Postnatal corticosteroids to treat or prevent 
chronic lung disease in preterm infants

A joint statement with the American Academy of Pediatrics (AAP) and 
the Canadian Paediatric Society (CPS)

Paediatr Child Health 2002;7(1):20-8
Reference No. FN02-01

Revision in progress February 2009

Index of position statements from the Fetus and Newborn Committee

The Canadian Paediatric Society gives permission to print single copies of this document from our website. Visit the index of position statements to see which are available as pdf files. For permission to reprint or reproduce multiple copies, please submit a detailed request to info@cps.ca.

Contents

This statement is intended for health care professionals caring for neonates and young infants. The objectives of this statement are to review the short and long term effects of systemic and inhaled postnatal corticosteroids for the prevention or treatment of evolving or established chronic lung disease, and to make recommendations for the use of corticosteroids in infants with very low birth weight. The routine use of systemic dexa-methasone for the prevention or treatment of chronic lung disease in infants with very low birth weight is not recommended.

Key Words: Chronic lung disease; Corticosteroids; Infant; Newborn; Preterm; Very low birth weight

Background

Chronic lung disease (CLD), also known as bronchopulmonary dysplasia, is an important cause of mortality and morbidity in preterm infants (1,2). The incidence of CLD among surviving infants with very low birth weight ([VLBW]; birth weight less than 1500 g) in two large databases was 26% in Canada (1996/97) (1) and 23% in the United States (1995/96) (2). CLD is usually defined as oxygen dependency at 36 weeks’ postmenstrual age (PMA) or 28 days’ postnatal age (PNA), in conjunction with persistent clinical respiratory symptoms and compatible abnormalities on chest radiographs (3-6).

Because inflammation plays an important role in the pathogenesis of CLD, corticosteroids, in particular dexamethasone, have been widely used to prevent or treat CLD (1,2,7). Postnatal corticosteroids were given to 25% of infants with VLBW in Canada (1996/97) (1) and to 19% in the United States (1995/96) (2). Corticosteroid use is higher in infants with a birth weight less than 1000 g (1,2). Numerous studies suggest that the use of systemic corticosteroids decreases the duration of ventilator dependence (8-16). However, early beneficial effects on the pulmonary system may be outweighed by an increased risk of serious short and long term adverse effects (8-24).

Objectives

The objectives of this statement are to review the short and long term effects of systemic and inhaled postnatal corticosteroids for the prevention or treatment of evolving or established CLD, and to make recommendations for the use of corticosteroids in infants with VLBW. The focus of this statement is limited to the use of corticosteroids in neonates with VLBW for the prevention or treatment of CLD.

Literature review
An attempt was made to identify all published systematic reviews and meta-analyses on the use of corticosteroids (systemic or inhaled) for the prevention or treatment of CLD in preterm infants, using the MEDLINE, EMBASE, CINAHL and Cochrane Library electronic databases, and personal files from 1983 to April 2001. Data were also included from two trials published after the identified systematic reviews (19,25). Twelve systematic reviews published between 1992 and 2001 were identified (8-16,26-28). Nine addressed the use of systemic steroids (8-11,13-16,28), two described the use of inhaled steroids (26,27) and one addressed both (12). Numerous outcomes were evaluated. The results are presented in five sections: the first three sections report on the effects of systemic corticosteroids on the basis of age at which the infants were treated; the fourth section reports on the effects of inhaled steroids; and the fifth section describes the effects of systemic corticosteroids on neurodevelopmental outcomes.

Systemic early postnatal corticosteroid therapy (less than 96 h of age)
The most complete systematic reviews were published in 2001 (13,16). In addition, the meta-analysis for systemic early postnatal corticosteroid therapy by Shah and Ohlsson (16) was updated by incorporating data from two subsequently published studies (19,25). Infants studied were preterm, demonstrated respiratory distress syndrome on chest radiographs and required mechanical ventilation with oxygen at the time of enrollment (8-11,13,16,19,25). Systemic corticosteroids were given intravenously within 96 h of birth; dexamethasone was used in all but two studies (29,30). The most commonly used dosages were 0.5 mg/kg body weight per day for three days, followed by a tapering course of 0.25, 0.125 and 0.05 mg/kg/day each for three days (13,16). One study (19) used a considerably lower dosage (0.15 mg/kg/day for three days, 0.10 mg/kg/day for three days, 0.05 mg/kg/day for two days and 0.02 mg/kg/day for two days). The combined outcome of death or CLD at 28 days’ PNA or at 36 weeks’ PMA (13,16) was significantly decreased by early corticosteroid treatment. There was no effect on mortality at 28 days’ PNA, at 36 weeks’ PMA, or at discharge (13,16). Corticosteroid treatment decreased CLD incidence at 28 days’ PNA and at 36 weeks’ PMA (8-11,13,16). On the basis of an analysis including data from the most recently published trials (19,25), 10 infants would need to be treated with corticosteroids to prevent one from developing CLD at 28 days’ PNA or at 36 weeks’ PMA.

Weaning from mechanical ventilation was more successful in infants treated with dexamethasone (13,16). The use of additional systemic dexamethasone by clinicians outside of the study protocols (open-label use) was decreased (13,16).

The incidences of hypertension (16), hyperglycemia (13), insulin therapy for hyperglycemia (16), gastrointestinal bleeding (16) or perforation (13), and hypertrophic obstructive cardiomyopathy (13) were increased by early corticosteroid treatment. The rates of pulmonary air leaks (13) and patent ductus arteriosus were decreased (13,16). There was no difference in the incidence of infection (13,16), necrotizing enterocolitis (NEC) (16), intraventricular hemorrhage (13,16) or severe retinopathy of prematurity (13,16). Weight gain was decreased during dexamethasone therapy (13,16). A borderline increased risk of periventricular leukomalacia (PVL) in the infants who received dexamethasone was noted in one (13) but not in the other recent systemic review (16). In an update of the review by Shah and Ohlsson (16), including the two recently published studies (n=1096) (19,25), the relative risk of PVL was 1.41 (95% CI 0.93 to 2.13). Long term outcomes are shown in Table 1.

Table 1: Neurodevelopmental outcome data for early (less than 96 h of age) postnatal corticosteroid use for prevention of chronic lung disease in infants

Author

Drug, dosage and duration of therapy

 Number of patients enrolled  Outcome data
Fitzhardinge et al, 1974 (39); original study by Baden et al, 1972 (29) Hydrocortisone (12.5 mg/kg of body weight) was administered 12 h apart in the first 24 h, or two placebo injections of a lactose solution were administered  44 28 of 44 survived the neonatal period. 24 of 28 were evaluated for a minimum of one year. Follow-up data were not available on two subjects. One control infant died at 10 months with microcephaly and extensive brain damage. One study infant had limited data that was obtained by letter
Three of 13 infants in the steroid group had evidence of neuromotor dysfunction (one had moderate degree of spastic quadriplegia, one had hypotonia and slow motor development, and one had increased extensor tone and slow motor development)
Two of 13 infants in the placebo group had evidence of neuromotor dysfunction (one had mild spastic diplegia, one had microcephaly and spastic diplegia [RR 1.50, 95% CI 0.30–7.55])
Four of 13 infants in the steroid group had EEG abnormalities (mild paroxysmal changes with no epileptiform patterns). No EEG abnormalities were noted in the placebo group 
Mean developmental quotient (using Griffith Developmental Scale): no statistically significant differences were noted between groups (steroid group, 95.4 compared with placebo group, 97.9)
Locomotor scale: there was a significant difference in the results for gross motor development (steroid group, 93 compared with placebo group, 104 [P<0.05])
Stark et al, 2002 (41); original study by Stark et al, 2001 (19) Dexamethasone was administered within 24 h after birth (0.15 mg/kg/day for three days, then tapered over seven days) or placebo was administered 220 Of the 166 survivors, 123 (74%) were evaluated at 18 to 22 months of age using the BSID II, a standardized neurological examination and hearing and vision assessment. Neurodevelopmental impairment was defined as a Bayley score less than 70, abnormal neurological examination, or deafness or blindness
34 of 67 infants in the steroid group had MDI of less than 70, compared with 24 of 56 in the placebo group (RR 1.18, 95% CI 0.81–1.74)
20 of 67 in the steroid group had a PDI of less than 70 compared with 20 of 56 in the placebo group (RR 0.84, 95% CI 0.50–1.39)
Abnormal neurological examination was noted in 17 of 67 infants in the steroid group compared with 14 of 56 infants in the placebo group (RR 1.02, 95% CI 0.55–1.87)
Shinwell et al, 2000 (38) Dexamethasone was administered (0.5 mg/kg/day) in two divided doses for three days (administered before 12 h of age)or saline placebo was administered 248 Of the 195 infants who survived to discharge, five died in the postneonatal period. Follow-up data were obtained on 159 of 190 (84%) survivors at a mean (± SD) age of 53±18 months. 31 were  lost to follow-up (10 in the placebo group and 21 in the steroid group)
As detailed, Bayley, Griffith or other developmental assessments were not available in all cases, developmental status was defined as normal, mildly abnormal or severely abnormal 
Severe abnormality was defined as any of the following: motor disability in children who were not independently ambulatory, global retardation, deafness requiring hearing aids and blindness
39 of 80 infants in the steroid group developed cerebral palsy compared with 12 of 79 infants in the placebo group (RR 3.21, 95% CI 1.82–5.66). Spastic diplegia was the most common form of cerebral palsy noted
44 of 80 infants in the steroid group were noted to have developmental delay compared with 23 of 79 in the placebo group (RR 1.89; 95% CI 1.27–2.81)
No differences were found in visual or hearing problems between groups
Subhedar et al, 2000 (40) Dexamethasone was administered at 96 h of age (1 mg/kg/day for three days) For three infants, the starting dosage was decreased to 0.5 mg/kg/day because of an observed increase in gastrointestinal adverse effects. No placebo was administered 42 Of the 42 infants in the trial, 20 died (17 before discharge and three in the postneonatal period)
Detailed assessment was performed in 21 of the 22 survivors at 30 months of age (one was lost to follow-up) using the BSID II
Cerebral palsy was defined as the presence of any abnormal motor 0.5 mg/kg/day for signs. Developmental delay was defined as an MDI or PDI less than 70. Severe neurodisability was defined as cerebral palsy with or  without significant developmental delay and with or without significant visual or hearing impairment
Cerebral palsy was noted in 0 of 10 infants in the steroid group compared with two of 11 in the control group (RR 0.22, 95% CI 0.01–4.06). Significant developmental delay was noted in 0 of 10  in the steroid group compared with four of 11 in the control  group (RR 0.12, 95% CI 0.01–2.00). Severe neurodisability was  noted in one of 10 infants in the treated group compared with four of 11 in the control group (RR 0.28, 95% CI 0.04–2.07).
Yeh et al, 1998 (31)  Dexamethasone administration commenced at less than 12 h of age (0.5 mg/kg/day for seven days, then 0.24 mg/kg/day for seven days, then 0.1 mg/kg/day for seven days, and then 0.04 mg/kg/day for seven days), or saline placebo was administered  270 Of the 270 infants included in the initial study, eight were excluded from data analysis (six died from culture-proven sepsis within 12 h of birth, two had severe asphyxia), and 83 infants died in the neonatal period. Of the 179 survivors, nine infants in the control group and 13  in the steroid group were lost to follow-up
Follow-up data at two years of age is available for 133 of 157 patients (in nine infants, follow-up study could not be completed because of the  lack of parental consent or cooperation from the child). In addition, 15  infants died in the postneonatal period. Neuromotor dysfunction was classified as mild, moderate or severe on the basis of mobility of
the child. EEG was also performed, including visual and auditory stimulation. Psychometric evaluations were performed using BSID II
25 of 63 infants in the steroid group had neuromotor dysfunction compared with 12 of 70 in the control group (RR 2.32, 95% CI 1.27–4.21)
Significant handicap, defined as severe neurological defect and/or intellectual defects (MDI and/or PDI less than 70), was seen in 26 of 63 in the steroid group compared with 22 of 70 in the control group (RR 1.31, 95% CI 0.83-2.07) 
RR and 95% CI were calculated using SAS Version 8 for Windows (SAS Institute Inc, USA). When there was no outcome event in one group, 0.5 was added to each cell to calculate the RR. BSID II Bayley Scales of Infant Development II; EEG Electroencephalography; MDI Mental developmental index; PDI Psychomotor developmental index

Systemic moderately early postnatal corticosteroid therapy (seven to 14 days’ PNA)
The most current reviews were published in 2001 (14,16). Infants in the studies included in the meta-analyses were preterm and dependent on mechanical ventilation with oxygen at enrollment (9-11,14,16). All trials used dexamethasone. The drug was administered intravenously for two to 42 days, starting between seven and 14 days of age or given as a pulse dose for three days at 10-day intervals until the infant no longer required supplemental oxygen or ventilation, or had reached 36 weeks’ PMA. The initial dosage was 0.5 mg/kg/day, which was maintained for the duration of the study period, decreased over seven to 42 days or followed by inhaled budesonide (9,14,16).

The combined outcome of death or CLD was decreased at 28 days’ PNA and at 36 weeks’ PMA (14,16). Mortality was not decreased in the treatment group at the time of discharge (14,16). In one review, mortality was not decreased at 28 days’ PNA or 36 weeks’ PMA (16); the other showed decreased mortality at 28 days’ PNA (14). The incidence of CLD at 28 days’ PNA and 36 weeks’ PMA (14,16) was decreased. The number of infants who needed to be treated with dexamethasone was seven and four to prevent CLD at 28 days’ PNA and 36 weeks’ PMA, respectively (16). Infants were more likely to be extubated by seven and 28 days after initiation of treatment with dexamethasone (14,16). However, the duration of hospitalization or need for supplemental oxygen was not decreased (16). The subsequent use of additional systemic steroids in the infants who had received dexamethasone during the study period was decreased (14,16).

The incidences of pneumothorax, severe retinopathy of prematurity, intraventricular hemorrhage and NEC were not increased (14,16). Infants in the dexamethasone group had an increased risk of developing hypertension (14,16). The two reviews differed in reporting statistically significant differences between treatment and control groups for hyperglycemia, gastrointestinal bleeding, hypertrophic obstructive cardiomyopathy and infection (14,16). Long term outcomes are shown in Table 2.

Table 2: Neurodevelopmental outcome data for moderately early (seven to 14 days) postnatal corticosteroid use for the prevention of chronic lung disease

Author

Drug, dosage, and duration of therapy

Number of patients enrolled

Outcome data

Cummings et al, 1989 (32)

 

 

 

 

 

 

 

 

 

 

 

 

Dexamethasone was administered to infants at 14 days of age (0.5 mg/kg per day for 3 days, then 0.3 mg/kg per day for three days, and then decreased by 10% every three days until 0.1 mg/kg per day was administered for three days, and then 0.1 mg/kg per day on alternate days for one week [total duration of therapy, 42 days]; or in a dose of 0.5 mg/kg per day for 3 days and then decreased by 50% every 3 days to 0.06 mg/kg per day for 3 days and then 0.06 mg/kg per day on alternate days for 1 week [total duration of therapy, 18 days]), or placebo was administered.

36

 

 

 

 

 

 

 

 

 

 

 

 

 

Neurodevelopmental outcomes were assessed at 6 and 15 months of age. Developmental evaluations were made using BSID II.

Good neurologic outcome was defined as normal neurologic findings and Bayley mental and psychomotor indices ≥ 84.

23 of 36 (64%) survived to discharge.

Good outcome was noted in 7 of 9 infants in the 42-day course. Two of nine infants in the 18-day course, and 2 of 5 in the placebo group (P < 0.05). The results for bad outcome in the 2 groups that were given steroids were combined and compared with the placebo group (RR, 0.83; 95% CI, 0.36-1.95).

Hofkosh et al 1995 (42); original study by Brozanski et al, 1995 (43)

Infants with VLBW who were ventilator dependent at 7 days PNA were randomly assigned to receive pulse doses of dexamethasone (0.5 mg/kg per day, divided twice daily [n = 39]) or saline placebo (n = 39), for 3 days at 10-day intervals until they no longer required supplemental oxygen or ventilation or reached 36 weeks PMA.

78

65 infants survived to term. 44 were available for follow-up at 12 months adjusted age (25 in the dexamethasone group and 19 in the control group).

Outcome measures included MDI and PDI indices of the BSID II. Mean (± SD) MDI was 89.5 ± 23.7 in the dexamethasone group and 80.8 ± 26.0 in the control group (P = .18). PDI scores were 87.0 ± 26.1 in the dexamethasone group and 75.2 ± 24.8 in the control group (P = .14). Measurements of length, weight, and head circumference did not differ between groups.

O’Shea et al, 1999 (37); original study by Kothadia et al, 1999 (36)

Dexamethasone administration commenced at between 15 and 25 days of age (0.5 mg/kg per day for 3 days, then 0.3 mg/kg per day for 3 days, and then decreased by 10% every 3 days until 0.1 mg/kg per day was administered for 3 days, and then 0.1 mg/kg per day on alternate days for 1 week [total duration of therapy, 42 days]), or saline placebo was administered.

118

Neurodevelopmental assessment was performed at 1-year adjusted age

using the BSID II, Vineland Adaptive Behavioral scales, a physical and neurologic examination by a developmental pediatrician, and auditory testing.

Cerebral palsy was diagnosed only if a pediatrician and a physical therapist agreed on the presence of abnormal control of movement and posture with impaired motor function.

Of the 118 infants enrolled in the study, 95 survived to discharge.

Follow-up data is available from 93 infants, and 2 parents refused evaluation of their infant.

Cerebral palsy was diagnosed in 12 of 48 infants in the steroid group, compared with 3 of 45 in the placebo group (RR, 3.75; 95% CI, 1.13-12.43).

No differences were noted between groups for MDI or PDI scores.
BSID II Bayley Scales of Infant Development II; MDI Mental developmental index; PDI Psychomoto developmental index; PMA Postmenstrual age; PNA Postnatal age; RR Relative risk; VLBW Very low birth weight

Systemic delayed postnatal cortcosteroid therapy (older than three weeks of age)
There are two overlapping systematic reviews on systemic corticosteroid use started after three weeks of age (12,15). All infants enrolled in the primary studies were preterm and were dependent on oxygen or mechanical ventilation at approximately three weeks of age and older, with or without abnormalities of CLD evident on chest radiographs. Dexamethasone was administered intravenously or enterally at 0.5 to 1 mg/kg/day for a duration of three days to three weeks. The dosage was then tapered every three days in different ways; in some studies, the infants subsequently received hydrocortisone.

The combined outcome of death or CLD at 36 weeks’ PMA was decreased by dexamethasone treatment. Dexamethasone did not affect survival at discharge or duration of hospitalization, but fewer infants were discharged home from the hospital on oxygen therapy. Extubation was facilitated by seven and 28 days after initiation of the treatment. Dexamethasone also improved respiratory compliance and decreased the need for oxygen supplementation, resulting in a borderline significant decrease in the incidence of CLD at 36 weeks’ PMA. Late rescue treatment with dexamethasone was decreased in the treated infants. The risk of hypertension was increased by dexamethasone, but there was no difference in incidence of infection, NEC or gastrointestinal bleeding compared with controls. More infants in the dexamethasone group than in the control group experienced poor weight gain or even weight loss (12,15). Long term outcomes are shown in Table 3.

Table 3: Neurodevelopmental outcome data for late (older than 3 weeks of age) postnatal corticosteroid use for treatment of chronic lung disease

Author

Drug, dosage, and duration of therapy

Number of patients enrolled

Outcome data

Vincer et al, 1998 (35)

Dexamethasone was administered after 28 days of age in infants who were ventilator dependent (0.5 mg/kg per day for 3 days and 0.3 mg/kg per day for the final 3 days), or saline placebo was administered.

20

Of the 20 infants enrolled in the study, 11 received dexamethasone and 9 received placebo.

3 infants died before discharge from the hospital (2 from the steroid group and 1 from the placebo group).

Cerebral palsy was reported in 4 of 9 in the steroid group versus 2 of 8 in the placebo group (RR, 1.78; 95% CI, 0.44-7.25).

Ohlsson, 1992 (20); original study by Ohlsson, 1990 (44)

Dexamethasone was administered to infants at between 21 and 35 days of age (1 mg/kg per day for 3 days, then 0.5 mg/kg per day for the next 3 days, then 0.25 mg/kg per day for the next 3 days, and then 0.125 mg/kg per day for the last 3 days), or sham injections were given.

25

Outcome data available on 24 of 25 infants enrolled in the study (1 infant died at 238 days).

Mean corrected age (± SD) was 26.5 ± 7.8 months in the steroid group versus 28.8 + 7.5 months in the control group.

Cerebral palsy was noted in 1 of 11 infants in the steroid group, compared with 3 of 13 in the control group (RR, 0.39; 95% CI, 0.05-3.27).

Delayed motor development was noted in 3 of 11 in the treatment group versus 2 of 13 in the control group (RR, 1.77; 95% CI, 0.36-8.77).

Bayley scores were 90 ± 15 in the treatment group, compared with 100 ± 20 in the control group (P = .287).

Jones et al, 1995(34); original study by Collaborative Dexamethasone Trial Group, 1991 (33)

Dexamethasone was administered at between two and 12 weeks of age (0.5 mg/kg per day for a week), or normal saline placebo was administered. There was an option to administer a second tapering 9-day course of steroids if relapse occurred after the initial improvement.

287

Information regarding cerebral palsy, global retardation, and visual or hearing loss was obtained from health visitors and general practitioners. Information from parents was obtained using a questionnaire regarding the use of health services such as physiotherapy, speech therapy, and occupational therapy. Also, information on development from parents was obtained using a Minnesota Child Development Inventory.

Follow-up data were obtained on 209 of the 223 survivors at three years of age.

Cerebral palsy was noted in 20 of 100 infants in the steroid group, compared with 18 of 109 in the placebo group (RR, 1.21; 95% CI, 0.68-2.16).

Global retardation was noted in 15 of 100 in the steroid group, compared with 13 of 109 in the placebo group (RR, 1.26; 95% CI, 0.63-2.51).

Inhaled steroids
Two systematic reviews (12,26) address the effectiveness of inhaled corticosteroids to prevent CLD in ventilated infants with VLBW enrolled within two weeks after birth. No benefit of inhaled corticosteroids was shown, except the borderline significant decrease of subsequent administration of systemic dexamethasone. It is uncertain whether inhaled corticosteroids simply do not work for this condition or whether the type, dosage or delivery methods were inadequate. Other meta-analyses studied infants with VLBW enrolled after two weeks of age, with administration of inhaled corticosteroids for one to four weeks (12,27). Inhaled corticosteroids appeared to improve the extubation rate; however, there was heterogeneity among studies for this finding. No other differences were found, possibly because of lack of statistical power. Additional studies may help to determine whether inhaled corticosteroids decrease the need for systemic treatment or facilitate extubation.

Neurodevelopmental outcome
Two systematic reviews are available that focus on mortality and long term neurodevelopment of infants enrolled in randomized controlled trials of corticosteroids (11,28). In one review of five trials (31-37), 475 (91%) of 522 survivors were followed. Mortality was not significantly different in the steroid and control groups (11). Motor dysfunction was significantly greater with postnatal corticosteroid treatment, with an event rate difference of 11.9% favouring the controls (95% CI 4.6 to 19.2). The rate of survival free of motor dysfunction was lower in the postnatal corticosteroid-treated group (event rate difference of 7.8% favouring controls [95% CI 0.5 to 15.1]).

Barrington (28) identified three additional trials (29,38-40) that reported on long term outcome after postnatal exposure to corticosteroids. These eight studies represent 1052 infants; 292 of them died and 679 (89%) of the 760 survivors were followed for one year or longer. One important difficulty in evaluating long term effects of corticosteroids is that many control subjects were treated with open-label dexamethasone after the initial study period. Barrington (28) tried to take this into account by arbitrarily dividing the studies into two groups on the basis of whether they had less than 30% contamination (corticosteroids given to infants in the control group) (group 1), or more than 30% contamination or did not report on contamination (group 2). The outcomes evaluated were the incidences of cerebral palsy and neurodevelopmental impairment; the latter was defined as a developmental score more than two SD below the mean, or cerebral palsy or blindness.

The studies demonstrated a relative risk of neurodevelopmental impairment among surviving children exposed to corticosteroids of 1.34 (95% CI 1.09 to 1.64), compared with controls (28). In the four studies with less than 30% contamination, the relative risk was 1.66 (95% CI 1.26 to 2.19) (28). Including all studies, the relative risk of developing cerebral palsy in the surviving infants exposed to corticosteroids was 2.02 (95% CI 1.51 to 2.71) (28). For infants from studies with less than 30% contamination, the relative risk of developing cerebral palsy among exposed infants was 2.89 (95% CI 1.96 to 4.27) (28). Thus, there appears to be a trend in the size of the apparent effect, which decreases as the degree of contamination increases (28).

Three additional trials (19,20,41-44) that reported long term outcomes after exposure to corticosteroids for the prevention or treatment of CLD were identified, increasing the sample size to a total of 870 children evaluated at one year of age or later (Tables 1-3). The identified trials are heterogeneous in the study populations, timing and dosage of postnatal corticosteroid treatment, crossover rates, event rates in the control groups, follow-up rates, time of assessment of neurodevelopment, and instruments used to assess neurodevelopment. Furthermore, not all are peer-reviewed publications. Discrepancies between results reported in abstracts and full publications of the same randomized controlled trial are common (45). Therefore, the data were not combined using meta-analytic techniques; instead, available details are presented in Tables 1 to 3.

Discussion

Systemic dexamethasone administration with the intent to prevent or treat CLD in the preterm infant does not affect mortality by the time of discharge or length of hospitalization. Early and moderately early systemic administration of dexamethasone decreases the incidence of CLD at 28 days’ PNA and 36 weeks’ PMA and allows for earlier extubation and fewer ventilator days. However, for these short term benefits, there are many short term adverse effects, including hyperglycemia often requiring insulin therapy, hypertension, gastrointestinal bleeding and intestinal perforation, hypertrophic obstructive cardiomyopathy, poor weight gain and poor growth of the head circumference, and a trend toward higher incidence of PVL.

The short term pulmonary benefits of systemic dexamethasone do not appear to confer long term benefits. Survival does not improve after dexamethasone administration. Furthermore, data indicating an increased incidence of neurodevelopmental delay and cerebral palsy raise serious concerns about adverse long term outcomes.

Dexamethasone is a potent anti-inflammatory corticosteroid. The pharmacological doses commonly used in trials and in practice are more than 10 to 15 times the estimated physiological secretion rate of cortisol in neonates. Furthermore, the limited pharmacokinetic data available in infants with extremely low birth weight indicate a prolonged half-life of dexamethasone compared with that in children and adults (46,47). High levels of dexamethasone may increase the rate of adverse effects. Possible alternatives to dexamethasone that may have fewer adverse effects include methylprednisolone, low hydrocortisone doses administered before chronic lung changes have developed or inhaled corticosteroids (48). These interventions require further investigation. However, it is uncertain whether neurodevelopmental abnormalities are linked to the systemic use of corticosteroids in general or just to dexamethasone (28).

The additional three trials noted in the tables (19,20,41-44) increased the sample size by 191 children followed compared with the review by Barrington (28), and by 395 compared with the review by Doyle and Davis (11); this increase in sample size would affect the results of these two previously published meta-analyses (11,28). The results of the three additional trials support the concept that corticosteroids should not be used routinely to prevent or treat infants at high risk of developing CLD or those with established CLD.

In view of the concerns regarding short and long term adverse effects, dexamethasone should not be routinely used to prevent or treat CLD. Enough uncertainty remains with regard to short and long term benefits and harms of corticosteroids to justify further well-designed and executed trials that would use a combination of survival and long term developmental impairments as the primary outcome.

Summary

Recommendations

References

  1. Lee SK, McMillan DD, Ohlsson A, et al. Variations in practice and outcomes in the Canadian NICU Network 1996-1997. Pediatrics 2000;106:1070-9.
  2. Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institutes of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 2001;107:E1. <www.pediatrics.org/cgi/content/full/107/1/e1> (Version current at December 17, 2001)
  3. O’Brodovich HM, Mellins RB. Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. Am Rev Respir Dis 1985;132:694-709.
  4. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: Prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32.
  5. Kinali M, Greenough A, Dimitriou G, Yuksel B, Hooper R. Chronic respiratory morbidity following premature delivery – prediction by prolonged respiratory support requirement? Eur J Pediatr 1999;158:493-6.
  6. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9.
  7. Speer CP. New insights into the pathogenesis of pulmonary inflammation in preterm infants. Biol Neonate 2001;79:205-9.
  8. Ehrenkranz RA, Mercurio MR. Bronchopulmonary dysplasia. In: Sinclair JC, Bracken MB, eds. Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:399-424.
  9. Bhuta T, Ohlsson A. Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Arch Dis Child Fetal Neonatal Ed 1998;79:F26-33.
  10. Arias-Camison JM, Lau J, Cole CH, Frantz ID III. Meta-analysis of dexamethasone therapy started in the first 15 days of life for prevention of chronic lung disease in premature infants. Pediatr Pulmonol 1999;28:167-74.
  11. Doyle L, Davis P. Postnatal corticosteroids in preterm infants: Systematic review of effects on mortality and motor function. J Paediatr Child Health 2000;36:101-7.
  12. Halliday H. Clinical trials of postnatal corticosteroids: Inhaled and systemic. Biol Neonate 1999;76(Suppl 1):29-40.
  13. Halliday HL, Ehrenkranz RA. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). Cochrane Database Syst Rev 2001;1:CD00146.
  14. Halliday HL, Ehrenkranz RA. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). Cochrane Database Syst Rev 2001;1:CD001144.
  15. Halliday HL, Ehrenkranz RA. Delayed (> 3weeks) postnatal corticosteroids for chronic lung disease in preterm infants (Cochrane Review). Cochrane Database Syst Rev 2001;2:CD001145.
  16. Shah V, Ohlsson A. Postnatal dexamethasone in the prevention of chronic lung disease. In: David TJ, ed. Recent Advances in Paediatrics 19. London: Churchill Livingstone, 2001:77-96.
  17. Garland JS, Alex CP, Pauly TH, et al. A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: A randomized trial. Pediatrics 1999;104:91-9.
  18. Ng PC. The effectiveness and side effects of dexamethasone in preterm infants with bronchopulmonary dysplasia. Arch Dis Child 1993;68:330-6.
  19. Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. N Engl J Med 2001;344:95-101.
  20. Ohlsson A, Calvert SA, Hosking M, Shennan AT. A randomized controlled trial of dexamethasone treatment in very-low-birth-weight infants. Acta Paediatr 1992;81:751-6.
  21. Ohlsson A, Heyman E. Dexamethasone-induced bradycardia. Lancet 1988;2:1074.
  22. Ohlsson A, Bottu J, Govan J, Ryan ML, Myhr T, Fong K. The effect of dexamethasone on time averaged mean velocity in the middle cerebral artery in very low birth weight infants. Eur J Pediatr 1994;153:363-6.
  23. Matthews SG. Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res 2000;47:291-300.
  24. Murphy BP, Inder TE, Huppi PS, et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics 2001;107:217-21.
  25. The Vermont Oxford Network Steroid Study Group. Early postnatal dexamethasone therapy for the prevention of chronic lung disease. Pediatrics 2001;108:741-8.
  26. Shah V, Ohlsson A, Halliday HL, Dunn MS. Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates (Cochrane Review). Cochrane Database Syst Rev 2000;2:CD001969.
  27. Lister P, Iles R, Shaw B, Ducharme F. Inhaled steroids for neonatal chronic lung disease (Cochrane Review). Cochrane Database Syst Rev 2000;3:CD002311.
  28. Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: A systematic review of RCTs. BMC Pediatrics 2001;1:1-14.
  29. Baden M, Bauer CR, Colle E, Klein G, Taeusch HW Jr, Stern L. A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome. Pediatrics 1972;50:526-34.
  30. Watterberg KL, Gerdes JS, Gifford KL, Lin HM. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 1999;104:1258-63.
  31. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: A follow-up study. Pediatrics 1998;101:E7. <www.pediatrics.org/cgi/content/full/101/5/e7> (Version current at December 17, 2001)
  32. Cummings JJ, D’Eugenio DB, Gross SJ. A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med 1989;320:1505-10.
  33. Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: An international placebo-controlled trial. Pediatrics 1991;88:421-7.
  34. Jones R, Wincott E, Elbourne D, Grant A. Controlled trial of dexamethasone in neonatal chronic lung disease: A 3-year follow-up. Pediatrics 1995;96:897-906.
  35. Vincer MJ, Allen AC. Double blind controlled trial of 6-day pulse of dexamethasone for very low birth weight infants (VLBW < 1,500 grams) who are ventilator dependent at 4 weeks of age. Pediatr Res 1998;43:201A.
  36. Kothadia JM, O’Shea TM, Roberts D, Auringer ST, Weaver RG III, Dillard RG. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants. Pediatrics 1999;104:22-7.
  37. O’Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: Outcome of study participants at 1-year adjusted age. Pediatrics 1999;104:15-21.
  38. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed 2000;83:F177-81.
  39. Fitzhardinge PM, Eisen A, Lejtenyi C, Metrakos K, Ramsay M. Sequelae of early steroid administration to the newborn infant. Pediatrics 1974;53:877-83.
  40. Subhedar NV, Bennett AJ, Wardle SP, Shaw NJ. More trials on early treatment with corticosteroids are needed. BMJ 2000;320:941.
  41. Stark AR, Carlo W, Vohr BR, et al. Neurodevelopmental outcome and growth at 18-22 months in infants treated with early dexamethasone. Pediatr Res 2001;49:388A. (Abst)
  42. Hofkosh D, Brozanski BS, Edwards MD, Williams LA, Jones JG, Cheng KP. One year outcome of infants treated with pulse dexamethasone for prevention of BPD. Pediatr Res 1995;37:259A. (Abst)
  43. Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995;126:769-76.
  44. Ohlsson A. A randomized controlled trial of dexamethasone treatment in very low birthweight infants with ventilator dependent chronic lung disease. Master of Science Thesis, McMaster University, Hamilton, Ontario, Canada 1990.
  45. Walia R, Ohlsson A. All is gold, is it? Differences between abstracts of randomised controlled trials in neonates submitted to the conference and their final publication – implications for meta-analysis. Arch Dis Child 2000;82(Suppl 1):A3. (Abst)
  46. Charles B, Schild P, Steer P, Cartwright D, Donovan T. Pharmacokinetics of dexamethasone following single-dose intravenous administration to extremely low birth weight infants. Dev Pharmacol Ther 1993;20:205-10.
  47. Lugo RA, Nahata MC, Menke JA, McClead RE Jr. Pharmacokinetics of dexamethasone in premature neonates. Eur J Clin Pharmacol 1996;49:477-83.
  48. Thebaud B, Lacaze-Masmonteil T, Watterberg K. Postnatal glucocorticoids in very preterm infants: "The good, the bad and the ugly"? Pediatrics 2001;107:413-5.

Fetus and Newborn Committee, Canadian Paediatric Society 

Members: Drs Keith J Barrington, Chair; Arne Ohlsson, immediate past Chair; Khalid Aziz, Director Responsible; Deborah Davis; Shoo Lee; Koravangattu Sankaran; John Van Aerde
Liaisons: Dr Lillian Blackmon, American Academy of Pediatrics; Dr Jill Boulton, Canadian Paediatric Society, Neonatal-Perinatal Medicine Section; Dr Joan Crane, Society of Obstetricians and Gynecologists of Canada; Dr Catherine McCourt, Health Canada; Dr Larry Reynolds, College of Family Physicians of Canada; Amanda Symington, Neonatal Nursing
Consultants: Drs James Lemons; Vibhuti Shah
Prinicipal authors: Drs John Van Aerde, Vibhuti Shah, Ann R Stark, Arne Ohlsson

Committee on Fetus and Newborn, 2001-2002, American Academy of Pediatrics

Members: Drs Lillian R Blackmon, Chairperson; Edward F Bell; William A Engle; William P Kanto Jr; Gilbert I Martin; Carol A Miller; Warren Rosenfeld; Michael E Speer; Ann R Stark
Liaisons: Jenny Ecord, American Nurses Association, Association of Women’s Health, Obstetric and Neonatal Nurses, National Association of Neonatal Nurses; Solomon Iyasu, Centers for Disease Control and Prevention; Dr Charles J Lockwood, American College of Obstetricians and Gynecologists; Dr Keith J Barrington, Canadian Paediatric Society; Linda L Wright MD, National Institutes of Health
Consultant: Dr Arne Ohlsson

Internet addresses are current at the time of publication.

Also published in Pediatrics 2002 Volume 109 Number 2 February.
Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.