Postnatal Glucocorticoids in Very Preterm Infants: “The Good, the Bad, and the Ugly”?

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1 (but nobody would interpret the transformed per-sonnel Army data as indicative of rising numbers of militaries!). The point is that, in both examples, there was no passage of time allowing inferences to be made on trends over time.

The misuse of these data by some investigators6is

another tribute to their poor research methodology. To date, the epidemiologic evidence for a secular increase in the incidence of PDDs is both meager and negative.1We simply lack good data to test

hypoth-eses on secular changes in the incidence of autism. Because of specific methodologic limitations, the high prevalence rates reported in recent autism sur-veys cannot be used to derive conclusions on this issue.1,2 Prevalence data nevertheless point to the

magnitude of the problem, which had clearly been underestimated in the past. But there is no need to raise false alarms on putative epidemics nor to prac-tice poor science to draw the attention to the unmet needs of large numbers of seriously impaired chil-dren and adults. More complex monitoring systems than those currently in place are needed to address the issue of secular changes in the incidence of PDDs. Maintaining case definition and identification con-stant, focusing on children in the upper range of school age years, controlling for changes in the pop-ulation (ie, differential migration, etc. . . ) and relying on adequate sample sizes are required for future epidemiologic efforts in this area.

Eric Fombonne, MD, FRCPsych

MRC Child Psychiatry Unit/Institute of Psychiatry Denmark Hill

De Crespigny Park

London SE5 8AF, United Kingdom

REFERENCES

1. Fombonne E. The epidemiology of autism and related pervasive devel-opmental disorders. In: Lord C, ed.Educating Children With Autism.

Washington, DC: National Academy of Sciences Press; 2001. In press 2. Fombonne E. Epidemiological surveys of autism: a review.Psychol Med.

1999;29:769 –786

3. Fombonne E, du Mazaubrun C, Cans C, Grandjean H. Autism and associated medical disorders in a large French epidemiological sample.

J Am Acad Child Adolesc Psychiatry. 1997;36:1561–1569

4. Department of Developmental Services.Changes in the Population of Persons With Autism and Pervasive Developmental Disorders in California’s Developmental Services System: 1987 Through 1998. Report to the Legisla-ture, March 1, 1999.Available at: http://www.dds.ca.gov

5. Volkmar F, Shaffer D, First M. PDD-NOS in DSM IV.J Autism Dev Disord. 2000;30:74 –75. Letter

6. Wakefield A. MMR vaccination and autism.Lancet. 1999;354:949 –950. Letter

Postnatal Glucocorticoids in Very

Preterm Infants: “The Good, the

Bad, and the Ugly”?

ABBREVIATIONS. BPD, bronchopulmonary dysplasia; DXM, dexamethasone.

P

remature births represent 7% to 10% of all births, but account for ⬎85% of all perinatal complications and death. Survival of extremely premature newborns (⬍28 weeks’ gestation) has in-creased because of the widespread use of surfactant treatment for respiratory distress syndrome, together with antenatal glucocorticoids and new ventilator strategies.1 However, these infants are at high risk

for long-term injury of both the lungs and the brain. Bronchopulmonary dysplasia (BPD) is one of the most frequent sequelae in extremely premature in-fants and results in increased health care costs, pro-longed hospital stays with frequent rehospitaliza-tions, and deleterious effects on subsequent growth and neurodevelopment.2Periventricular

leukomala-cia, the most severe form of white matter brain dam-age, is a frequent cause of cerebral palsy in children surviving preterm birth, with lifelong consequences.3

Recent data suggest that a common treatment for one, dexamethasone for BPD, may have deleterious effects on both sequelae.

Northway et al4first described BPD as severe lung

injury resulting from mechanical ventilation and ox-ygen exposure. With improved prenatal and postna-tal care, preterm infants developing BPD now are generally very immature, and have antenatal and postnatal histories that differ from those of preterm infants in previous eras. The “new BPD,” as de-scribed by Jobe,5is characterized by an arrest of lung

development and interference with alveolarization. This more complex view of the pathogenesis of BPD includes prenatal lung inflammation in response to proinflammatory cytokine exposure in utero, to-gether with postnatal exposure to proinflammatory stimuli, such as ventilation and oxygen. Jobe5

postu-lates that these stimuli, together with glucocorticoid exposure and inadequate nutrition, can result in inhibition of alveolar and vascular development. Therein lies the irony: the postnatal dexamethasone (DXM) widely used for the treatment or prevention of BPD may suppress inflammation, but also may impair alveolarization and interfere with lung devel-opment.

Initial trials of DXM, a potent and long-acting glu-cocorticoid, in preterm infants with BPD showed short-term improvement in pulmonary function and weaning from the ventilator.6,7 Over time, with

in-creased survival of extremely premature infants, there has been a shift toward earlier use of DXM in newborns of lower and lower gestational ages.8,9The

plethora of trials conducted over the past 2 decades have recently been evaluated in 3 meta-analyses ac-cording to the onset of treatment: 1) early postnatal (⬍96 hours of life),10 2) moderately early postnatal

(7–14 days),11and 3) delayed (⬎3 weeks).12Although

moderately early treatment decreased mortality and

Received for publication Nov 17, 2000; accepted Dec 27 2000.

Address correspondence to Thierry Lacaze-Masmonteil, MD, PhD, Service de Pediatrie et Reanimation Neonatale, Hopital Antoine Beclere, 157, rue de la Porte de Trivaux 92141 Clamart Cedex France. E-mail: tlacaze@club-internet.fr

PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad-emy of Pediatrics.

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BPD, a number of significant short-term adverse ef-fects have been reported, including growth retarda-tion, hyperglycemia, hypertension, infecretarda-tion, hyper-trophic cardiomyopathy, gastrointestinal bleeding and intestinal perforation, regardless to the onset of treatment.10 –12

Of major new concern are the recent data suggest-ing an increased risk of adverse development of the central nervous system. The best currently available evidence recently has been summarized by Tarnow-Mordi and Mitra,13 who highlight the increasing

number of alarming clinical observations concerning the deleterious effects of postnatal corticosteroids in premature infants. Although experimental data indi-cated potential deleterious long-term effects of brain growth after postnatal steroids as early as in 1968,14

the first data showing adverse effects of DXM on neurodevelopmental outcome in the clinical setting were only published in 1998.8 Several subsequent

studies have reported an increased incidence of periventricular leukomalacia, neuromotor abnormal-ities, or cerebral palsy in infants treated early with DXM.9,15,16 The Vermont Oxford Network Steroid

Study Group trial was prematurely stopped because of adverse effects in the DXM treatment group, in-cluding a significantly higher incidence of periven-tricular leukomalacia.17Recently, the National

Insti-tute of Child Health and Human Developmental Neonatal Research Network2also reported that

post-natal steroid exposure was an independent risk fac-tor for neurodevelopmental impairment at 18 to 22 months adjusted age. Thus, although there are still very few follow-up studies, there are compelling experimental and clinical data warning us that ste-roids do have immediate and long-term effects on brain development.

Because of these data, DXM has become one of the most controversial medications in today’s neonatal intensive care units. Despite evidence of its adverse effects presented above, new DXM trials are still a matter of debate, using DXM at lower doses, intro-duced later and with long-term follow-up. Moreover, recent publications advocate the early use of DXM to treat disorders other than BPD in preterm in-fants.18,19 But what is the rationale for the exclusive

use of DXM for the treatment of BPD in preterm infants? The initial choice of this steroid appears to have been empirical, based on the fact that DXM is the most potent antiinflammatory steroid. On the other hand, DXM has a very long plasma half-life, compared with cortisol, and has been used for long treatment periods,16 at 8 to 10 times the physiologic

secretion of cortisol, in more and more premature infants with immature detoxification processes. In addition, DXM contains sulfites, which are poten-tially toxic to the developing brain.20 A number of

other steroids have been and are still used in diverse inflammatory and immune diseases in adults and children, such as acute graft rejection, nephrotic syn-drome, status asthmaticus, unresolving acute respi-ratory distress syndrome, and multiple sclerosis.21

Why then has BPD been considered apart from other inflammatory diseases in pediatric medicine? And why do neonatologists continue to use DXM to treat

BPD? The real question to answer may not be the right timing or the right dose of DXM, but rather the right molecule, as has been recently suggested with antenatal steroid therapy.22

Different corticosteroid molecules produce quite different clinical effects.23,24 The classical pathway

for glucocorticoid effects, through gene transcrip-tion, or genomic actranscrip-tion, is not the only one. These molecules also act through more rapid nongenomic actions, such as modifying cell membrane properties and decreasing cytosolic free calcium. These non-genomic effects become more prominent with higher doses, and the relative potencies of the various glu-cocorticoid molecules for these effects are quite dif-ferent from their relative potencies for genomic ac-tions. For example, DXM, which is 5 times more potent than methylprednisolone in its genomic activ-ity, is only 1.2 times as potent in its nongenomic activity. Thus, DXM is likely to have a very different side effect profile than methylprednisolone or pred-nisolone. One could also speculate that hydrocorti-sone may produce different effects because of its mineralocorticoid properties. Animal experiments investigating the neurotoxicity of glucocorticoids showed that exposure to high-dose DXM promoted neuronal apoptosis, and adrenal insufficiency accen-tuated this effect.25 However, pretreatment with

physiologic doses of corticosterone (the cortisol equivalent in the rat) was protective, because of its affinity for the mineralocorticoid receptor in the brain. These differential effects afford opportunities to obtain the benefits we seek while minimizing side effects by selecting the right glucocorticoid.

Because of the strong evidence for an inflamma-tory component in the pathogenesis of BPD, steroid treatment will be difficult to avoid. We have recently described 2 possible alternatives, one as a treatment to accelerate weaning from the ventilator, the other as a prophylactic therapy to prevent BPD. The first alternative is methylprednisolone, a glucocorticoid with a shorter half-life and a lower antiinflammatory activity than DXM, a negligible mineralocorticoid effect, and no sulfiting agents. Methylprednisolone has been safely used in various clinical conditions.21

Recently, the benefits and medium-term side effects of methylprednisolone were evaluated for the first time among 90 preterm infants (⬍30 week’s gesta-tion) at risk for BPD.26 In this study,

methylpred-nisolone was as effective as DXM in weaning from mechanical ventilation, with fewer side effects. Inter-estingly, the incidence of periventricular leukomala-cia was significantly lower among infants treated with methylprednisolone as compared with those treated with DXM. This open study had too few patients to draw any conclusion concerning the lower incidence of side effects. Therefore, a large randomized, controlled trial with assessment and comparison of long-term adverse effects on growth and development is needed.

More appealing is the use of low-dose hydrocorti-sone therapy early in life to prevent the development of BPD.27 This novel approach to the prevention of

BPD is based on work showing evidence of early adrenal insufficiency and increased lung

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tion in premature infants who subsequently develop BPD.28,29 To test the hypothesis that prevention of

this systemic insufficiency would improve outcome, a randomized, placebo-controlled pilot study of 40 extremely low birth weight infants was performed. Low-dose hydrocortisone treatment (1 mg/kg/day) during the first 2 weeks of life increased survival without BPD and improved other measures of respi-ratory and systemic outcome, without apparent in-crease in adverse effects.27 Again, this pilot study

was too small to draw conclusions about adverse effects; therefore, a multicenter trial with long-term follow-up is the required next step in the evaluation of this therapy.

In conclusion, steroids have shown benefit in re-ducing BPD, but DXM has been associated with an unacceptable adverse effect profile. Therefore, there is an urgent need for alternatives to the present ex-clusive use of DXM. Together with a better knowl-edge about the pharmacologic effects of steroids, which may have therapeutic impact in selecting the right molecule, we urgently need both additional basic research to understand which factors regulate alveolarization in the immature lung and new clini-cal trials to identify the “good” steroids (or at least better ones), to avoid the “bad” (DXM?), and to eliminate the “ugly” (early DXM?).

Bernard The´baud, MD, PhD*

Thierry Lacaze-Masmonteil, MD, PhD*

*Service de Pe´diatrie et de Re´animation Ne´onatale Hoˆpital Antoine Be´cle`re

Assistance Publique-Hoˆpitaux de Paris Universite´ Paris-Sud, France

Kristi Watterberg, MD‡

‡Department of Pediatrics Division of Neonatalogy

University of New Mexico School of Medicine Albuquerque, NM 87131

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2. Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and func-tional outcomes of extremely low birth weight infants in the Nafunc-tional Institute of Child Health and Human Developmental Neonatal Re-search Network, 1993–1994.Pediatrics.2000;105:1216 –1226

3. Perlman JM. White matter injury in the preterm infant: an important determination of abnormal neurodevelopment outcome. Early Hum Dev.1998;53:99 –120

4. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline membrane disease. Bronchopulmonary dysplasia.N Engl J Med.1967;276:357–368

5. Jobe A. The new BPD: an arrest of lung development. Pediatr Res.

1999;46:641– 643

6. Mammel MC, Green TP, Johnson DE, Thompson TR. Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia.

Lancet.1983;1:1356 –1358

7. Schick B, Goetzman BW. Corticosteroid response in chronic lung

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8. Yeh TF, Lin YJ, Huang CC, Chen YJ, Tsai WF, Lien YJ. Early dexameth-asone therapy in preterm infants: a follow-up study.Pediatrics.1998; 101(5). URh: http://www.pediatrics.org/cgi/content/full/101/5/e7 9. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone

treatment and increased incidence of cerebral palsy.Arch Dis Child Fetal Neonatal Educ.2000;83:F177–F181

10. Halliday HL, Ehrenkranz RA. Early postnatal (⬍96 hours) corticoste-roids for preventing chronic lung disease in preterm infants. In:

Cochrane Database Syst Rev.2000;2:CD001146

11. Halliday HL, Ehrenkranz RA. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. In:Cochrane Database Syst Rev.2000;2:CD001144

12. Halliday HL, Ehrenkranz RA. Delayed (⬎3 weeks) postnatal corticoste-roids for preventing chronic lung disease in preterm infants. In:

Cochrane Database Syst Rev.2000;2:CD001145

13. Tarnow-Mordi W, Mitra A. Postnatal dexamethasone in preterm in-fants. Is potentially life saving, but follow up studies are urgently needed.Br J Med.1999;319:1385–1386

14. Howard H. Reductions in size and total DNA of cerebrum and cerebel-lum in adult mice after corticosteroid treatment in infancy.Exp Neurol

1968;22:191–208

15. Baud O, Zupan V, Lacaze-Masmonteil T, Dehan M. Neurological ad-verse effects of early postnatal dexamethasone therapy in very preterm infants.Arch Dis Child.1999;80:F159. Letter

16. O’Shea TM, Kothadia J, 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

17. Soll RF. Early postnatal dexamethasone therapy for the prevention of chronic lung disease.Pediatr Res.1999;45:226A

18. Gaissmaier RE, Pohlandt F. Single-dose dexamethasone treatment of hypotension in preterm infants.J Pediatr.1999;134:701–5

19. Kopelman AE, Moise AA, Holbert D, Hegemier SE. A single very early dexamethasone dose improves respiratory and cardiovascular adapta-tion in preterm infants.J Pediatr.1999;135:345–350

20. Reist M, Marshall KA, Jenner P, Halliwell B. Toxic effects of sulfite in combination with peroxynitrite on neuronal cells.J Neurochem.1998;71: 2431–2438

21. Haynes RC. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of adrenocortical steroid biosynthesis. In:Goodman & Gilman’s The Pharmacological Basis of Therapeutics.New York, NY: Macmillan Publishing Co; 1992;1431–1462

22. Baud O, Foix-L’Helias L, Kaminski M, et al. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants.N Engl J Med.1999;341:1190 –1196

23. Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revis-ited.Arthritis Rheum.1998;41:761–767

24. Lipworth BJ. Therapeutic implications of non-genomic glucocorticoid activity.Lancet.2000;356:87– 89

25. Almeida OFX, Conde GL, Chrochemore C, et al. Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticoste-roid receptors decide neuronal fate.FASEB J.14:779 –790, 2000 26. Andre´ P, The´baud B, Odie`vre MH, et al. Methylprednisolone, an

alter-native to dexamethasone in very premature infants at risk for chronic lung disease.Intensive Care Med.2000;26:1496 –1500

27. Watterberg KL, Gerdes JS, Gifford KL, Lin H-M. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants.Pediatrics.1999;104:1258 –1263

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29. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dys-plasia develops.Pediatrics.1996;97:210 –215

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DOI: 10.1542/peds.107.2.413

2001;107;413

Pediatrics

Bernard Thébaud, Thierry Lacaze-Masmonteil and Kristi Watterberg

Ugly''?

Postnatal Glucocorticoids in Very Preterm Infants: ''The Good, the Bad, and the

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DOI: 10.1542/peds.107.2.413

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Postnatal Glucocorticoids in Very Preterm Infants: ''The Good, the Bad, and the

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