Postnatal steroids for chronic lung disease
Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. Steroidsgiven either soon after birth to prevent CLD, or later to reduce its severity, are effective, but thereare acute and long-term adverse effects. When steroids are given early (first 4 days) there is anincreased risk of cerebral palsy in surviving infants which precludes their use at this time. Dexamethasone may be effective in far lower doses than used in most of the randomised trialsto date. There are probably situations where its use is associated with more benefit than harm. There is no convincing evidence that inhaled steroids alter the course of CLD. More research isneeded into ways of preventing or reducing CLD in at risk preterm infants. Henry L Halliday Chronic lung disease
arrested development, also known as ‘the
respiratory distress syndrome (RDS) in the
1990s, survival rates of preterm babies have
Department of Child HealthQueen’s University Belfast
modest effect on reducing the incidence of
translates into an increased overall number
dysplasia (BPD) are used interchangeably,
academic difficulties, delayed speech and
until recently there has been no consistent
definition of these conditions5. The best
CLD persist into adolescence with reduced
corrected age of 36 weeks after efforts have
been made to ensure that oxygen is indeed
significantly different from very preterm
dysplasia; corticosteroids; dexamethasone;
88%; the so called ‘physiologic definition’6.
sequelae are important it is not surprising
weight and gestational age, with rates of
less than 5% in infants weighing more than
Halliday, H.L. (2007) Postnatal steroids for
1500 grams, increasing to 85% in those of
chronic lung disease Infant 3(2): 78-81.
less than 700 grams7. Overall at least 20%
1. Chronic lung disease is associated with
respiratory outcomes would be expected.
described by Bill Northway and colleagues
History of postnatal steroids
in 1967 as a severe sequela of mechanical
There is a long history of use of postnatal
ventilation – the so called ventilator lung
disease8 (FIGURE 1). Pathologically in classic
was first reported in 1956 in the US as a
BPD there is severe alveolar fibrosis and
potential treatment for respiratory distress
3. Inhaled steroids have little effect on the
in infants of diabetic mothers15. Later in
strategies of mechanical ventilation, the
RDS16, but the first randomised controlled
infants with significant chronic lungdisease or at high risk of developing it.
trial was not reported until 197217. This
V O L U M E 3 I S S U E 2 2 0 0 7 infant Subjects RR (95%CI) NNT (95%CI)
and perforation. Some of these arepotentially reversible after corticosteroid
treatment has been discontinued. However, the long term adverse
increased risk of cerebral palsy after early treatment with postnatal steroids (TABLE 2).
It appears that this increased risk in earlytreated infants is due to their lower risk of
steroids is weighted towards harm ratherthan benefit. With risks of CLD below 35%
corticosteroid treatment significantlyincreases the chance of death or cerebral
RR=relative risk, CI=confidence interval, NNT=number needed to treat, CLD=chronic
lung disease, PDA=persistent ductus arteriosus. Data derived from Cochrane
65%, it reduces the chance of these adverse
TABLE 1 Beneficial effects of systemic postnatal steroids.
used dexamethasone but the dose andduration varied considerably23. The most
Systematic reviews of systemic corticosteroids
reducing course over two to six weeks.
increased risk of severe intraventricular
postnatal steroids were first published in
results of these systematic reviews is the
problems20. As a result of these concerns
cross over effect of the use of open label
about serious long term adverse effects of
reviews are classified according to postnatal
corticosteroids in the control groups.
age at the start of treatment: early (<96
high dose dexamethasone was used to treat
delayed (>3 weeks). Postnatal steroids,
babies and this had the effect of reducing
ventilator-dependent infants with CLD 21,22.
whether started early, moderately early or
late, facilitate earlier extubation and reduce
the risk of developing CLD at 36 weeks’
corrected age (TABLE 1). Neonatal mortality
studies with less than 30% cross over (or
significant long term benfits. Few adverse
effects were reported in these early studies
about the safety of postnatal steroids and
steroids was first shaken in 1998 with thepublication of a large multicentre follow-
up study from Taiwan25. This study showed
infants (TABLE 1).
lems and a doubling of the risk of cerebral
palsy at two years in infants who had been
treated with a 4 week course of dexametha-
sone, started within 12 hours of birth. This
study and others that followed in 1999 and
steroids (TABLE 2).
postnatal corticosteroids to prevent CLD. FIGURE 1 Ventilator-dependent baby with chronic lung disease. infant VO L U M E 3 I S S U E 2 2 0 0 7
prevent CLD and later to treat babies with
inhaled and systemic corticosteroids, again
cerebral palsy was as high as one for every
both early (<2 weeks)38 and late (>2
four treated infants30. It seems likely that
included five randomised controlled trials
that outweigh its benefits. Its initial choice
but did not show any reduction in CLD36.
suggesting that either the doses used were
risk of hyperglycaemia. In summary, there
safe, or alternatively were ineffective. A
second systematic review also included five
physiological secretion rate of cortisol in
effective for prevention and treatment of
corticosteroids have been used infrequently
dexamethasone in reducing ventilation and
Other systemic corticosteroids Methylprednisolone has been compared with dexamethasone in a non-randomised Subjects RR (95%CI) NNH (95%CI)
preterm infants at risk31. Although therewere no differences in oxygen requirements
or in the rate of weaning from ventilation,
the methylprednisolone-treated infantshad better weight gain, less hyperglycaemia
than those treated with dexamethasone.
However, there have been no randomisedtrials with methylprednisolone, nor withbetamethasone, a drug commonly used
antenatally to mature the fetal lungs. Hydrocortisone, prescribed in a
relatively low dose as prophylaxis againstadrenal insufficiency, appeared to reduce
the risk of CLD in a small pilotrandomised trial32. However, two larger
early because of an excess ofgastrointestinal perforations in the
cause of these perforations may have beenan interaction between early hydro-
cortisone treatment and prophylacticindomethacin. Hydrocortisone has also
been compared with dexamethasone fortreatment of CLD in non-randomised
outcome may be better with hydro-cortisone. These findings need to be
confirmed in randomised comparativetrials before alternative steroids can be
RR = relative risk, CI = confidence interval, NNH = number needed to harm. HCM =
These should have direct beneficial effects
hypertrophic cardiomyopathy, GI = gastrointestinal, CP = cerebral palsy. Data derived
from Cochrane systematic reviews26-28.
systemic effects of dexamethasone. Inhaledsteroids have been used early to try to
TABLE 2 Adverse effects of systemic postnatal steroids.
V O L U M E 3 I S S U E 2 2 0 0 7 infant
membrane disease: Bronchopulmonary dysplasia.
29. Doyle L.W., Halliday H.L., Ehrenkranz R.A., Davis Overall conclusions N Engl J Med 1967; 276: 357-68. P.G., Sinclair J.C. Impact of postnatal systemic
Following the publication of guidelines for
9. Coalson J.J. Pathology of new bronchopulmonary
corticosteroids on mortality and cerebral palsy in
postnatal steroid treatment in Europe40 and
dysplasia. Semin Neonatol 2003; 8: 73-81.
preterm infants: Effect modification by risk of
10. Jobe A.H. The new BPD: An arrest of lung
chronic lung disease. Pediatrics 2005; 115: 655-61.
development. Pediatr Res 1999; 46: 641-43.
30. Barrington K.J. The adverse neuro-developmental
11. Speer C.P. New insights into the pathogenesis of
effects of postnatal steroids in the preterm infant: A
Israel steroid use in very low birthweight
pulmonary inflammation in preterm infants. Biol
systematic review of RCTs. BMC Pediatrics 2001; 1.
infants fell from 23% in 1997-8 to 11% in
Neonate 2001; 79: 205-09.
31. Andre P, Thebaud B, Odievre MH et al. Methylpred-
2003-442. However, this was associated with
12. Saugstad O.D. Bronchopulmonary dysplasia-
nisolone, an alternative to dexamethasone in very
oxidative stress and antioxidants. Semin Neonatol
premature infants at risk of chronic lung disease.
2003; 8: 39-49.
and 36 weeks’ corrected age, together with
Intensive Care Med 2000; 26: 1496-500.
13. Anderson P.J., Doyle L.W. Neurodevelopmental
32. Watterberg K.L., Gerdes J.S., Gilford K.L., Lin H.M.
outcome of bronchopulmonary dysplasia. Semin
Prophylaxis against early adrenal insufficiency to
postnatal steroids should be avoided if at
Perinatol 2006; 30: 227-32.
prevent chronic lung disease in premature infants.
all possible there are still occasions when
14. Doyle L.W., Faber B., Callanan C., Freezer N., Ford Pediatrics 1999; 104: 1258-63.
their use may provide benefits in excess of
G.W., Davis N.M. Bronchopulmonary dysplasia in
33. Watterberg K.L., Gerdes J.S., Cole C.H. et al.
very low birthweight subjects and lung function in
Prophylaxis of early adrenal insufficiency to prevent
late adolescence. Pediatrics 2006; 118: 108-13.
bronchopulmonary dysplasia: A multicenter trial.
15. Haddad H.M., Hsia D.Y., Gellis S.S. Studies on Pediatrics 2004; 114: 1649-57.
respiratory rate in the newborn: Its use in the
34. Peltoniemi O., Kari M.A., Heinonen K. et al.
evaluation of respiratory distress in infants of
Pretreatment cortisol values may predict responses
diabetic mothers. Pediatrics 1956; 17: 204-13.
to hydrocortisone administration for the prevention
16. Altman H. The respiratory distress syndrome of the
of bronchopulmonary dysplasia in high risk infants. J Pediatr 2005; 146: 632-37.
conservatively. S Afr Med J 1965; 39: 746-48.
respiratory function with a starting dose
35. Karemaker R., Heijnen C.J., Veen S. et al. Differences
17. Baden M., Bauer C.R., Colle E., Klein G., Taeusch
in behavioural outcome and motor development at
H.W. Jr., Stern L. A controlled trial of hydrocortisone
school age after neonatal treatment for chronic
there is also anecdotal evidence that doses
therapy in infants with respiratory distress
syndrome. Pediatrics 1972; 50: 526-34.
hydrocortisone. Pediatr Res 2006; 60: 745-50.
18. Ewerbeck H., Helwig H., Reynolds J.W., Provenzano
36. Shah V., Ohlsson A., Halliday H.L., Dunn M.S. Early R.W. Treatment of idiopathic respiratory distress
administration of inhaled corticosteroids for
with large doses of corticoids. Pediatrics 1972; 49:
needed to determine the best corticosteroid
preventing chronic lung disease in ventilated very
low birth weight preterm neonates. Cochrane
19. Taeusch H.W. Jr., Wang N.S., Baden M., Bauer C.R., Database Sys Rev 2000; (2): CD001969. Stern L. A controlled trial of hydrocortisone therapy
37. Lister P., Iles R., Shaw B., Ducharme F. Inhaled
in infants with respiratory distress syndrome: II.
steroids for neonatal chronic lung disease.
Pathology. Pediatrics 1973; 52: 850-54. Cochrane Database Syst Rev 2000; (3): CD002311.
20. Fitzhardinge P.M., Eisen A., Lejtenyi C., Metrakos K.,
38. Shah S.S., Ohlsson A., Halliday H.L., Shah V.S. Ramsay M. Sequelae of early steroid administration
Inhaled versus systemic corticosteroids for
to the newborn infant. Pediatrics 1974; 53: 877-83.
preventing chronic lung disease in ventilated very
21. Mammel M.C., Green T.P., Johnson D.E., Thompson
1. Schwartz R.M., Luby A.M., Scanlon J.W., Kellogg R.J.
low birth weight preterm neonates. CochraneT.R. Controlled trial of dexamethasone therapy in
Effect of surfactant on morbidity, mortality, and
Database Syst Rev 2003; (1): CD002058.
infants with bronchopulmonary dysplasia. Lancet
resource use in newborn infants weighing 500 to
39. Shah S.S., Ohlsson A., Halliday H.L., Shah V.S.
1983; 1(8338): 1356-58.
1500 g. N Engl J Med 1994; 330: 1476-80.
Inhaled versus systemic corticosteroids for the
22. Avery G.B., Fletcher A.B., Kaplan M., Brudno D.S.
2. Corcoran J.D., Patterson C.C., Thomas P.S., Halliday
treatment of chronic lung disease in ventilated very
Controlled trial of dexamethasone in respirator-
H.L. Reduction in the risk of bronchopulmonary
low birth weight preterm infants. Cochrane
dysplasia from 1980-1990: Results of a multivariate
dysplasia. Pediatrics 1985; 75: 106-11. Database Syst Rev 2003; (2): CD002057.
logistic regression analysis. Eur J Pediatr 1993; 152:
23. Grier D.G., Halliday H.L. Management of
40. Halliday H.L. Guidelines on neonatal steroids.
bronchopulmonary dysplasia in infants: Guidelines
Prenat Neonatal Med 2001; 6: 371-73.
3. Egberts J., Brand R., Walti H., Bevilacqua G., Breart
for corticosteroid use. Drugs 2005; 66: 15-29.
41. American Academy of Pediatrics Committee on G., Gardini F. Mortality, severe respiratory distress
24. Hack M., Fanaroff A.A. Outcomes of children of Fetus and Newborn, Canadian Paediatric Society
syndrome and chronic lung disease of the newborn
extremely low birthweight and gestational age in
Fetus and Newborn Committee. Postnatal
are reduced more after prophylactic than after
the 1990s. Early Hum Dev 1999; 53: 193-218.
corticosteroids to treat or prevent chronic lung
therapeutic administration of the surfactant
25. Yeh T.F., Lin Y.J., Huang C.C. et al. Early
disease in preterm infants. Pediatrics 2002; 109:
Curosurf. Pediatrics 1997; 100: e4.
dexamethasone therapy in preterm infants: A
4. Halliday H.L. Postnatal steroids and chronic lung
follow-up study. Pediatrics 1998; 101: e7.
42. Shinwell E.S., Lerner-Geva L., Lusky A., Reichman B.,
disease in the newborn. Paediatr Resp Rev 2004;
26. Halliday H.L., Ehrenkranz R.A., Doyle L.W. Early in collaboration with the Israel Neonatal Network. 5(Suppl A): S245-8.
5. Jobe A.H., Bancalari E. Bronchopulmonary dysplasia.
postnatal (<96 hours) corticosteroids for preventing
Less postnatal steroids, more bronchopulmonary
Am J Respir Crit Care Med 2001; 163: 1723-29.
chronic lung disease in preterm infants. Cochrane
dysplasia: A population-based study in very low
6. Walsh M.C., Wilson-Costello D., Zadell A., Newman Database Syst Rev 2003; (1): CD001146.
birthweight infants. Arch Dis Child Fetal Neonatal EdN., Fanaroff A. Safety, reliability, and validity of a
27. Halliday H.L., Ehrenkranz R.A., Doyle L.W.
2007; 92: F30-33.
physiologic definition of bronchopulmonary
43. Doyle L.W., Davis P.G., Morley C.J., McPhee A., Carlin
dysplasia. J Perinatol 2003; 23: 451-56.
corticosteroids for preventing chronic lung disease
J.B.; DART Study Investigators. Low-dose
7. Parker R.A., Lindstrom D.P., Cotton R.B. Improved
in preterm infants. Cochrane Database Syst Rev
dexamethasone facilitates extubation among
survival accounts for most, but not all, of the
2003; (1): CD001144.
chronically ventilator-dependent infants: A
increase in bronchopulmonary dysplasia. Pediatrics
28. Halliday H.L., Ehrenkranz R.A., Doyle L.W. Delayed
multicenter, international, randomised, controlled
1992; 90: 663-68.
(>3 weeks) postnatal corticosteroids for chronic lung
trial. Pediatrics 2006; 117: 75-83.
8. Northway W.H. Jr., Rosan R.C., Porter D.Y. Pulmonary
disease in preterm infants. Cochrane Database Syst
44. Halliday H.L. Postnatal steroids: A dilemma for the
disease following respirator therapy of hyaline
Rev 2003; (1): CD001145.
neonatologist. Acta Paediatr 2001; 90: 116-18. infant VO L U M E 3 I S S U E 2 2 0 0 7
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