- Email: [email protected]
Dexamethasone and the Brain at Age 18 Years: Randomize the First Baby—and Follow-Up
EDITORIALS
April 2014 S. Bruce Greenberg, MD University of Arkansas for Medical Sciences Arkansas Children’s Hospital Little Rock, Arkansas Reprint requests: S. Bruce Greenberg, MD, Arkansas Children’s Hospital, 1 Children’s Way, Slot #105, Little Rock, AR 72202. E-mail: greenbergsbruce@ uams.edu
References 1. Glatz AC, Purrington KS, Klinger A, King AR, Hellinger J, Zhu X, et al. Cumulative exposure to medical radiation for children requiring surgery for congenital heart disease. J Pediatr 2014;164:789-94. 2. Pache G, Grohmann J, Bulla S, Arnold R, Stiller B, Schlensak C, et al. Prospective electrocardiography-triggered CT angiography of the great thoracic vessels in infants and toddlers with congenital heart disease: feasibility and image quality. Eur J Radiol 2011;80:e440-5.
3. Greenberg SB, Bhutta S, Braswell L, Chan F. Computed tomography angiography in children with cardiovascular disease: low dose techniques and image quality. Int J Cardiovasc Imaging 2012;28:163-70. 4. Al-Mousily F, Shifrin RY, Fricker FJ, Feramec N, Quinn NS, Chandran A. Use of 320-detector computed tomographic angiography for infants and young children with congenital heart disease. Pediatr Cardiol 2011;32: 426-32. 5. Sauer CG, Kuqathasan S, Martin DR, Applegate KE. Medical radiation exposure in children with inflammatory bowel disease estimates high cumulative doses. Inflamm Bowel Dis 2011;17:2326-32. 6. Van Aaist J, Jeukens CR, Vles JS, van Maren EA, Kessels AG, Soudant DL, et al. Diagnostic radiation exposure in children with spinal dysraphism: an estimation of the cumulative effective dose in a cohort or 135 children from The Netherlands. Arch Dis Child 2013;98:680-5. 7. Griffey RT, Sodickson A. Cumulative radiation exposure and cancer risk estimates in emergency department patients undergoing repeat or multiple CT. AJR Am J Roentgenol 2009;192:887-92. 8. Tepper B, Brice JH, Hobgood CD. Evaluation of radiation exposure to pediatric trauma patients. J Emerg Med 2013;44:646-52.
Dexamethasone and the Brain at Age 18 Years: Randomize the First Baby—and Follow-Up
I
n this issue of The Journal, Cheong et al report magnetic and grey matter volumes, and smaller basal ganglia and resonance imaging (MRI) results at 18 years of age from thalami than term-born controls.4 Those authors concluded a large prospective cohort study of all infants born at that even in the absence of significant postnatal medical <28 weeks gestation in Victoria, Australia, 1991-1992.1 The sequelae, preterm birth has a profound effect on neuroanatomical structure in middle childhood. authors are to be highly commended both for continuing These studies highlight the difficulty of to follow this comprehensive geographical See related article, p 737 sorting out the effects of prematurity and cohort into young adulthood, and for its attendant complications from the effects of a specific therachieving a follow-up rate of 80%, of whom 82% (146/180) apeutic intervention. Drawing conclusions about a therapeuhad usable MRI scans. This large cohort will add valuable intic intervention from a cohort study is hazardous, and the formation to the growing literature on long-term structural authors appropriately describe their findings as an “associaand functional neurologic outcomes after extremely preterm tion, albeit a robust one.” It is highly unlikely that one can birth. determine and control for all the variables affecting the outThey found that high-dose postnatal dexamethasone treatcomes associated with a therapy without doing a randomized ment for bronchopulmonary dysplasia (BPD) was associated controlled trial (RCT). Cohort studies, even very large ones, with decreased brain volumes on MRI scan at 18 years of age, have misled us in the past. For example, the Nurses’ Health specifically total brain tissue, cortical white matter, thalamus, Study of almost 60 000 women found a large decrease in and basal ganglia nuclei.1 Surprisingly, they found no signifthe risk of major coronary heart disease for women taking icant differences in the hippocampus or cerebellum, 2 areas hormone replacement therapy, which was not substantiated of the brain with very high concentrations of glucocorticoid in subsequent RCTs.5,6 For postnatal dexamethasone therapy receptors. In this same cohort, the authors have reported that individuals born extremely preterm have smaller brain volspecifically, exposure is inextricably linked to the diagnosis of umes than term-born controls at age 18 years, including BPD. Lung disease itself, without any glucocorticoid therapy, the hippocampus and cerebellum as well as other brain reresults in alterations in brain white matter development.7 2 gions. Other authors have reported similar findings in childBPD is also linked to adverse neurodevelopmental outcomes, hood and adolescence following preterm birth,3,4 including 1 although those outcomes may have been affected by exposure to dexamethasone.8 study of extremely preterm infants without “serious neurologic or medical conditions” at age 7-10 years, which found that these children had smaller total brain volumes, white
BPD MRI RCT
Bronchopulmonary dysplasia Magnetic resonance imaging Randomized controlled trial
Funded by a grant from National Institute of Child Health and Development (NICHD; U10HD053089) and am the Principal Investigator for the NICHD Neonatal Research Network RCT of hydrocortisone therapy for BPD (NCT 01353313) The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.12.036
687
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Adding “BPD” to the analysis as a single factor cannot adequately account for the effect of lung disease on the outcomes. BPD is highly variable; even within that diagnosis, it is likely that sicker babies are more often treated with dexamethasone, and those babies are also more likely to have worse outcomes. On the other hand, several previous RCTs of high-dose dexamethasone therapy have demonstrated adverse long-term effects on growth, including head circumference, and on functional neurodevelopmental outcomes, adding weight to the likelihood that high-dose dexamethasone therapy was a factor in the decreased brain tissue volumes found in this study.9,10 That this therapy was one of many contributing factors is underscored by the authors’ finding that the strength of the association between dexamethasone therapy and decreased brain volumes was weakened when other factors (gestational age, sex, small for gestational age status, BPD, major brain injury) were added to the model. The authors also appropriately caution against extending their observation to hydrocortisone, where they note that 1 cohort study has suggested that hydrocortisone impairs cerebellar growth.11 Those authors showed that among many factors affecting cerebellar volume, the diagnosis of hypotension had an effect size similar to that of hydrocortisone. Here again, a diagnosis often associated with adverse outcomes—hypotension—is linked to the therapeutic intervention in question, and sicker babies would be more likely to receive both the diagnosis and the therapy.12 In contrast to RCTs of high-dose dexamethasone, however, longer-term outcomes from other cohort studies and RCTs of hydrocortisone have not demonstrated similar findings.13,14 Such studies are thus far quite limited, however, and should not lead to complacency, but to further RCTs to provide definitive answers regarding both efficacy and long-term outcomes. Because of the demonstrated benefits of dexamethasone for treatment of BPD,10 many extremely preterm babies continue to receive this therapy, although usually in much lower doses than had been given in 1991-1992. Although decreasing the dose and the length of exposure may shift the risk/benefit ratio in favor of providing dexamethasone therapy to some infants, in the absence of additional RCTs that include evaluation of long-term outcomes, we will not know. Instead, we will be left with cohort studies to evaluate a therapeutic intervention—a lamentable situation. Ironically, early investigators in this area heeded Thomas Chalmers’ classic advice to “randomize the first patient,” but for many years these RCTs told only half of the story—the short-term respiratory benefits.15 When long-term adverse outcomes of high-dose dexamethasone were identified, RCTs of lower doses and shorter durations of therapy were stalled.16 In conclusion, I again congratulate the authors on their achievement in following this large, comprehensive geographic cohort of children born extremely preterm into adulthood. Fortunately, we are not likely to see confirmation of highdose dexamethasone effects on brain growth from future RCTs, but it is hoped that we will continue to employ this robust 688
Vol. 164, No. 4 and vital study design to determine whether lower doses, shorter courses, and alternative medications can optimize benefit and reduce risk. We have learned from the ‘dexamethasone story’ the compelling need for long-term follow-up to provide a more complete picture of the effects of therapies we employ in the neonatal period. Research sponsors should be urged to establish mechanisms to provide assurance of longer-term funding to evaluate outcomes of all RCTs in newborns. n Kristi L. Watterberg, MD Professor of Pediatrics Department of Neonatology University of New Mexico Albuquerque, New Mexico Reprint requests: Kristi Watterberg, MD, Professor of Pediatrics/Neonatology, MSC10 5590, University of New Mexico, Albuquerque, NM 87131-0001. E-mail: [email protected]
References 1. Cheong JL, Burnett AC, Lee KJ, Roberts G, Thompson DK, Wood SJ, et al. for the Victorian Infant Collaborative Study Group. Association between postnatal dexamethasone for treatment of bronchopulmonary dysplasia and brain volumes at adolescence in infants born very preterm. J Pediatr 2014;164:737-43. 2. Cheong JL, Anderson PJ, Roberts G, Burnett AC, Lee KJ, Thompson DK, et al. Contribution of brain size to IQ and educational underperformance in extremely preterm adolescents. PLoS One 2013;8: e77475. 3. de Kieviet JF, Zoetebier L, van Elburg RM, Vermeulen RJ, Oosterlaan J. Brain development of very preterm and very low-birthweight children in childhood and adolescence: a meta-analysis. Dev Med Child Neurol 2012;54:313-23. 4. Lax ID, Duerden EG, Lin SY, Mallar Chakravarty M, Donner EJ, Lerch JP, et al. Neuroanatomical consequences of very preterm birth in middle childhood. Brain Struct Funct 2013;218:575-85. 5. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453-61. Erratum in: N Engl J Med 1996;335:1406. 6. Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy and health outcomes during the intervention and extended post-stopping phases of the Women’s Health Initiative randomized trials. JAMA 2013; 310:1353-68. 7. Ball G, Counsell SJ, Anjari M, Merchant N, Arichi T, Doria V, et al. An optimized tract-based spatial statistics protocol for neonates: applications to prematurity and chronic lung disease. Neuroimage 2010;53: 94-102. 8. Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998. Pediatrics 2005;116:635-43. 9. Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, Tsai CH. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304-13. 10. Doyle LW, Ehrenkranz RA, Halliday HL. Dexamethasone treatment after the first week of life for bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology 2010;98:289-96. 11. Tam EW, Chau V, Ferriero DM, Barkovich AJ, Poskitt KJ, Studholme C, et al. Preterm cerebellar growth impairment after postnatal exposure to glucocorticoids. Sci Transl Med 2011;3:105ra105. 12. Batton B, Zhu X, Fanaroff J, Kirchner HL, Berlin S, WilsonCostello D, et al. Blood pressure, anti-hypotensive therapy, and
EDITORIALS
April 2014 neurodevelopment in extremely preterm infants. J Pediatr 2009;154: 351-7. 357.e1. 13. terWolbeek M, de Sonneville LM, de Vries WB, Kavelaars A, Veen S, Kornelisse RF, et al. Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14-17 year-old adolescents. Psychoneuroendocrinology 2013;38:975-86. 14. Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ, et al. Growth and neurodevelopmental outcomes after early
low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics 2007;120:40-8. 15. Chalmers TC. Randomize the first patient. N Engl J Med 1977;296: 107. 16. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB, DART Study Investigators. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics 2006;117:75-83.
Increasing Expertise in Caring for the Gender Dysphoric Child and Transgender Adolescent
W
hen I became a pediatric endocrinologist in the atric endocrinologists have been using to suppress puberty in early 1980s, I was asked to see a 3-year-old boy children with precocious puberty.2 The period of pubertal because he liked to wear dresses and preferred suppression allows for further mental health exploration in to play with what were then traditionally “girls toys.” His an attempt to ensure that the decision about gender change parents were concerned that he might have an endocrine is made only after careful consideration of all factors. Studies disorder that could be linked to his prefexamining the physical and emotional efSee related article, p 906 erence for feminine dress and behavior. fects of such interventions have found that At that time, all I could tell them, based on my training, the psychological benefit exceeds any negative effect of stopwas that the child did not have any endocrine disorder ping puberty.3 This period of suppression is followed by that I could diagnose. His parents left my office without transhormone therapy, similar to the process of prescribing any real answers to the questions they were asking. Now sex steroids to agonadal or hypogonadal adolescents. we know that many children will express questions about The medical care of this population in the US has the appropriateness of their assigned gender at birth and become more generally accepted over time. In 2009, the experience gender dysphoria; however, not all of these chilEndocrine Society published guidelines for the treatment dren will evolve into adolescents and adults wanting to live of transsexual persons that included guidelines for mantheir lives in the transgender. Some will later declare themagement of adolescents.4 In 2012, Spack et al5 published selves to be homosexual, and others will live well in the the first US retrospective review of the patients treated in gender assigned at birth. his clinic in Boston. Dr Spack has been a key figure in Later, in 1995, I was asked to see a girl who was starting bringing the Dutch studies to the attention of US physipuberty and wanted to “cut her breasts off.” Her mother cians, especially pediatricians. was panicked and concerned that she insisted on wearing In this issue of The Journal, Khatchadourian et al6 report boys’ clothing and being addressed with the masculine proanother important study detailing the experience of a center noun. Her onset of puberty triggered stronger feelings in British Columbia treating 84 youth with gender dysphoria against her developing feminine body. This time I could over a 13-year period. The report carefully describes the be of more assistance to my patient, given the progress in characteristics of the patient population, clinical manageunderstanding and caring for gender-dysphoric youth. I ment and response to treatment, options for surgical intercould now seek and receive information from a community ventions as young adults, and psychiatric comorbidities. Of of professionals. interest is that for many years, transgendered males to feThe first standards of care for diagnosis and management males were felt to outnumber females to males. This study of gender-dysphoric youth and transgendered adolescents shows what others have found, that there are almost equal were published in 1979 by the World Professional Associanumbers of patients in both categories. The findings of tion of Transgender Health (originally known as the Harry this report add data to suggest that stopping puberty in Benjamin Society), and updated versions have followed since gender-dysphoric children is safe and effective in carefully then.1 The Dutch have been pioneers in diagnosing and treatchosen children, and that cross-gender therapy is likewise efficacious. ing these youth. In studying the best practices for caring for Nonetheless, this report reminds us of issues that continue these children and adolescents, Dutch investigators have to challenge those who care for this population. The study developed a protocol for pubertal suppression of youth with gender dysphoria using the same medication, gonadotropin-releasing hormone (GnRH) analog, that pediThe author declares no conflicts of interest.
GnRH
Gonadotropin-releasing hormone
0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.11.067
689
April 2014 S. Bruce Greenberg, MD University of Arkansas for Medical Sciences Arkansas Children’s Hospital Little Rock, Arkansas Reprint requests: S. Bruce Greenberg, MD, Arkansas Children’s Hospital, 1 Children’s Way, Slot #105, Little Rock, AR 72202. E-mail: greenbergsbruce@ uams.edu
References 1. Glatz AC, Purrington KS, Klinger A, King AR, Hellinger J, Zhu X, et al. Cumulative exposure to medical radiation for children requiring surgery for congenital heart disease. J Pediatr 2014;164:789-94. 2. Pache G, Grohmann J, Bulla S, Arnold R, Stiller B, Schlensak C, et al. Prospective electrocardiography-triggered CT angiography of the great thoracic vessels in infants and toddlers with congenital heart disease: feasibility and image quality. Eur J Radiol 2011;80:e440-5.
3. Greenberg SB, Bhutta S, Braswell L, Chan F. Computed tomography angiography in children with cardiovascular disease: low dose techniques and image quality. Int J Cardiovasc Imaging 2012;28:163-70. 4. Al-Mousily F, Shifrin RY, Fricker FJ, Feramec N, Quinn NS, Chandran A. Use of 320-detector computed tomographic angiography for infants and young children with congenital heart disease. Pediatr Cardiol 2011;32: 426-32. 5. Sauer CG, Kuqathasan S, Martin DR, Applegate KE. Medical radiation exposure in children with inflammatory bowel disease estimates high cumulative doses. Inflamm Bowel Dis 2011;17:2326-32. 6. Van Aaist J, Jeukens CR, Vles JS, van Maren EA, Kessels AG, Soudant DL, et al. Diagnostic radiation exposure in children with spinal dysraphism: an estimation of the cumulative effective dose in a cohort or 135 children from The Netherlands. Arch Dis Child 2013;98:680-5. 7. Griffey RT, Sodickson A. Cumulative radiation exposure and cancer risk estimates in emergency department patients undergoing repeat or multiple CT. AJR Am J Roentgenol 2009;192:887-92. 8. Tepper B, Brice JH, Hobgood CD. Evaluation of radiation exposure to pediatric trauma patients. J Emerg Med 2013;44:646-52.
Dexamethasone and the Brain at Age 18 Years: Randomize the First Baby—and Follow-Up
I
n this issue of The Journal, Cheong et al report magnetic and grey matter volumes, and smaller basal ganglia and resonance imaging (MRI) results at 18 years of age from thalami than term-born controls.4 Those authors concluded a large prospective cohort study of all infants born at that even in the absence of significant postnatal medical <28 weeks gestation in Victoria, Australia, 1991-1992.1 The sequelae, preterm birth has a profound effect on neuroanatomical structure in middle childhood. authors are to be highly commended both for continuing These studies highlight the difficulty of to follow this comprehensive geographical See related article, p 737 sorting out the effects of prematurity and cohort into young adulthood, and for its attendant complications from the effects of a specific therachieving a follow-up rate of 80%, of whom 82% (146/180) apeutic intervention. Drawing conclusions about a therapeuhad usable MRI scans. This large cohort will add valuable intic intervention from a cohort study is hazardous, and the formation to the growing literature on long-term structural authors appropriately describe their findings as an “associaand functional neurologic outcomes after extremely preterm tion, albeit a robust one.” It is highly unlikely that one can birth. determine and control for all the variables affecting the outThey found that high-dose postnatal dexamethasone treatcomes associated with a therapy without doing a randomized ment for bronchopulmonary dysplasia (BPD) was associated controlled trial (RCT). Cohort studies, even very large ones, with decreased brain volumes on MRI scan at 18 years of age, have misled us in the past. For example, the Nurses’ Health specifically total brain tissue, cortical white matter, thalamus, Study of almost 60 000 women found a large decrease in and basal ganglia nuclei.1 Surprisingly, they found no signifthe risk of major coronary heart disease for women taking icant differences in the hippocampus or cerebellum, 2 areas hormone replacement therapy, which was not substantiated of the brain with very high concentrations of glucocorticoid in subsequent RCTs.5,6 For postnatal dexamethasone therapy receptors. In this same cohort, the authors have reported that individuals born extremely preterm have smaller brain volspecifically, exposure is inextricably linked to the diagnosis of umes than term-born controls at age 18 years, including BPD. Lung disease itself, without any glucocorticoid therapy, the hippocampus and cerebellum as well as other brain reresults in alterations in brain white matter development.7 2 gions. Other authors have reported similar findings in childBPD is also linked to adverse neurodevelopmental outcomes, hood and adolescence following preterm birth,3,4 including 1 although those outcomes may have been affected by exposure to dexamethasone.8 study of extremely preterm infants without “serious neurologic or medical conditions” at age 7-10 years, which found that these children had smaller total brain volumes, white
BPD MRI RCT
Bronchopulmonary dysplasia Magnetic resonance imaging Randomized controlled trial
Funded by a grant from National Institute of Child Health and Development (NICHD; U10HD053089) and am the Principal Investigator for the NICHD Neonatal Research Network RCT of hydrocortisone therapy for BPD (NCT 01353313) The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.12.036
687
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Adding “BPD” to the analysis as a single factor cannot adequately account for the effect of lung disease on the outcomes. BPD is highly variable; even within that diagnosis, it is likely that sicker babies are more often treated with dexamethasone, and those babies are also more likely to have worse outcomes. On the other hand, several previous RCTs of high-dose dexamethasone therapy have demonstrated adverse long-term effects on growth, including head circumference, and on functional neurodevelopmental outcomes, adding weight to the likelihood that high-dose dexamethasone therapy was a factor in the decreased brain tissue volumes found in this study.9,10 That this therapy was one of many contributing factors is underscored by the authors’ finding that the strength of the association between dexamethasone therapy and decreased brain volumes was weakened when other factors (gestational age, sex, small for gestational age status, BPD, major brain injury) were added to the model. The authors also appropriately caution against extending their observation to hydrocortisone, where they note that 1 cohort study has suggested that hydrocortisone impairs cerebellar growth.11 Those authors showed that among many factors affecting cerebellar volume, the diagnosis of hypotension had an effect size similar to that of hydrocortisone. Here again, a diagnosis often associated with adverse outcomes—hypotension—is linked to the therapeutic intervention in question, and sicker babies would be more likely to receive both the diagnosis and the therapy.12 In contrast to RCTs of high-dose dexamethasone, however, longer-term outcomes from other cohort studies and RCTs of hydrocortisone have not demonstrated similar findings.13,14 Such studies are thus far quite limited, however, and should not lead to complacency, but to further RCTs to provide definitive answers regarding both efficacy and long-term outcomes. Because of the demonstrated benefits of dexamethasone for treatment of BPD,10 many extremely preterm babies continue to receive this therapy, although usually in much lower doses than had been given in 1991-1992. Although decreasing the dose and the length of exposure may shift the risk/benefit ratio in favor of providing dexamethasone therapy to some infants, in the absence of additional RCTs that include evaluation of long-term outcomes, we will not know. Instead, we will be left with cohort studies to evaluate a therapeutic intervention—a lamentable situation. Ironically, early investigators in this area heeded Thomas Chalmers’ classic advice to “randomize the first patient,” but for many years these RCTs told only half of the story—the short-term respiratory benefits.15 When long-term adverse outcomes of high-dose dexamethasone were identified, RCTs of lower doses and shorter durations of therapy were stalled.16 In conclusion, I again congratulate the authors on their achievement in following this large, comprehensive geographic cohort of children born extremely preterm into adulthood. Fortunately, we are not likely to see confirmation of highdose dexamethasone effects on brain growth from future RCTs, but it is hoped that we will continue to employ this robust 688
Vol. 164, No. 4 and vital study design to determine whether lower doses, shorter courses, and alternative medications can optimize benefit and reduce risk. We have learned from the ‘dexamethasone story’ the compelling need for long-term follow-up to provide a more complete picture of the effects of therapies we employ in the neonatal period. Research sponsors should be urged to establish mechanisms to provide assurance of longer-term funding to evaluate outcomes of all RCTs in newborns. n Kristi L. Watterberg, MD Professor of Pediatrics Department of Neonatology University of New Mexico Albuquerque, New Mexico Reprint requests: Kristi Watterberg, MD, Professor of Pediatrics/Neonatology, MSC10 5590, University of New Mexico, Albuquerque, NM 87131-0001. E-mail: [email protected]
References 1. Cheong JL, Burnett AC, Lee KJ, Roberts G, Thompson DK, Wood SJ, et al. for the Victorian Infant Collaborative Study Group. Association between postnatal dexamethasone for treatment of bronchopulmonary dysplasia and brain volumes at adolescence in infants born very preterm. J Pediatr 2014;164:737-43. 2. Cheong JL, Anderson PJ, Roberts G, Burnett AC, Lee KJ, Thompson DK, et al. Contribution of brain size to IQ and educational underperformance in extremely preterm adolescents. PLoS One 2013;8: e77475. 3. de Kieviet JF, Zoetebier L, van Elburg RM, Vermeulen RJ, Oosterlaan J. Brain development of very preterm and very low-birthweight children in childhood and adolescence: a meta-analysis. Dev Med Child Neurol 2012;54:313-23. 4. Lax ID, Duerden EG, Lin SY, Mallar Chakravarty M, Donner EJ, Lerch JP, et al. Neuroanatomical consequences of very preterm birth in middle childhood. Brain Struct Funct 2013;218:575-85. 5. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453-61. Erratum in: N Engl J Med 1996;335:1406. 6. Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy and health outcomes during the intervention and extended post-stopping phases of the Women’s Health Initiative randomized trials. JAMA 2013; 310:1353-68. 7. Ball G, Counsell SJ, Anjari M, Merchant N, Arichi T, Doria V, et al. An optimized tract-based spatial statistics protocol for neonates: applications to prematurity and chronic lung disease. Neuroimage 2010;53: 94-102. 8. Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998. Pediatrics 2005;116:635-43. 9. Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, Tsai CH. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304-13. 10. Doyle LW, Ehrenkranz RA, Halliday HL. Dexamethasone treatment after the first week of life for bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology 2010;98:289-96. 11. Tam EW, Chau V, Ferriero DM, Barkovich AJ, Poskitt KJ, Studholme C, et al. Preterm cerebellar growth impairment after postnatal exposure to glucocorticoids. Sci Transl Med 2011;3:105ra105. 12. Batton B, Zhu X, Fanaroff J, Kirchner HL, Berlin S, WilsonCostello D, et al. Blood pressure, anti-hypotensive therapy, and
EDITORIALS
April 2014 neurodevelopment in extremely preterm infants. J Pediatr 2009;154: 351-7. 357.e1. 13. terWolbeek M, de Sonneville LM, de Vries WB, Kavelaars A, Veen S, Kornelisse RF, et al. Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14-17 year-old adolescents. Psychoneuroendocrinology 2013;38:975-86. 14. Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ, et al. Growth and neurodevelopmental outcomes after early
low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics 2007;120:40-8. 15. Chalmers TC. Randomize the first patient. N Engl J Med 1977;296: 107. 16. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB, DART Study Investigators. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics 2006;117:75-83.
Increasing Expertise in Caring for the Gender Dysphoric Child and Transgender Adolescent
W
hen I became a pediatric endocrinologist in the atric endocrinologists have been using to suppress puberty in early 1980s, I was asked to see a 3-year-old boy children with precocious puberty.2 The period of pubertal because he liked to wear dresses and preferred suppression allows for further mental health exploration in to play with what were then traditionally “girls toys.” His an attempt to ensure that the decision about gender change parents were concerned that he might have an endocrine is made only after careful consideration of all factors. Studies disorder that could be linked to his prefexamining the physical and emotional efSee related article, p 906 erence for feminine dress and behavior. fects of such interventions have found that At that time, all I could tell them, based on my training, the psychological benefit exceeds any negative effect of stopwas that the child did not have any endocrine disorder ping puberty.3 This period of suppression is followed by that I could diagnose. His parents left my office without transhormone therapy, similar to the process of prescribing any real answers to the questions they were asking. Now sex steroids to agonadal or hypogonadal adolescents. we know that many children will express questions about The medical care of this population in the US has the appropriateness of their assigned gender at birth and become more generally accepted over time. In 2009, the experience gender dysphoria; however, not all of these chilEndocrine Society published guidelines for the treatment dren will evolve into adolescents and adults wanting to live of transsexual persons that included guidelines for mantheir lives in the transgender. Some will later declare themagement of adolescents.4 In 2012, Spack et al5 published selves to be homosexual, and others will live well in the the first US retrospective review of the patients treated in gender assigned at birth. his clinic in Boston. Dr Spack has been a key figure in Later, in 1995, I was asked to see a girl who was starting bringing the Dutch studies to the attention of US physipuberty and wanted to “cut her breasts off.” Her mother cians, especially pediatricians. was panicked and concerned that she insisted on wearing In this issue of The Journal, Khatchadourian et al6 report boys’ clothing and being addressed with the masculine proanother important study detailing the experience of a center noun. Her onset of puberty triggered stronger feelings in British Columbia treating 84 youth with gender dysphoria against her developing feminine body. This time I could over a 13-year period. The report carefully describes the be of more assistance to my patient, given the progress in characteristics of the patient population, clinical manageunderstanding and caring for gender-dysphoric youth. I ment and response to treatment, options for surgical intercould now seek and receive information from a community ventions as young adults, and psychiatric comorbidities. Of of professionals. interest is that for many years, transgendered males to feThe first standards of care for diagnosis and management males were felt to outnumber females to males. This study of gender-dysphoric youth and transgendered adolescents shows what others have found, that there are almost equal were published in 1979 by the World Professional Associanumbers of patients in both categories. The findings of tion of Transgender Health (originally known as the Harry this report add data to suggest that stopping puberty in Benjamin Society), and updated versions have followed since gender-dysphoric children is safe and effective in carefully then.1 The Dutch have been pioneers in diagnosing and treatchosen children, and that cross-gender therapy is likewise efficacious. ing these youth. In studying the best practices for caring for Nonetheless, this report reminds us of issues that continue these children and adolescents, Dutch investigators have to challenge those who care for this population. The study developed a protocol for pubertal suppression of youth with gender dysphoria using the same medication, gonadotropin-releasing hormone (GnRH) analog, that pediThe author declares no conflicts of interest.
GnRH
Gonadotropin-releasing hormone
0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.11.067
689