondary outcomes.

Bonsante 2007: Oxygen‐free survival was significantly greater in the hydrocortisone group than in the control group (64% vs 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 with 10 in the control group (16% vs 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 was used less in the hydrocortisone‐treated group, significantly so on the second day of life. Results showed no significant differences in cortisol levels between groups at any time point, and no significant differences in mortality, duration of ventilation, BPD (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. Data show no differences in the 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 than placebo‐treated controls to survive without BPD (83/118 vs 71/123; P = 0.03). They also were less likely to develop BPD if they survived to 28 days of life (16/99 vs 27/98; P = 0.042). Mortality rates were not significantly different. Subsequent dexamethasone therapy was used less often among early dexamethasone‐treated infants who survived (68/99 vs 81/98; P = 0.01). Intestinal perforation was more common, but not significantly so, among dexamethasone‐treated infants (12/118 vs 7/122; P = 0.20); during the first week of life, the difference was significant (9/118 vs 1/122; P = 0.009). Infants in the dexamethasone group also spent less time receiving oxygen (median days 43 vs 50; P = 0.04). Any grade of intraventricular haemorrhage (36% vs 52%; P = 0.02) and of patent ductus arteriosus ligation (14% vs 28%; P = 0.01) was also less common in the dexamethasone group. Hypertension (P<0.001) and treatment with insulin (P=0.007) ocurred more often for dexamethasone‐treated infants than controls.

Halac 1990: Investigators reported 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.

Hochwald 2014: Data show no statistically significant effects of hydrocortisone on mortality to hospital discharge, BPD, death or BPD, necrotising enterocolitis, or sepsis.

Kopelman 1999: Intermittent mandatory ventilation (IMV) rate and ventilation index improved more rapidly in the dexamethasone‐treated group. Mean blood pressure was higher in the dexamethasone group after the first day. Patent ductus arteriosus was less common in dexamethasone‐treated infants (13/37 vs 19/33; P = 0.08), and fewer received indomethacin (8/37 vs 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 vs 2/16, P < 0.03). Results show no difference in intraventricular haemorrhage and no occurrence of adverse effects.

Lin 1999: For the endpoint of BPD at 28 days of life, statistical significance favouring dexamethasone was reached when analysis of 12 consecutive pairs in which one infant had BPD 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 BPD at 28 days of life in the dexamethasone group (n = 4) than in the control group (n = 11; P < 0.05). Duration of oxygen therapy was also shorter in the dexamethasone group, at 7 ± 6 days versus 13 ± 12 days (P < 0.05). Among survivors, 12 of 15 in the dexamethasone group were extubated compared with 9 of 16 in the control group at the end of the study. Infants in the treated group had transient hyperglycaemia and hypertension, but data showed no differences between groups for mortality, incidence of sepsis, or intraventricular haemorrhage.

Mukhopadhyay 1998: Oxygen requirement was lower in the treated group than in the control group on days three, four, and five, although differences were not statistically significant. Mean duration of ventilation was shorter in the dexamethasone group (87 ± 42 hours) than in the control group (120 ± 46 hours; P value not given). Study authors reported one case of culture‐positive sepsis in the dexamethasone group, and two in the control group. None of the infants developed BPD (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). Cumulative doses of dopamine and dobutamine after randomisation were significantly lower in the hydrocortisone group. Duration of ventilation, duration of oxygen, and incidence of BPD (oxygen at 36 weeks' postmenstrual age) were not significantly different between groups. Results showed 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 show a significant increase in survival without BPD (64% vs 54% placebo) or a significant decrease in BPD among 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 and three in the placebo group died. During the first week of life, infants in the hydrocortisone group needed lower mean airway pressures than infants in the placebo group (P = 0.03). Patent ductus arteriosus (36% vs 73%; P = 0.01) and duration of oxygen therapy (34 vs 62 days; P = 0.02) occurred less often in the hydrocortisone group, but intraventricular haemorrhage, cystic periventricular leukomalacia, retinopathy of prematurity, sepsis, necrotising enterocolitis, gastrointestinal haemorrhage, open corticosteroid treatment, and duration of intubation and of hospitalisation were not different between groups. Risk of gastrointestinal perforation was increased in the hydrocortisone group (16% vs 0%; P = 0.05). Data showed no differences in the rate of hyperglycaemia requiring insulin nor in blood pressures (diastolic and systolic). At six‐year follow‐up, data showed no substantial differences between groups in rates of cerebral palsy, blindness, deafness, or intellectual impairment (IQ < 69; steroid group 8% (2/25) vs placebo group 4% (1/26)).

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

Romagnoli 1999: The incidence of BPD at 28 days of life and at 36 weeks' postmenstrual age was significantly lower in the dexamethasone group than in 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. Data show no significant differences in 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 4 (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 7 (P = 0.02). The dexamethasone group required a shorter time in hospital (median 95 days vs 106 days; P = 0.01). Survival in the dexamethasone group was 89% versus 67% in the placebo group (P = 0.08). Survival without BPD was 68% in the dexamethasone group versus 43% in the placebo group (P = 0.14). Mean blood pressure was elevated on study days 4 to 7. Data show no differences in rates of hyperglycaemia, incidence or severity of intraventricular haemorrhage, or days to regain birth weight, and no significant differences in rates of cerebral palsy, blindness, deafness, or intellectual impairment, nor in the combined rate of death or cerebral palsy (Sinkin 2002 (personal communication follow‐up to Sanders 1994)).

Shinwell 1996: Results showed no differences in any outcome variable, except for a reduction in the need for mechanical ventilation at three days in dexamethasone‐treated infants (54/122, 44% vs 71/106, 67%; P = 0.001). Gastrointestinal haemorrhage, hypertension, and hyperglycaemia were more common among 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 rates of blindness, deafness, or major neurosensory disability, nor in the combined rate of death or major neurosensory disability. However, data showed significant increases in rates of abnormal neurological examination findings, developmental delay, and cerebral palsy, and a significant increase in the combined rate of death or cerebral palsy (Shinwell 2002).

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

Soll 1999: Results showed no differences in the primary outcome of BPD or death at 36 weeks' postmenstrual age (early therapy 135/272 vs 143/267; 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 vs 164/267; RR 0.69, 95% CI 0.58 to 0.81). They also had a lower risk of patent ductus arteriosus (92/272 vs 117/269; RR 0.78, 95% 0.63 to 0.96) and were less likely to receive indomethacin therapy (132/273 vs 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 vs 151/263; RR 1.29, 95% CI 1.13 to 1.46) and to require insulin therapy (168/271 vs 102/267; RR 1.62, 95% CI 1.36 to 1.94). Data show trends towards increased gastrointestinal haemorrhage (33/271 vs 21/267; RR 2.55, 95% CI 0.92 to 2.61) and gastrointestinal perforation (31/271 vs 20/267; RR 1.53, 95% CI 0.89 to 2.61). Infants who had cranial ultrasound scans showed a trend towards an increase in periventricular leukomalacia in the early corticosteroid group (18/252 vs 8/250; RR 2.23, 95% CI 0.99 to 5.04). Infants who received early corticosteroid therapy received fewer days of supplemental oxygen but experienced poorer weight gain.

Stark 2001: Corticosteroid‐treated infants had a lower incidence of the primary outcome, death or BPD at 36 weeks' postmenstrual age (63% vs 69%; P < 0.05). Fewer infants in the corticosteroid group had pulmonary interstitial emphysema (9% vs 23%; P < 0.05), required oxygen at 28 days of life (78% vs 94%; P < 0.05), or received subsequent corticosteroid treatment (34% vs 51%; P < 0.05). 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% vs 4% and 23% vs 12%, respectively; both with P < 0.05). During the first 14 days, 14/111 (13%) infants in the corticosteroid group and 3/109 (3%) 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), as was an interaction between indomethacin and corticosteroid therapy (P = 0.04). Data showed no significant differences in rates of cerebral palsy, developmental delay, or major neurosensory disability, in the combined rate of death or cerebral palsy, or in the combined rate of death or major neurosensory disability (Stark 2001).

Subhedar 1997: Results showed no differences in the combined incidence of BPD and/or death before discharge from hospital between infants treated with dexamethasone and control infants (RR 0.95, 95% CI 0.79 to ‐1.18) or between those treated with inhaled nitric oxide and controls (RR 1.05, 95% CI 0.84 to 1.25). Data showed no significant differences in 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 (personal communication follow‐up to Subhedar 1997)).

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

Tapia 1998: Results showed no significant differences in mortality and/or BPD between groups. The number of infants requiring oxygen at 36 weeks' postmenstrual age was significantly reduced in the dexamethasone group (8% vs 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. Data showed no differences between groups in the number of days of mechanical ventilation and oxygen treatment, and no differences in the incidence 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. Data showed 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 1 of treatment. They also had significantly higher dynamic compliance values compared with control infants (P < 0.01) as early as day 2 of treatment. Inspired oxygen concentrations were significantly lower on day 2 (0.24 vs 0.31; P < 0.05), and mean airway pressure on day 5 (4.8 vs 7.2 cmH₂O; 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. Surfactant protein (SP)‐A concentrations in tracheal aspirates were increased at days 7 and 14, and SP‐D concentrations were increased from days 3 to 14 in the dexamethasone‐treated group, compared with the control group.

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

Watterberg 2004: Results showed no differences in primary outcomes between groups (hydrocortisone vs placebo): survival without BPD (35% vs 34%), death before 36 weeks' postmenstrual age (15% vs 16%), and death before discharge (16% vs 17%). In a subgroup of infants exposed to chorioamnionitis, the hydrocortisone‐treated group had significantly improved survival without BPD (38% vs 24%; P = 0.005) and lower mortality at 36 weeks' postmenstrual age (10% vs 18%; P = 0.02) and before discharge (12% vs 21%; P = 0.02). During treatment, rates of hyponatraemia, hypernatraemia, hyperkalaemia, hyperglycaemia, hypertension, and gastrointestinal bleeding were similar between groups. Seventy‐four infants (41%) in the hydrocortisone group and 62 (34%) in the placebo group were treated with insulin (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% vs 28%; P = 0.02) and were more likely to have a spontaneous gastrointestinal perforation (9% vs 2%; P = 0.01). Follow‐up data reveal no significant differences in rates of cerebral palsy, major neurological disability, developmental delay, or rehospitalisation, or in 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 vs 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 injury characterised by the following: surviving infants with BPD; infants who died of intractable respiratory failure and had evidence of BPD at autopsy; and infants who died of intractable respiratory failure with clinical evidence of BPD. Dexamethasone therapy was associated with a temporary increase in blood pressure and plasma glucose concentration and delayed somatic growth.

Yeh 1997: Infants in the dexamethasone group had a significantly lower incidence of BPD than those in the placebo group, judged at 28 postnatal days (21/132 vs 40/130, P < 0.05) or at 36 weeks' postmenstrual age (20/132 vs 37/130, P < 0.05). More infants in the dexamethasone group were extubated during the study. Data showed no difference in mortality between groups (39/130 vs 44/132); however, a higher proportion of infants in the dexamethasone group died during the late study period, probably as the result of infection. Results showed no differences between groups in duration of oxygen therapy and hospitalisation. Significantly more infants in the dexamethasone group had bacteraemia or clinical sepsis (44/132 vs 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, data revealed no significant differences in rates of blindness, developmental delay, or major neurosensory disability, or in the combined rate of death or cerebral palsy, or the combined rate of death or major neurosensory disability. However, we noted significant increases in 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, overall motor performance on the Movement ABC was worse than in controls. IQ and other cognitive performance were significantly worse in the dexamethasone group. Overall, survivors in the dexamethasone group had greater major neurological disability.