Postnatal steroids: Short-term gain, long-term pain?
2000; Elsevier BV; Volume: 137; Issue: 1 Linguagem: Inglês
10.1067/mpd.2000.107799
ISSN1097-6833
AutoresNeil N. Finer, Alissa Craft, Yvonne E. Vaucher, Reese H. Clark, Augusto Sola,
Tópico(s)Congenital Diaphragmatic Hernia Studies
ResumoSee editorial, p. 1. Liggins and Howie1Liggins GC Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.Pediatrics. 1972; 50: 515-525PubMed Google Scholar published the first study demonstrating the value of maternal antenatal steroids in 1972, reporting decreased mortality and morbidity rates in preterm infants. Subsequently, many randomized trials have confirmed the benefit of prenatal steroids in reducing the mortality rate, decreasing the incidence of respiratory distress syndrome and intraventricular hemorrhage, and improving long-term neurodevelopmental outcome of prematurely born neonates.2Crowley P Chalmers I Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials.Br J Obstet Gynaecol. 1990; 97: 133Crossref Scopus (718) Google Scholar, 3Consensus Development Panel Effect of corticosteroids for fetal maturation on perinatal outcomes. National Institutes of Health Conference Statement. 12(2). : US Dept of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda (MD)Feb 28-Mar 2, 1994Google Scholar, 4Rennie JM Wheater M Cole TJ. Antenatal steroid administration is associated with an improved chance of intact survival in preterm infants.Eur J Pediatr. 1996; 155: 576-579Crossref PubMed Scopus (31) Google Scholar, 5Crowley P. Prophylactic corticosteroids for preterm birth [Cochrane Review].The Cochrane Library. Issue 4. : Update Software, Oxford1999Google Scholar Recently, antenatal steroids have been shown to reduce the incidence of periventricular leukomalacia and ventriculomegaly6Leviton A Dammann O Allred EN Kuban K Pagano M VanMarter L et al.Antenatal corticosteroids and cranial ultrasonographic abnormalities.Am J Obstet Gynecol. 1999; 181: 1007-1017Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and improve long-term health.7Salokorpi T Sajaniemi N Hallback H Kari A Rita H von Wendt L. Randomized study of the effect of antenatal dexamethasone on growth and development of premature children at the corrected age of 2 years.Acta Pediatr. 1997; 86: 294-298Crossref PubMed Scopus (58) Google Scholar The first study of postnatal steroids in the preterm infant was published approximately 16 years before the initial reports of prenatal steroids and evaluated postnatal corticosteroids in 32 infants of diabetic mothers. Haddad et al8Haddad H Hsia D Gellis S. Studies on respiratory rate in the newborn. Its use in the evaluation of RDS in IDM.Pediatrics. 1956; 17: 204-212PubMed Google Scholar reported that there was no significant reduction in the incidence and severity of RDS. Altman9Altman H. The respiratory distress syndrome in the newborn.S Afr Med J. 1965; 39: 746-748PubMed Google Scholar suggested a benefit for such treatment in infants with moderate to severe distress in 1965, but the first controlled evaluation was performed by Baden et al10Baden M Bauer CR Colle E Klein G Taeusch Jr, HWW Stern L. A controlled trial of hydrocortisone therapy in infants with RDS.Pediatr. 1972; 50: 526-534PubMed Google Scholar in 1972. This study was a blinded comparison of 12.5 mg/kg hydrocortisone versus placebo given at admission and 12 hours later in 44 premature infants with RDS, and no significant benefit was found for steroid administration. In the same year Ewerbeck and Helwig11Ewerbech H Helwig H. Treatment of idiopathic respiratory distress with large doses of corticoids.Pediatrics. 1972; 49: 467-468PubMed Google Scholar reported on the outcome of 10 infants with severe RDS who were treated with prednisolone; 5 died, 3 of whom had autopsy evidence of massive intraventricular hemorrhage. Approximately 10 years later, several further studies were conducted, which suggested that postnatal steroids were associated with a reduced duration of oxygen requirements and mechanical ventilation and a worrisome increased risk of infection.12Mammel MC Green TP Johnson DE Thompson TR. Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia.Lancet. 1983; 1: 1356-1358Abstract PubMed Scopus (232) Google Scholar, 13Avery GB Fletcher AB Kaplan M Brudno DS. Controlled trial of dexamethasone in respirator dependent infants with bronchopulmonary dysplasia.Pediatrics. 1985; 75: 106-111PubMed Google Scholar Over the past 10 years, a plethora of studies have evaluated the effects of postnatal steroids.14Bhuta 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-F33Crossref PubMed Scopus (123) Google Scholar, 15Halliday HL. Clinical trials of postnatal corticosteroids: inhaled and systemic.Biol Neonate. 1999; 76: 29-40Crossref PubMed Scopus (91) Google Scholar Most have used intravenous dexamethasone at pharmacologic doses and measured the incidence and severity of chronic lung disease in low birth weight infants as the primary outcome variable. Therapy has been started as early as 2 hours of age and as late as 30 days of age. Secondary outcomes that have been commonly reported include duration of hospitalization and respiratory support and the incidences of sepsis, hypertension, hyperglycemia, retinopathy of prematurity, and necrotizing enterocolitis. A meta-analysis of 4 studies on the early (<36 hours of age) use of dexamethasone and 6 studies in which treatment was initiated between 7 and 14 days of life showed a reduction in the mortality rate in the 7- to 14-day-old group.14Bhuta 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-F33Crossref PubMed Scopus (123) Google Scholar A subsequent review of 39 prospective randomized trials revealed that systemic steroid use improved gas exchange and lung mechanics and shortened the duration of mechanical ventilation in neonates who were ventilator-dependent.15Halliday HL. Clinical trials of postnatal corticosteroids: inhaled and systemic.Biol Neonate. 1999; 76: 29-40Crossref PubMed Scopus (91) Google Scholar This meta-analysis also showed that steroids given between 7 and 14 days reduced neonatal mortality rates with one extra survivor for approximately every 16 babies treated (95% CI, 9-55). A more recent meta-analysis evaluated the early (<96 hours of age) use of postnatal steroids and reported that the results of these 11 trials demonstrated that early postnatal steroids were associated with earlier extubation, a decreased risk of CLD at 28 days and 36 weeks, decreased death or CLD at 28 days, and a decreased incidence of patent ductus arteriosus.16Halliday HL Ehrenkranz RA Early postnatal ( 3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants [Cochrane Review].in: The Cochrane Library, Issue 4. : Update Software, Oxford1999Google Scholar These reviews were unable to evaluate the longer-term neurodevelopmental outcome of the infants included in these trials, because such information was not available to the reviewers. Nevertheless, their conclusion was that more research was needed before such therapy could be recommended as routine for ventilatordependent infants. As a result of these observations, we have become seduced by the siren song of postnatal steroids. A 1993 survey of 483 neonatologists in the United States regarding the use of postnatal steroids revealed that 95% of these practitioners used steroids in premature infants at risk for CLD.19Bull D Wakeley A Sola A. Current use of steroids in newborns with lung disease: results of a national survey [abstract].Clin Res. 1993; 41: 89AGoogle Scholar Currently, over 50% of extremely low birth weight infants are likely to receive this medication during their stay in the neonatal unit. A review of the Vermont Oxford Network Summary Reports for 1997 and 1998 indicates that postnatal steroids are given to 57% (range, 39%-71%) of infants with a birth weight between 501 and 750 g.20Vermont Oxford Network 1997 Database Summary. : Vermont Oxford Network, Burlington (VT)1998Google Scholar This frequency exceeds that of a complete course of antenatal steroids for the same population (49%-50% for 1997 and 1998; interquartile range, 36% to 64%).21Vermont Oxford Network 1998 Database Summary. : Vermont Oxford Network, Burlington (VT)1999Google Scholar Similarly, a recent study from the National Institute of Child Health and Development Neonatal Network has reported that postnatal steroid use, 49% (range, 27%-64%), exceeded antenatal steroid use, 39% (range 16%-61%), in extremely low birth weight infants cared for in these units.22Vohr BR Wright LL Poole K Effects of site differences at 12 participating NICHD centers on 18 month outcomes of extremely low birth weight (ELBW) < 1000gm infants—The NICHD Neonatal Research Outcome Study [abstract].Pediatr Res. 1999; 45: 258ACrossref Google Scholar There is emerging evidence that postnatal steroids are associated with both increased short-term neonatal complications and long-term adverse effects. At least 2 large prospective trials of postnatal steroids have been terminated because of short-term adverse events, including gastrointestinal hemorrhage and intestinal perforation requiring surgery.23Stark AR Carlo W Bauer C Donovan E Oh W Papile L et al.Complications of early steroid therapy in a randomized controlled trial [abstract].Pediatrics. 1999; 104: 739AGoogle Scholar, 24Soll RF for the Vermont Oxford Network Steroid Study Group Early postnatal dexamethasone therapy for the prevention of chronic lung disease [abstract].Pediatr Res. 1999; 42: 123AGoogle Scholar Other prospective trials have also reported a high incidence of intestinal perforation in dexamethasone-treated infants.25Garland JS Alex CP Pauly TH Whitehead VL Brand J Winston JF et al.A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial.Pediatrics. 1999; 104: 91-99Crossref PubMed Scopus (129) Google Scholar Papile et al26Papile LA Tyson JE Stoll BJ Wright LL Donovan EF Bauer CR et al.A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants.N Engl J Med. 1998; 338: 1112-1118Crossref PubMed Scopus (143) Google Scholar, 27Stoll BJ Temprosa M Tyson JE Papile L Wright LL Bauer CR et al.Dexamethasone therapy increases infection in very low birth weight infants.Pediatrics [serial online]. 1999; 104 (Available from)http://www.pediatrics.org/cgi/content/full/104/5/e63Google Scholar reported that dexamethasone treatment, starting at 2 weeks of age, was associated with an increase in nosocomial sepsis, meningitis, and hyperglycemia; whereas later treatment, at 4 weeks of age, was associated with hypertension. Dexamethasone therapy, in premature infants, has also been associated with hypertriglyceridemia in the presence of hyperinsulinemia and increased free fatty acid levels.28Amin SB Sinkin RA McDermott MP Kendig JW. Lipid intolerance in neonates receiving dexamethasone for bronchopulmonary dysplasia.Arch Pediatr Adolesc Med. 1999; 153: 795-800Crossref PubMed Scopus (17) Google Scholar Dexamethasone therapy can result in pituitary–adrenal suppression,29Rizvi ZB Aniol HS Myers TF Zeller WP Fisher SG Anderson CL. Effects of dexamethasone on the hypothalamic-pituitary-adrenal axis in preterm infants.J Pediatr. 1992; 120: 961-965Abstract Full Text PDF PubMed Scopus (48) Google Scholar which can last for 1 month after therapy,30Ng PC Blackburn ME Brownlee KG Buckler JM Dear PRF. Adrenal response in very low birthweight babies after dexamethasone treatment for bronchopulmonary dysplasia.Arch Dis Child. 1989; 64: 1721-1726Crossref PubMed Scopus (31) Google Scholar, 31Kari MA Heinonen K Ikonen RS Koivisto M Raivio KO. Dexamethasone treatment in preterm infants at risk for bronchopulmonary dysplasia.Arch Dis Child. 1993; 68: 566-569Crossref PubMed Scopus (74) Google Scholar an effect also noted with inhaled steroid administration.32Cole CH Shah B Abbasi S Demissie S MacKinnon B Colton T et al.Adrenal function in premature infants during inhaled beclomethasone therapy.J Pediatr. 1999; 135: 65-70Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Dexamethasone increases protein catabolism and prevents adequate growth.33Leitch CA Ahlrichs J Karn C Denne SC. Energy expenditure and energy intake during dexamethasone therapy for chronic lung disease.Pediatr Res. 1999; 46: 109-113Crossref PubMed Scopus (49) Google Scholar, 34Berry MA Abrahamowicz M Usher RH. Factors associated with growth of extremely premature infants during initial hospitalization.Pediatrics. 1997; 100: 640-646Crossref PubMed Scopus (36) Google Scholar This is especially true in neonates with reduced levels of insulin growth factor and its binding protein levels.35Van Goudoever JB Wattimena JDL Carnielli VP Sulkers EJ Degenhart HJ Sauer PJJ. Effect of dexamethasone on protein metabolism in infants with bronchopulmonary dysplasia.J Pediatr. 1994; 124: 112-118Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar A recent study from Italy has demonstrated poor weight gain and poor head growth during postnatal treatment courses of dexamethasone started at 7 or 10 days of life. That study also reported cardiac hypertrophy in over 50% of the treated infants,36Romagnoli C Zecca E Vento G Maggio L Papacci P Tortorolo G Effect on growth of two different dexamethasone courses for preterm infants at risk of chronic lung disease—a randomized trial.Pharmacology. 1999; 59: 266-274Crossref PubMed Scopus (33) Google Scholar a previously described complication of postnatal dexamethasone treatment.37Mirandamallea J Perezverdu J Gascolacalle B Saezpalacios JM Fernandezgilino C Izquierdomacian I. Hypertrophic cardiomyopathy in preterm infants treated with dexamethasone.Eur J Pediatr. 1997; 156: 394-396Crossref PubMed Scopus (12) Google Scholar Papile et al26Papile LA Tyson JE Stoll BJ Wright LL Donovan EF Bauer CR et al.A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants.N Engl J Med. 1998; 338: 1112-1118Crossref PubMed Scopus (143) Google Scholar also reported a very significant decrease in both somatic and head growth in dexamethasone-treated infants (P <.001). These observations are particularly worrisome because a head circumference <3% at 4 months, 8 months, and 12 months and head growth velocity of ≤10% from birth to 4 months have been associated with low cognitive ability at 6 years.38Stathis SL O'Callaghan M Harvey J Rogers Y Head circumference in ELBW babies is associated with learning difficulties and cognition but not ADHD in the school aged child.Dev Med Child Neurol. 1999; 41: 375-380Crossref PubMed Scopus (69) Google Scholar Very few of the published trials have been designed to evaluate long-term follow-up. At present, detailed follow-up has been presented from only 2 prospective randomized trials published before 1999. Fitzhardinge et al39Fitzhardinge PM Eisen A Lejtenyi C Metrakos K Ramsay M. Sequelae of early steroid administration to the newborn infant.Pediatrics. 1974; 53: 877-883PubMed Google Scholar reported on the follow-up of 24 of the infants in the trial of Baden et al.10Baden M Bauer CR Colle E Klein G Taeusch Jr, HWW Stern L. A controlled trial of hydrocortisone therapy in infants with RDS.Pediatr. 1972; 50: 526-534PubMed Google Scholar They reported that the infants who received steroids tended to have a slightly increased incidence of gross neurologic and electroencephalographic abnormalities and lowered gross motor development at 1 year of age. Ewerbeck and Helwig11Ewerbech H Helwig H. Treatment of idiopathic respiratory distress with large doses of corticoids.Pediatrics. 1972; 49: 467-468PubMed Google Scholar noted that 4 of their 5 survivors had mild neurologic deficits. Yeh et al40Yeh TF Lin YJ Huang CC Chen YJ Lin CH Lin HC et al.Early dexamethasone therapy in preterm infants: a follow-up study.Pediatrics. 1998; 101: E71-E78Crossref Scopus (364) Google Scholar reported that infants who received dexamethasone during the neonatal period had a higher incidence of neuromotor dysfunction and lower psychomotor developmental index scores at 2 years of age. A significant handicap, defined as severe neurologic defect and/or intellectual defect (mental developmental index and/or psychomotor developmental index ≤69), was seen in 31.4% of the control group and 41.2% of the dexamethasone-treated group. In 1999, at least 11 studies evaluated the use of postnatal dexamethasone in ventilated preterm infants.25Garland JS Alex CP Pauly TH Whitehead VL Brand J Winston JF et al.A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial.Pediatrics. 1999; 104: 91-99Crossref PubMed Scopus (129) Google Scholar, 36Romagnoli C Zecca E Vento G Maggio L Papacci P Tortorolo G Effect on growth of two different dexamethasone courses for preterm infants at risk of chronic lung disease—a randomized trial.Pharmacology. 1999; 59: 266-274Crossref PubMed Scopus (33) Google Scholar, 41Merz U Peschgens T Kusenbach G Hornchen H. Early versus late dexamethasone treatment in preterm infants at risk for chronic lung disease: a randomized pilot study.Eur J Pediatr. 1999; 158: 318-322Crossref PubMed Scopus (27) Google Scholar, 42Fok TF Lam K Dolovich M Ng PC Wong W Cheung KL et al.Randomised controlled study of early use of inhaled corticosteroid in preterm infants with respiratory distress syndrome.Arch Dis Child. 1999; 80: F203-F208Crossref Scopus (49) Google Scholar, 43Tsukahara H Watanabe Y Yasutomi M Kobata R Tamura S Kimura K et al.Early (4-7 days of age) dexamethasone therapy for prevention of chronic lung disease in preterm infants.Biol Neonate. 1999; 76: 283-290Crossref PubMed Scopus (21) Google Scholar, 44Cole CH Colton T Shah BL Abbasi S MacKinnon BL Demissie S et al.Early inhaled glucocorticoid therapy to prevent bronchopulmonary dysplasia.N Engl J Med. 1999; 340: 1005-1010Crossref PubMed Scopus (138) Google Scholar, 45Merz U Kusenbach G Hausler M Peschgens T Hornchen H. Inhaled budesonide in ventilator-dependent preterm infants: a randomized, double-blind pilot study.Biol Neonate. 1999; 75: 46-53Crossref PubMed Scopus (35) Google Scholar, 46Kopelman AE Moise AA Holbert D Hegemier SE. A single very early dexamethasone dose improves respiratory and cardiovascular adaptation in preterm infants.J Pediatr. 1999; 135: 345-350Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 47O'Shea T Kothadia J Klinepeter K Goldstein DJ Jackson BG Weaver III, RG 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: 15-21Crossref PubMed Scopus (307) Google Scholar, 48Baud O Zupan V Lacaze-Masmonteil T Dehan M. Neurological adverse effects of early postnatal dexamethasone in very preterm infants [letter, comment].Arch Dis Child Fetal Neonatal Ed. 1999; 80: F159Crossref PubMed Google Scholar, 49Watterberg KL Gerdes JS Gifford KL Lin HM. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants.Pediatrics. 1999; 104: 1258-1263Crossref PubMed Scopus (216) Google Scholar However, in the only study that reported long-term neurodevelopmental outcomes, O'Shea et al47O'Shea T Kothadia J Klinepeter K Goldstein DJ Jackson BG Weaver III, RG 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: 15-21Crossref PubMed Scopus (307) Google Scholar confirmed the observations of Yeh et al40Yeh TF Lin YJ Huang CC Chen YJ Lin CH Lin HC et al.Early dexamethasone therapy in preterm infants: a follow-up study.Pediatrics. 1998; 101: E71-E78Crossref Scopus (364) Google Scholar and showed that more of the dexamethasone-treated infants had cerebral palsy (25% vs 7%) and abnormal neurologic examination findings than control infants (45% vs 16%). At the recent Hot Topics meeting in Washington, DC, Shinwell et al50Shinwell ES Karplus M Zamora E Reich D Rothschild A Blazer S et al.Failure of early postnatal dexamethasone to prevent chronic lung disease in infants with respiratory distress syndrome.Arch Dis Child Fetal Neonatal Ed. 1996; 74: F33-F37Crossref PubMed Google Scholar presented the follow-up results of surviving infants enrolled in a randomized, placebo-controlled trial of a 3-day course of postnatal dexamethasone, beginning at 12 hours of age, which was conducted in Israel. They presented information for 159 of their 190 survivors (83.6%) and reported that the incidence of cerebral palsy was significantly higher in the dexamethasone-treated infants (39/80, 49% treated vs 12/79, 15% control; odds ratio = 4.62 [2.38, 8.98]), an association that persisted after adjustment for confounders.51Shinwell ES, Karplus M, Reich D, Weintraub Z, Blazer S, Bader D, et al. Early postnatal dexamethasone therapy is associated with increased incidence of cerebral palsy. Presented at Hot Topics '99 in Neonatology; December 6, 1999; Washington, DC.Google Scholar In addition, significantly fewer dexamethasone-treated infants had normal development at 2 to 6 years of age (36/80, 45% vs 56/79, 71%). A brief meta-analysis of the follow-up results of these 3 studies reveals a significantly increased OR for the occurrence of cerebral palsy or an abnormal neurologic examination finding (OR = 4.86, 95% CI 2.73, 8.65, OR = 3.88, 95% CI 2.42, 6.23). These results suggest that for every 3 to 4 surviving treated infants, one infant would experience an adverse neurodevelopmental outcome. Another recent brief communication reported a significantly higher incidence of periventricular leukomalacia in neonates treated with steroids as compared with control infants after controlling for gestational age (23% vs 9%).41Merz U Peschgens T Kusenbach G Hornchen H. Early versus late dexamethasone treatment in preterm infants at risk for chronic lung disease: a randomized pilot study.Eur J Pediatr. 1999; 158: 318-322Crossref PubMed Scopus (27) Google Scholar There is biologic plausibility for these observations. As early as 1968, Howard52Howard H. Reductions in size and total DNA of cerebrum and cerebellum in adult mice after corticosterone treatment in infancy.Exp Neurol. 1968; 22: 191-208Crossref PubMed Scopus (132) Google Scholar showed that corticosterone, given between 2 and 14 days of age in mice, interfered with the synthesis of DNA, RNA, and protein in the brain and produced an irreversible reduction in brain size, weight, and cell numbers that endured for virtually the entire life span. Dexamethasone treatment with doses similar to those used in clinical trials not only significantly inhibits brain and body growth but also lowers plasma osteocalcin, urinary N-telopeptide, and whole-body and femur bone mineral density, compared with control values.53Ohtsu N Ariagno RL Sweeney TE Davis L Moses L Petriceks R. The effect of dexamethasone on chronic pulmonary oxygen toxicity in infant mice.Pediatr Res. 1989; 25: 353-359Crossref PubMed Scopus (11) Google Scholar, 54Weiler HA Wang Z Atkinson SA. Whole body lean mass is altered by dexamethasone treatment through reductions in protein and energy utilization in piglets.Biol Neonate. 1997; 71: 53-59Crossref PubMed Scopus (42) Google Scholar, 55Ward WE Donovan SM Atkinson SA. Dexamethasone-induced abnormalities in growth and bone metabolism in piglets are partially attenuated by growth hormone with no synergistic effect of insulin-like growth factor-I.Pediatr Res. 1998; 44: 215-221Crossref PubMed Scopus (20) Google Scholar In animal studies dexamethasone decreased intestinal growth through increased degradation and decreased synthesis of protein.56Burrin DG Wester TJ Davis TA Fiorotto ML Chang XY. Dexamethasone inhibits small intestinal growth via increased protein catabolism in neonatal pigs.Am J Physiol Endocr Metab. 1999; 39: E269-E277Google Scholar Dexamethasone significantly decreased the number of surviving motoneurons after nerve transection57Prodanov D Mantchev G Iliev A Traykov V Yakimova K Kaneva R et al.Effects of dexamethasone in rat neonatal model of axotomy-induced motoneuronal cell death.Arch Physiol Biochem. 1998; 106: 355-361Crossref PubMed Scopus (13) Google Scholar and aggravated ischemic brain damage after carotid artery occlusion in rats.58Tsubota S Adachi N Chen J Yorozuya T Nagaro T Arai T. Dexamethasone changes brain monoamine metabolism and aggravates ischemic neuronal damage in rats.Anesthesiology. 1999; 90: 515-523Crossref PubMed Scopus (46) Google Scholar Glucocorticoids administered during critical periods of brain development may impair myelinization and brain cell division and result in longer-term behavioral effects.59Weichsel ME. The therapeutic use of glucocorticoid hormones in the perinatal period. Potential neurological hazards.Ann Neurol. 1977; 46: 364-366Crossref Scopus (93) Google Scholar Single doses of dexamethasone on day 4 or 7, in rats, were associated with subsequent impairment of spatial learning,60Vicedomini JP Nonneman AJ DeKosky ST Scheff SW. Perinatal glucocorticoids disrupt learning: a sexually dimorphic response.Physiol Behav. 1986; 36: 145-149Crossref PubMed Scopus (51) Google Scholar deficits in motor coordination, behavioral deviations, and reduced cerebellar weights.61Benesova O Pavlik A. Perinatal treatment with glucocorticoids and the risk of maldevelopment of the brain.Neuropharmacology. 1989; 28: 89-97Crossref PubMed Scopus (110) Google Scholar The balance of evidence for the use of postnatal steroids has shifted from short-term gain to both short- and long-term pain. We believe there is inadequate evidence to support the current widespread use of postnatal steroids, especially dexamethasone, in low birth weight neonates. Our well-intended zeal for the use of postnatal steroids to reduce the early mortality rate, eradicate CLD, and decrease ventilator dependence has produced significant unintended consequences including intestinal perforation, poor growth, and an increased risk of cerebral palsy. It is now time to reconsider and curtail our current clinical practices until such time as appropriate studies demonstrate acceptable short- and long-term benefit without unacceptable harm. We believe it is also appropriate to suggest a moratorium on further studies of systemic or inhaled postnatal steroids in premature neonates unless they are well designed, adequately powered, and include an evaluation of neurodevelopmental outcome as a primary end point. Such studies should determine the timing and duration of the lowest effective dose of the least toxic glucocorticoid preparation49Watterberg KL Gerdes JS Gifford KL Lin HM. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants.Pediatrics. 1999; 104: 1258-1263Crossref PubMed Scopus (216) Google Scholar, 62Baud O Foix-L'Helias L Kaminski M Audibert F Jarreau PH Papiernik E et al.Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants.N Engl J Med. 1999; 341: 1190-1196Crossref PubMed Scopus (371) Google Scholar that reduces the incidence of CLD, ventilator dependence, and oxygen exposure while minimizing adverse effects. All such studies should be mandated and funded to evaluate long-term neurodevelopmental outcome and somatic growth. Only clinical trials that meet these minimal criteria should receive institutional review board approval and local or national funding. In addition, we need to modify our early approach to the respiratory support of the extremely low birth weight infant and pay more attention to the lessons of the past.63Avery ME Tooley WH Keller JB Hurd SS Bryan H Cotton RB. Is chronic lung disease in low birth weight infants preventable? A survey of eight centers.Pediatrics. 1987; 79: 26-30PubMed Google Scholar We need to use less invasive modes, including early continuous positive airway pressure and shorter durations of intubation for surfactant delivery,64Verder H Albertson P Ebbesen F Greisen G Robertson B Bertelsen A et al.Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks' gestation.Pediatrics. 1999; 103: E241-E246Crossref Scopus (331) Google Scholar, 65Lindner W Vossbeck S Hummler H Pohlandt F. Delivery room management of extremely low birth weight infants: Spontaneous breathing or intubation?.Pediatrics. 1999; 103: 961-967Crossref PubMed Scopus (272) Google Scholar in an effort to remove the stimulus for the consideration of postnatal steroid treatment. The continued prescription of postnatal steroids in the absence of adequate evidence of their ultimate benefit could undermine the substantial progress that has been made in the care of our most fragile infants. "Life can only be understood backwards, but it must be lived forwards."Soren Kierkegaard (1813-1855) Glucocorticoids in perinatal medicine: Misguided rockets?The Journal of PediatricsVol. 137Issue 1PreviewSee related article, p. 9. Full-Text PDF
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