Glucocorticoids in perinatal medicine: Misguided rockets?
2000; Elsevier BV; Volume: 137; Issue: 1 Linguagem: Inglês
10.1067/mpd.2000.107801
ISSN1097-6833
Autores Tópico(s)Infant Development and Preterm Care
ResumoSee related article, p. 9.Once the rockets are up, who cares where they come down? 'That's not my department,' says Wernher von Braun.Tom Lehrer as quoted by W. A. Silverman (page 5 )1Silverman WA Where is the evidence?.in: Debates in modern medicine. : Oxford University Press, Oxford1998Google ScholarGlucocorticoids are one of the most potent classes of drugs used in perinatal medicine. Neonatologists like results, and glucocorticoids have immediate physiologic effects on lung function of preterm infants, which are clinically apparent (even to parents) and demonstrable in clinical trials.2Halliday HL Clinical trials of postnatal corticosteroids: inhaled and systemic.Biol Neonate. 1999; 76: 29-40Crossref PubMed Scopus (91) Google Scholar They get the rockets up. Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar summarize recent information indicating that there are significant short-term (days to weeks) and long-term (1 to 2 years) adverse effects that should make us seriously question where and how the rockets come down. The problem with integrating the information from the multiple clinical trials into a consensus recommendation for clinical practice results from 2 overlapping factors. Glucocorticoid treatment effects (beneficial or adverse) are perhaps as sensitive to dose and duration of treatment as any class of pharmacologic agents, and the very preterm infant is at a developmental stage that may be particularly susceptible to glucocorticoid effects.4Jobe AH Ikegami M Lung development and function in preterm infants in the surfactant treatment era.Annu Rev Physiol. 2000; 62: 825-846Crossref PubMed Scopus (158) Google Scholar Those effects likely are secondarily modified by common superimposed events in the preterm infant such as antenatal or postnatal proinflammation or infection and catabolic state. Most clinical trials have used high-dose dexamethasone (acute asthma doses) that were weaned over periods as long as 42 days. Infants have been treated early (<72 hours) in attempts to prevent chronic lung disease, and infants have been treated later (7 to 28 days) in attempts to minimize progression of chronic lung disease. The trials in aggregate provide little guidance on dose, when to initiate treatment, or duration of treatment. Almost any treatment schedule imaginable has been tried, but few have heeded the general guidelines to initially try the lowest possible doses of glucocorticoids to achieve a therapeutic effect.5Schimmer BP Parker KL Adrenocorticotropic hormone. Adrenocortical steroids and their synthetic analogs: inhibitors of the synthesis and actions of adrenocortical hormones.in: The pharmacological basis of therapeutics. : McGraw-Hill, New York1996: 1459-1485Google ScholarIf one chooses to use glucocorticoids, it seems to me that there should be a clear short-term clinical goal (perhaps extubation), and if that goal is not achieved within 3 to 4 days, then therapy should be stopped. Furthermore, the "standard" initial dose of 0.5 mg/kg/d (equivalent to 12 mg of cortisol) is very high relative to the 24-hour basal production rate of about 0.5 mg cortisol for a preterm infant weighing 1 kg and a stress production rate of perhaps 1.5 mg/d. The recently terminated National Institute Child Health and Human Development trial used an initial dose of 0.15 mg/kg/d dexamethasone and found an increased incidence of gastrointestinal perforations, demonstrating complications at lower doses.6Stark AF Carlo W Bauer C Complications of early steroid therapy in a randomized controlled trial [abstract].Pediatrics. 1999; 104: 739AGoogle Scholar Initial doses of 0.1 to 0.2 mg/kg/d dexamethasone should be sufficient and may be too high. Watterberg et al7Watterberg 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 (221) Google Scholar recently reported in a small trial that 1 mg of hydrocortisone per day, begun at <48 hours of age and continued for 9 days followed by 0.5 mg of hydrocortisone per day for 3 days, increased survival without supplemental oxygen at 36 weeks' postconceptional age. This strategy is based on the frequent occurrence of low plasma cortisol values in very low birth weight infants (adrenal insufficiency?). The issue of minimal effective dose is ripe for more clinical research.What should be the criteria for good targeting of where the rockets come down? Short-term benefits can be important, and a decreased mortality rate for infants when treatment was initiated between 7 and 21 days has been demonstrated by meta-analysis.2Halliday HL Clinical trials of postnatal corticosteroids: inhaled and systemic.Biol Neonate. 1999; 76: 29-40Crossref PubMed Scopus (91) Google Scholar However, the overriding concerns of Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar are the discouraging outcomes at 1 to 2 years. There is no follow-up information to school age or older ages. A point that needs emphasis is that there are only a few reports in which reasonable numbers of infants were followed up—and those numbers are small. The glucocorticoid doses used for the trials that reported adverse outcomes are worth noting. Yeh et al8Yeh 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: E7Crossref PubMed Scopus (366) Google Scholar gave 0.5 mg/kg/d dexamethasone, beginning at 8 hours of age, with the dose tapered over 3 weeks. O'Shea et al9O'Shea TM Kothadia JM Klinepeter KL Goldstein DJ Jackson BG Weaver 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: 15-27Crossref PubMed Scopus (309) Google Scholar randomized infants to 0.5 mg/kg/d dexamethasone between 15 and 25 days of age and tapered the dose over 42 days. Shinwell et al10Shinwell ES, Karplus M, Reich D, Weintraub Z, Blazer S, Bader D. Early postnatal dexamethasone therapy is associated with increased incidence of cerebral palsy. Presented at Hot Topics in Neonatology 1999; 1999 Dec 6; Washington, DC.Google Scholar began 0.25 mg/kg dexamethasone within 12 hours of age and gave 6 doses over 3 days. These trials used high doses very early after birth, long courses of dexamethasone, or both. I agree with Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar that all future trials should include a plan for collecting and reporting follow-up results.There also are some concerns about where the rockets are landing after the use of antenatal glucocorticoids. A single course of antenatal glucocorticoids for women at risk for preterm delivery before 32 weeks should be the standard of care.11National Institutes of Health Consensus development panel on the effect of corticosteroids for fetal maturation on perinatal outcomes. Effect of corticosteroids for fetal maturation on perinatal outcomes.JAMA. 1995; 273: 413-418Crossref PubMed Scopus (811) Google Scholar However, repetitive courses of glucocorticoids at weekly intervals may have no benefit and may increase the risk of adverse outcomes.12French NP Hagan R Evans SF Godfrey M Newnham JP Repeated antenatal corticosteroids: size at birth and subsequent development.Am J Obstet Gynecol. 1999; 180: 114-121Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar, 13Banks BA Cnaan A Morgan MA Parer JT Merrill JD Ballard PL et al.Multiple courses of antenatal corticosteroids and outcome of premature neonates.Am J Obstet Gynecol. 1999; 181: 709-717Abstract Full Text Full Text PDF PubMed Scopus (255) Google ScholarAll the available data concerning the clinical use of repetitive courses of glucocorticoids are from retrospective analyses, which do little more than generate hypotheses that need to be tested in prospective randomized trials. Those trials are now underway and should include assessments at follow-up. A recent report about choice of antenatal glucocorticoid is of particular concern. Baud et al14Baud 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 (374) Google Scholar reported that antenatal dexamethasone (4 doses of 6 mg every 12 hours) increased periventricular leukomalacia relative to antenatal betamethasone (2 doses of 12 mg of betamethasone given 24 hours apart). These glucocorticoids and dosage schedules are the 2 standard treatment courses used for antenatal glucocorticoids, although an "accelerated" betamethasone course is also used with no apparent added benefit. Fetal heart rate variability and breathing patterns change more after administration of betamethasone than after administration of dexamethasone to mothers.15Rotmensch S Liberati M Vishne TH Celentano C Ben-Rafael Z Bellati U The effect of betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities. A prospective randomized trial.Acta Obstet Gynecol Scand. 1999; 78: 493-500Crossref PubMed Scopus (68) Google Scholar In sheep, fetal infusions of betamethasone cause preterm labor, whereas fetal infusions of dexamethasone do not consistently cause preterm labor.16Derks JB Giussani DA Van Dam LM Jenkins SL Winter JA Zhao XF et al.Differential effects of betamethasone and dexamethasone fetal administration of parturition in sheep.J Soc Gynecol Investig. 1996; 3: 336-341Crossref PubMed Scopus (24) Google Scholar The clinical data suggest that antenatal betamethasone is more effective than dexamethasone in preventing death.17Ballard PL Ballard RA Scientific basis and therapeutic regimens for use of antenatal glucocorticoids.Am J Obstet Gynecol. 1995; 173: 254-262Abstract Full Text PDF PubMed Scopus (385) Google Scholar Although these glucocorticoids are stereoisomers thought to have equivalent pharmacologic effects,5Schimmer BP Parker KL Adrenocorticotropic hormone. Adrenocortical steroids and their synthetic analogs: inhibitors of the synthesis and actions of adrenocortical hormones.in: The pharmacological basis of therapeutics. : McGraw-Hill, New York1996: 1459-1485Google Scholar there are a number of unexplained differences. Baud et al14Baud 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 (374) Google Scholar suggested that the 0.15 mg sulfite preservative per milligram of dexamethasone might be responsible for the increased incidence of periventricular leukomalacia. I think this not a likely explanation. Sulfites are common food additives and are present in cardiovascular drugs, and 3 g of protein for hyperalimentation contains about 20 mg of sulfites. The maternal exposure will be small relative to the postnatal exposure of very preterm infants. The weight of evidence is that betamethasone is the preferred glucocorticoid for antenatal use. Perhaps we should question our choice of dexamethasone for postnatal use.Glucocorticoids will continue to be used in perinatal medicine. However, Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar are correct to point out that we need to be very concerned about long-term outcomes. Future studies need to focus on the perhaps unrealistic goal of finding the minimum dose and duration of treatments that will be effective. Adverse neurodevelopmental outcomes no doubt result from the effects of these potent agents on developing systems and should come as no surprise. We should not accept short-term benefits as demonstrating therapeutic gains without understanding the implications for neurodevelopmental outcomes. We should not view glucocorticoids from Galen's perspective.All who drink of this treatment recover in a short time, Except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable casesGalen as quoted by W. A. Silverman (page 3 )1Silverman WA Where is the evidence?.in: Debates in modern medicine. : Oxford University Press, Oxford1998Google Scholar See related article, p. 9. Once the rockets are up, who cares where they come down? 'That's not my department,' says Wernher von Braun.Tom Lehrer as quoted by W. A. Silverman (page 5 )1Silverman WA Where is the evidence?.in: Debates in modern medicine. : Oxford University Press, Oxford1998Google Scholar Glucocorticoids are one of the most potent classes of drugs used in perinatal medicine. Neonatologists like results, and glucocorticoids have immediate physiologic effects on lung function of preterm infants, which are clinically apparent (even to parents) and demonstrable in clinical trials.2Halliday HL Clinical trials of postnatal corticosteroids: inhaled and systemic.Biol Neonate. 1999; 76: 29-40Crossref PubMed Scopus (91) Google Scholar They get the rockets up. Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar summarize recent information indicating that there are significant short-term (days to weeks) and long-term (1 to 2 years) adverse effects that should make us seriously question where and how the rockets come down. The problem with integrating the information from the multiple clinical trials into a consensus recommendation for clinical practice results from 2 overlapping factors. Glucocorticoid treatment effects (beneficial or adverse) are perhaps as sensitive to dose and duration of treatment as any class of pharmacologic agents, and the very preterm infant is at a developmental stage that may be particularly susceptible to glucocorticoid effects.4Jobe AH Ikegami M Lung development and function in preterm infants in the surfactant treatment era.Annu Rev Physiol. 2000; 62: 825-846Crossref PubMed Scopus (158) Google Scholar Those effects likely are secondarily modified by common superimposed events in the preterm infant such as antenatal or postnatal proinflammation or infection and catabolic state. Most clinical trials have used high-dose dexamethasone (acute asthma doses) that were weaned over periods as long as 42 days. Infants have been treated early (<72 hours) in attempts to prevent chronic lung disease, and infants have been treated later (7 to 28 days) in attempts to minimize progression of chronic lung disease. The trials in aggregate provide little guidance on dose, when to initiate treatment, or duration of treatment. Almost any treatment schedule imaginable has been tried, but few have heeded the general guidelines to initially try the lowest possible doses of glucocorticoids to achieve a therapeutic effect.5Schimmer BP Parker KL Adrenocorticotropic hormone. Adrenocortical steroids and their synthetic analogs: inhibitors of the synthesis and actions of adrenocortical hormones.in: The pharmacological basis of therapeutics. : McGraw-Hill, New York1996: 1459-1485Google Scholar If one chooses to use glucocorticoids, it seems to me that there should be a clear short-term clinical goal (perhaps extubation), and if that goal is not achieved within 3 to 4 days, then therapy should be stopped. Furthermore, the "standard" initial dose of 0.5 mg/kg/d (equivalent to 12 mg of cortisol) is very high relative to the 24-hour basal production rate of about 0.5 mg cortisol for a preterm infant weighing 1 kg and a stress production rate of perhaps 1.5 mg/d. The recently terminated National Institute Child Health and Human Development trial used an initial dose of 0.15 mg/kg/d dexamethasone and found an increased incidence of gastrointestinal perforations, demonstrating complications at lower doses.6Stark AF Carlo W Bauer C Complications of early steroid therapy in a randomized controlled trial [abstract].Pediatrics. 1999; 104: 739AGoogle Scholar Initial doses of 0.1 to 0.2 mg/kg/d dexamethasone should be sufficient and may be too high. Watterberg et al7Watterberg 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 (221) Google Scholar recently reported in a small trial that 1 mg of hydrocortisone per day, begun at <48 hours of age and continued for 9 days followed by 0.5 mg of hydrocortisone per day for 3 days, increased survival without supplemental oxygen at 36 weeks' postconceptional age. This strategy is based on the frequent occurrence of low plasma cortisol values in very low birth weight infants (adrenal insufficiency?). The issue of minimal effective dose is ripe for more clinical research. What should be the criteria for good targeting of where the rockets come down? Short-term benefits can be important, and a decreased mortality rate for infants when treatment was initiated between 7 and 21 days has been demonstrated by meta-analysis.2Halliday HL Clinical trials of postnatal corticosteroids: inhaled and systemic.Biol Neonate. 1999; 76: 29-40Crossref PubMed Scopus (91) Google Scholar However, the overriding concerns of Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar are the discouraging outcomes at 1 to 2 years. There is no follow-up information to school age or older ages. A point that needs emphasis is that there are only a few reports in which reasonable numbers of infants were followed up—and those numbers are small. The glucocorticoid doses used for the trials that reported adverse outcomes are worth noting. Yeh et al8Yeh 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: E7Crossref PubMed Scopus (366) Google Scholar gave 0.5 mg/kg/d dexamethasone, beginning at 8 hours of age, with the dose tapered over 3 weeks. O'Shea et al9O'Shea TM Kothadia JM Klinepeter KL Goldstein DJ Jackson BG Weaver 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: 15-27Crossref PubMed Scopus (309) Google Scholar randomized infants to 0.5 mg/kg/d dexamethasone between 15 and 25 days of age and tapered the dose over 42 days. Shinwell et al10Shinwell ES, Karplus M, Reich D, Weintraub Z, Blazer S, Bader D. Early postnatal dexamethasone therapy is associated with increased incidence of cerebral palsy. Presented at Hot Topics in Neonatology 1999; 1999 Dec 6; Washington, DC.Google Scholar began 0.25 mg/kg dexamethasone within 12 hours of age and gave 6 doses over 3 days. These trials used high doses very early after birth, long courses of dexamethasone, or both. I agree with Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar that all future trials should include a plan for collecting and reporting follow-up results. There also are some concerns about where the rockets are landing after the use of antenatal glucocorticoids. A single course of antenatal glucocorticoids for women at risk for preterm delivery before 32 weeks should be the standard of care.11National Institutes of Health Consensus development panel on the effect of corticosteroids for fetal maturation on perinatal outcomes. Effect of corticosteroids for fetal maturation on perinatal outcomes.JAMA. 1995; 273: 413-418Crossref PubMed Scopus (811) Google Scholar However, repetitive courses of glucocorticoids at weekly intervals may have no benefit and may increase the risk of adverse outcomes.12French NP Hagan R Evans SF Godfrey M Newnham JP Repeated antenatal corticosteroids: size at birth and subsequent development.Am J Obstet Gynecol. 1999; 180: 114-121Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar, 13Banks BA Cnaan A Morgan MA Parer JT Merrill JD Ballard PL et al.Multiple courses of antenatal corticosteroids and outcome of premature neonates.Am J Obstet Gynecol. 1999; 181: 709-717Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar All the available data concerning the clinical use of repetitive courses of glucocorticoids are from retrospective analyses, which do little more than generate hypotheses that need to be tested in prospective randomized trials. Those trials are now underway and should include assessments at follow-up. A recent report about choice of antenatal glucocorticoid is of particular concern. Baud et al14Baud 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 (374) Google Scholar reported that antenatal dexamethasone (4 doses of 6 mg every 12 hours) increased periventricular leukomalacia relative to antenatal betamethasone (2 doses of 12 mg of betamethasone given 24 hours apart). These glucocorticoids and dosage schedules are the 2 standard treatment courses used for antenatal glucocorticoids, although an "accelerated" betamethasone course is also used with no apparent added benefit. Fetal heart rate variability and breathing patterns change more after administration of betamethasone than after administration of dexamethasone to mothers.15Rotmensch S Liberati M Vishne TH Celentano C Ben-Rafael Z Bellati U The effect of betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities. A prospective randomized trial.Acta Obstet Gynecol Scand. 1999; 78: 493-500Crossref PubMed Scopus (68) Google Scholar In sheep, fetal infusions of betamethasone cause preterm labor, whereas fetal infusions of dexamethasone do not consistently cause preterm labor.16Derks JB Giussani DA Van Dam LM Jenkins SL Winter JA Zhao XF et al.Differential effects of betamethasone and dexamethasone fetal administration of parturition in sheep.J Soc Gynecol Investig. 1996; 3: 336-341Crossref PubMed Scopus (24) Google Scholar The clinical data suggest that antenatal betamethasone is more effective than dexamethasone in preventing death.17Ballard PL Ballard RA Scientific basis and therapeutic regimens for use of antenatal glucocorticoids.Am J Obstet Gynecol. 1995; 173: 254-262Abstract Full Text PDF PubMed Scopus (385) Google Scholar Although these glucocorticoids are stereoisomers thought to have equivalent pharmacologic effects,5Schimmer BP Parker KL Adrenocorticotropic hormone. Adrenocortical steroids and their synthetic analogs: inhibitors of the synthesis and actions of adrenocortical hormones.in: The pharmacological basis of therapeutics. : McGraw-Hill, New York1996: 1459-1485Google Scholar there are a number of unexplained differences. Baud et al14Baud 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 (374) Google Scholar suggested that the 0.15 mg sulfite preservative per milligram of dexamethasone might be responsible for the increased incidence of periventricular leukomalacia. I think this not a likely explanation. Sulfites are common food additives and are present in cardiovascular drugs, and 3 g of protein for hyperalimentation contains about 20 mg of sulfites. The maternal exposure will be small relative to the postnatal exposure of very preterm infants. The weight of evidence is that betamethasone is the preferred glucocorticoid for antenatal use. Perhaps we should question our choice of dexamethasone for postnatal use. Glucocorticoids will continue to be used in perinatal medicine. However, Finer et al3Finer NN Craft A Vaucher YE Clark RH Sola A Postnatal steroids: Short-term gain, long-term pain?.J Pediatr. 2000; 137: 9-13Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar are correct to point out that we need to be very concerned about long-term outcomes. Future studies need to focus on the perhaps unrealistic goal of finding the minimum dose and duration of treatments that will be effective. Adverse neurodevelopmental outcomes no doubt result from the effects of these potent agents on developing systems and should come as no surprise. We should not accept short-term benefits as demonstrating therapeutic gains without understanding the implications for neurodevelopmental outcomes. We should not view glucocorticoids from Galen's perspective. All who drink of this treatment recover in a short time, Except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable casesGalen as quoted by W. A. Silverman (page 3 )1Silverman WA Where is the evidence?.in: Debates in modern medicine. : Oxford University Press, Oxford1998Google Scholar Postnatal steroids: Short-term gain, long-term pain?The Journal of PediatricsVol. 137Issue 1PreviewSee editorial, p. 1. Full-Text PDF A light in the darkness: Predicting outcomes for congenital cytomegalovirus infectionsThe Journal of PediatricsVol. 137Issue 1PreviewSee related article, p. 90. Full-Text PDF Side effects of steroids revisitedThe Journal of PediatricsVol. 137Issue 1PreviewSee related articles, p. 21 and p. 25. Full-Text PDF
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