PEDIATRICS Vol. 107 No. 2 February 2001, pp. 413-415

COMMENTARY:
Postnatal Glucocorticoids in Very Preterm Infants: "The Good, the Bad, and the Ugly"?

Premature 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 increased 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 infants and results in increased health care costs, prolonged hospital stays with frequent rehospitalizations, and deleterious effects on subsequent growth and neurodevelopment.² Periventricular leukomalacia, the most severe form of white matter brain damage, 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 al⁴ first described BPD as severe lung injury resulting from mechanical ventilation and oxygen exposure. With improved prenatal and postnatal 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 described by Jobe,⁵ is 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, together with postnatal exposure to proinflammatory stimuli, such as ventilation and oxygen. Jobe⁵ postulates 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 development.

Initial trials of DXM, a potent and long-acting glucocorticoid, in preterm infants with BPD showed short-term improvement in pulmonary function and weaning from the ventilator.^6,7 Over time, with increased survival of extremely premature infants, there has been a shift toward earlier use of DXM in newborns of lower and lower gestational ages.^8,9 The plethora of trials conducted over the past 2 decades have recently been evaluated in 3 meta-analyses according to the onset of treatment: 1) early postnatal (<96 hours of life),¹⁰ 2) moderately early postnatal (7-14 days),¹¹ and 3) delayed (>3 weeks).¹² Although moderately early treatment decreased mortality and BPD, a number of significant short-term adverse effects have been reported, including growth retardation, hyperglycemia, hypertension, infection, hypertrophic cardiomyopathy, gastrointestinal bleeding and intestinal perforation, regardless to the onset of treatment.^10-12

Of major new concern are the recent data suggesting 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 indicated 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 abnormalities, 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, including a significantly higher incidence of periventricular leukomalacia.¹⁷ Recently, the National Institute of Child Health and Human Developmental Neonatal Research Network² also reported that postnatal steroid exposure was an independent risk factor 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 steroids 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, introduced later and with long-term follow-up. Moreover, recent publications advocate the early use of DXM to treat disorders other than BPD in preterm infants.^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 potentially 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 syndrome, status asthmaticus, unresolving acute respiratory 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 transcription, or genomic action, 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 nongenomic effects become more prominent with higher doses, and the relative potencies of the various glucocorticoid molecules for these effects are quite different from their relative potencies for genomic actions. For example, DXM, which is 5 times more potent than methylprednisolone in its genomic activity, 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 prednisolone. One could also speculate that hydrocortisone 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 accentuated 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 inflammatory 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 gestation) at risk for BPD.²⁶ In this study, methylprednisolone was as effective as DXM in weaning from mechanical ventilation, with fewer side effects. Interestingly, the incidence of periventricular leukomalacia 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 hydrocortisone 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 inflammation 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 respiratory and systemic outcome, without apparent increase 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 reducing BPD, but DXM has been associated with an unacceptable adverse effect profile. Therefore, there is an urgent need for alternatives to the present exclusive use of DXM. Together with a better knowledge 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 clinical trials to identify the "good" steroids (or at least better ones), to avoid the "bad" (DXM?), and to eliminate the "ugly" (early DXM?).

Bernard Thébaud
Thierry Lacaze-Masmonteil
^* Service de Pédiatrie et de Réanimation Néonatale
Hôpital Antoine Béclère
Assistance Publique-Hôpitaux de Paris
Université Paris-Sud, France

Kristi Watterberg
 Department of Pediatrics
Division of Neonatalogy
University of New Mexico School of Medicine
Albuquerque, NM 87131, USA

FOOTNOTES

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{at}club-internet.fr

ABBREVIATIONS

BPD, bronchopulmonary dysplasia; DXM, dexamethasone.

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