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PEDIATRICS Vol. 109 No. 2 February 2002, pp. 330-338

AMERICAN ACADEMY OF PEDIATRICS

Postnatal Corticosteroids to Treat or Prevent Chronic Lung Disease in Preterm Infants

	ABSTRACT

TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 
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 dexamethasone for the prevention or treatment of chronic lung disease in infants with very low birth weight is not recommended.

Abbreviations: CLD, chronic lung disease • VLBW, very low birth weight • PMA, postmenstrual age • PNA, postnatal age • NEC, necrotizing enterocolitis • PVL, periventricular leukomalacia, CI, confidence interval

	BACKGROUND

TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 
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 <1500 g) in 2 large databases was 26% in Canada (1996–1997)¹ and 23% in the United States (1995–1996).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 (1996–1997)¹ and 19% in the United States (1995–1996).² Corticosteroid use is higher in infants with birth weight <1000 g.^1,2 Numerous studies suggest that systemic corticosteroids decrease 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

TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 
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 will be limited to the use of corticosteroids in neonates with VLBW for the prevention or treatment of CLD.

	LITERATURE REVIEW

TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 
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 through April 2001. Data were also included from 2 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} 2 described the use of inhaled steroids,^26,27 and 1 addressed both.¹² Numerous outcomes were evaluated. The results are presented in 5 sections: the first 3 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 (<96 Hours 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 Ohlsson¹⁶ was updated by incorporating data from 2 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 hours after birth; dexamethasone was used in all but 2 studies.^29,30 The most commonly used dosages were 0.5 mg/kg of body weight per day for 3 days, followed by a tapering course of 0.25, 0.125, and 0.05 mg/kg per day each for 3 days.^13,16 One study¹⁹ used a considerably lower dosage (0.15 mg/kg per day for 3 days, 0.10 mg/kg per day for 3 days, 0.05 mg/kg per day for 2 days, and 0.02 mg/kg per day for 2 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 1 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 bleeding¹⁶ or perforation,¹³ and hypertrophic obstructive cardiomyopathy¹³ were increased by early corticosteroid treatment. The rates of pulmonary air leaks¹³ 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 1¹³ but not in the other recent systematic review.¹⁶ In an update of the review by Shah and Ohlsson,¹⁶ including the 2 recently published studies (n = 1096),^19,25 the relative risk of PVL was 1.41 (95% confidence interval [CI]: 0.93–2.13). Long-term outcomes are shown in Table 1.

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 1 review, mortality was not decreased at 28 days’ PNA or 36 weeks’ PMA¹⁶; 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 that needed to be treated with dexamethasone was 7 and 4 to prevent CLD at 28 days’ PNA and 36 weeks’ PMA, respectively.¹⁶ Infants were more likely to be extubated by 7 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 2 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.

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 from the hospital on oxygen therapy. Extubation was facilitated by 7 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.

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 1 review of 5 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% favoring the controls (95% CI: 4.6%–19.2%). The rate of survival free of motor dysfunction was lower in the postnatal corticosteroids group (event rate difference, 7.8% favoring controls [95% CI: 0.5%–15.1%]).

Barrington²⁸ identified 3 additional trials^29,38–40 that reported on long-term outcome after postnatal exposure to corticosteroids. These 8 studies represent 1052 infants; 292 of them died and 679 (89%) of the 760 survivors were followed for 1 year or longer. One important difficulty in evaluating long-term effects of corticosteroids is that many controls were treated with open-label dexamethasone after the initial study period. Barrington²⁸ tried to take this into account by arbitrarily dividing the studies into 2 groups on the basis of whether they had <30% contamination (corticosteroids given to infants in the control group [group 1]), or >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 2 standard deviations 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: 1.09–1.64), compared with controls.²⁸ In the 4 studies with <30% contamination, the relative risk was 1.66 (95% CI: 1.26–2.19).²⁸ Including all studies, the relative risk of developing cerebral palsy in the surviving infants exposed to corticosteroids was 2.02 (95% CI: 1.51–2.71).²⁸ For infants from studies with <30% contamination, the relative risk of developing cerebral palsy among exposed infants was 2.89 (95% CI: 1.96–4.27).²⁸ Thus, there appears to be a trend in the size of the apparent effect, which decreases as the degree of contamination increases.²⁸

We identified 3 additional trials^{19,20,41–44} that reported long-term outcomes after exposure to corticosteroids for the prevention or treatment of CLD increasing the sample size to a total of 870 children evaluated at 1 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

TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 
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 pharmacologic doses commonly used in trials and in practice are more than 10 to 15 times the estimated physiologic 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 consequences include methylprednisolone, low hydrocortisone doses administered before chronic lung changes have developed, or inhaled corticosteroids.⁴⁸ These require additional 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 3 trials noted in the tables^{19,20,41–44} increased the sample size by 191 children followed compared with the review by Barrington²⁸ and by 395 compared with the review by Doyle and Davis¹¹; this increased sample size would affect the results of the 2 previously published meta-analyses.^11,28 The results of the 3 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 additional well-designed and executed trials that would use a combination of survival and long-term developmental impairments as the primary outcome.

	SUMMARY

TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 

• Systemic administration of dexamethasone to preterm infants who are mechanically ventilated decreases the incidences of CLD and extubation failure but does not decrease overall mortality.
  
• Treatment of infants with VLBW with dexamethasone is associated with an increased risk of short- and long-term complications, including impaired growth and neurodevelopmental delay.
  
• No substantial short- or long-term benefits have been demonstrated from the use of inhaled corticosteroids in the prevention or treatment of CLD.
  

	RECOMMENDATIONS

TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 

1. On the basis of limited short-term benefits, the absence of long-term benefits, and the number of serious short- and long-term complications, the routine use of systemic dexamethasone for the prevention or treatment of CLD in infants with VLBW is not recommended.
   
2. Postnatal use of systemic dexamethasone for the prevention or treatment of CLD should be limited to carefully designed randomized double-masked controlled trials. The primary outcome of these trials should be survival without long-term developmental impairments, and the potential confounders of contamination and crossover should be avoided.
   
3. Long-term neurodevelopmental assessment of infants who are or have been subjects in trials of dexamethasone to prevent or treat CLD is strongly encouraged.
   
4. Clinical trials investigating the use of alternative anti-inflammatory corticosteroids, systemic and inhaled, are required before additional recommendations can be made.
   
5. Outside the context of a randomized, controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen support). In those circumstances, parents should be fully informed about the known short- and long-term risks and agree to treatment.
   

COMMITTEE ON FETUS AND NEWBORN, 2001–2002 

Lillian R. Blackmon, MD, Chairperson

Edward F. Bell, MD

William A. Engle, MD

William P. Kanto, Jr, MD

Gilbert I. Martin, MD

Carol A. Miller, MD

Warren Rosenfeld, MD

Michael E. Speer, MD

Ann R. Stark, MD

LIAISONS

Jenny Ecord, MS, RNC, NNP, PNP

American Nurses Association, Association of Women’s Health, Obstetric and Neonatal Nurses, National Association of Neonatal Nurses

Solomon Iyasu, MBBS, MPH

Centers for Disease Control and Prevention

Charles J. Lockwood, MD

American College of Obstetricians and Gynecologists

Keith J. Barrington, MD

Canadian Paediatric Society

Linda L. Wright, MD

National Institutes of Health

CONSULTANT

Arne Ohlsson, MD, MSc

STAFF

Jim Couto, MA

CANADIAN PAEDIATRIC SOCIETY, FETUS AND NEWBORN COMMITTEE, 2001–2002

Keith J. Barrington, MD, Chairperson

Arne Ohlsson, MD, MSc, Immediate Past Chairperson

Khalid Aziz, MD, Director

Deborah Davis, MD

Shoo Lee, MD

Koravangattu Sankaran, MD

John Van Aerde, MD

LIAISONS

Lillian R. Blackmon, MD

American Academy of Pediatrics

Jill Boulton, MD

Neonatal-Perinatal Medicine Section

Joan Crane, MD

Society of Obstetricians and Gynecologists of Canada

Catherine McCourt, MD

Health Canada

Larry Reynolds, MD

College of Family Physicians of Canada

Amanda Symington

Neonatal Nursing

CONSULTANTS

James Lemons, MD

Vibhuti Shah, MD

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TOP ABSTRACT BACKGROUND OBJECTIVES LITERATURE REVIEW DISCUSSION SUMMARY RECOMMENDATIONS REFERENCES

 

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				E. C Eichenwald and A. R Stark Are postnatal steroids ever justified to treat severe bronchopulmonary dysplasia? Arch. Dis. Child. Fetal Neonatal Ed., September 1, 2007; 92(5): F334 - F337. [Full Text] [PDF]

				K. L. Watterberg, M. L. Shaffer, M. J. Mishefske, C. L. Leach, M. C. Mammel, R. J. Couser, S. Abbasi, C. H. Cole, S. W. Aucott, E. H. Thilo, et al. Growth and Neurodevelopmental Outcomes After Early Low-Dose Hydrocortisone Treatment in Extremely Low Birth Weight Infants Pediatrics, July 1, 2007; 120(1): 40 - 48. [Abstract] [Full Text] [PDF]

				C. M. T. Robertson, M.-J. Watt, and Y. Yasui Changes in the Prevalence of Cerebral Palsy for Children Born Very Prematurely Within a Population-Based Program Over 30 Years JAMA, June 27, 2007; 297(24): 2733 - 2740. [Abstract] [Full Text] [PDF]

				L. W. Doyle, P. G. Davis, C. J. Morley, A. McPhee, J. B. Carlin, and and the DART Study Investigators Outcome at 2 Years of Age of Infants From the DART Study: A Multicenter, International, Randomized, Controlled Trial of Low-Dose Dexamethasonef Pediatrics, April 1, 2007; 119(4): 716 - 721. [Abstract] [Full Text] [PDF]

				M. Levene Minimising neonatal brain injury: how research in the past five years has changed my clinical practice Arch. Dis. Child., March 1, 2007; 92(3): 261 - 265. [Abstract] [Full Text] [PDF]

				N. A. Parikh, R. E. Lasky, K. A. Kennedy, F. R. Moya, L. Hochhauser, S. Romo, and J. E. Tyson Postnatal Dexamethasone Therapy and Cerebral Tissue Volumes in Extremely Low Birth Weight Infants Pediatrics, February 1, 2007; 119(2): 265 - 272. [Abstract] [Full Text] [PDF]

				R. Aneja and J. A Carcillo What is the rationale for hydrocortisone treatment in children with infection-related adrenal insufficiency and septic shock? Arch. Dis. Child., February 1, 2007; 92(2): 165 - 169. [Abstract] [Full Text] [PDF]

				D. Wilson-Costello, H. Friedman, N. Minich, B. Siner, G. Taylor, M. Schluchter, and M. Hack Improved Neurodevelopmental Outcomes for Extremely Low Birth Weight Infants in 2000-2002 Pediatrics, January 1, 2007; 119(1): 37 - 45. [Abstract] [Full Text] [PDF]

				E S Shinwell, L Lerner-Geva, A Lusky, B Reichman, and in collaboration with the Israel Neonatal Network Less postnatal steroids, more bronchopulmonary dysplasia: a population-based study in very low birthweight infants Arch. Dis. Child. Fetal Neonatal Ed., January 1, 2007; 92(1): F30 - F33. [Abstract] [Full Text] [PDF]

				B. Luke and M. B. Brown The Changing Risk of Infant Mortality by Gestation, Plurality, and Race: 1989-1991 Versus 1999-2001 Pediatrics, December 1, 2006; 118(6): 2488 - 2497. [Abstract] [Full Text] [PDF]

				M. C. Walsh, Q. Yao, J. D. Horbar, J. H. Carpenter, S. K. Lee, and A. Ohlsson Changes in the Use of Postnatal Steroids for Bronchopulmonary Dysplasia in 3 Large Neonatal Networks Pediatrics, November 1, 2006; 118(5): e1328 - e1335. [Abstract] [Full Text] [PDF]

				L. K. Washburn, P. A. Nixon, and T. M. O'Shea Follow-up of a Randomized, Placebo-Controlled Trial of Postnatal Dexamethasone: Blood Pressure and Anthropometric Measurements at School Age Pediatrics, October 1, 2006; 118(4): 1592 - 1599. [Abstract] [Full Text] [PDF]

				M. Sheffield, S. Mabry, D. W. Thibeault, and W. E. Truog Pulmonary Nitric Oxide Synthases and Nitrotyrosine: Findings During Lung Development and in Chronic Lung Disease of Prematurity Pediatrics, September 1, 2006; 118(3): 1056 - 1064. [Abstract] [Full Text] [PDF]

				T. T. Wilson, L. Waters, C. C. Patterson, C. G. McCusker, N. M. Rooney, N. Marlow, and H. L. Halliday Neurodevelopmental and Respiratory Follow-up Results at 7 Years for Children From the United Kingdom and Ireland Enrolled in a Randomized Trial of Early and Late Postnatal Corticosteroid Treatment, Systemic and Inhaled (the Open Study of Early Corticosteroid Treatment). Pediatrics, June 1, 2006; 117(6): 2196 - 2205. [Abstract] [Full Text] [PDF]

				C. J. Fernandes and Y. R. Johnson Reopening the debate on corticosteroids: to the editor. Pediatrics, June 1, 2006; 117(6): 2321 - 2322. [Full Text] [PDF]

				C. Dani, G. Bertini, P. Simone, and F. F. Rubaltelli Hypertrophic Cardiomyopathy in Preterm Infants Treated With Methylprednisolone for Bronchopulmonary Dysplasia Pediatrics, May 1, 2006; 117(5): 1866 - 1867. [Full Text] [PDF]

				R. A. Ehrenkranz, A. M. Dusick, B. R. Vohr, L. L. Wright, L. A. Wrage, W. K. Poole, and for the National Institutes of Child Health and Hu Growth in the Neonatal Intensive Care Unit Influences Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants Pediatrics, April 1, 2006; 117(4): 1253 - 1261. [Abstract] [Full Text] [PDF]

				N. N. Finer, R. J. Powers, C.-h. S. Ou, D. Durand, D. Wirtschafter, J. B. Gould, and for the California Perinatal Quality Care Collabor Prospective Evaluation of Postnatal Steroid Administration: A 1-Year Experience From the California Perinatal Quality Care Collaborative Pediatrics, March 1, 2006; 117(3): 704 - 713. [Abstract] [Full Text] [PDF]