Abstract
Introduction:
Repeated courses of antenatal steroids in women at risk of preterm delivery have beneficial effects on lung maturation, but concern exists about the effects on brain development. We aimed to determine whether repeated courses of corticosteroids increased the risk of neuropathology as compared with single courses or no treatment.
Methods:
Single-course animals received a 6-mg dose of steroids at 123 and 124 d of gestation (dg; term, 185 dg; n = 6). Repeated-course animals received additional doses at 137 and 138 dg (n = 7). Controls received no steroids (n = 5). Baboons delivered naturally at term and necropsy was performed. Brains were assessed histologically for parameters of development and neuropathology.
Results:
Body weights did not differ between the groups (P > 0.05); neither did brain/body weight ratio. Density of glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes in white matter (WM) was increased in the single- (P < 0.05) and repeated-course (P < 0.01) groups as compared with controls. Density of myelin basic protein (MBP)-IR oligodendrocytes was reduced in the repeated-course animals as compared with both the control and single-course groups (P < 0.05); oligodendrocyte transcription factor 2 (Olig2)-IR showed no difference between groups.
Discussion:
Repeated courses of antenatal corticosteroids have effects on myelination in the developing nonhuman primate brain, which should be taken into account when determining a dosing regimen.
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References
Roberts D, Dalziel S . Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;19:CD004454.
McLaughlin KJ, Crowther CA, Walker N, Harding JE . Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Aust N Z J Obstet Gynaecol 2003;43:101–6.
Quinlivan JA, Evans SF, Dunlop SA, Beazley LD, Newnham JP . Use of corticosteroids by Australian obstetricians—a survey of clinical practice. Aust N Z J Obstet Gynaecol 1998;38:1–7.
Empana JP, Anceschi MM, Szabo I, Cosmi EV, Breart G, Truffert P; EURAIL Study Group. Antenatal corticosteroids policies in 14 European countries: factors associated with multiple courses. The EURAIL survey. Acta Paediatr 2004;93:1318–22.
French NP, Hagan R, Evans SF, Godfrey M, Newnham JP . Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114–21.
Banks BA, Cnaan A, Morgan MA, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group. Am J Obstet Gynecol 1999;181:709–17.
Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS; Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006;367:1913–9.
Murphy KE, Hannah ME, Willan AR, et al. Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 2008;372:2143–51.
Peltoniemi OM, Kari MA, Lano A, et al. Two-year follow-up of a randomised trial with repeated antenatal betamethasone. Arch Dis Child Fetal Neonatal Ed 2009;94:F402–6.
Asztalos EV, Murphy KE, Hannah ME, et al. Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes. Pediatrics 2010;126:e1045–55.
Crowther CA, Doyle LW, Haslam RR, Hiller JE, Harding JE, Robinson JS; ACTORDS Study Group. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1179–89.
Wapner RJ, Sorokin Y, Mele L, et al. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1190–8.
Spinillo A, Viazzo F, Colleoni R, et al. Two-year infant neurodevelopmental outcome after single or multiple antenatal courses of corticosteroids to prevent complications of prematurity. Am J Obstet Gynecol 2004;191:217–24.
French NP, Hagan R, Evans SF, Mullan A, Newnham JP . Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004;190:588–95.
Ikegami M, Jobe AH, Newnham J, Polk DH, Willet KE, Sly P . Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med 1997;156:178–84.
Moss TJ, Doherty DA, Nitsos I, Sloboda DM, Harding R, Newnham JP . Effects into adulthood of single or repeated antenatal corticosteroids in sheep. Am J Obstet Gynecol 2005;192:146–52.
Huang WL, Harper CG, Evans SF, Newnham JP, Dunlop SA . Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. Int J Dev Neurosci 2001;19:415–25.
Antonow-Schlorke I, Helgert A, Gey C, et al. Adverse effects of antenatal glucocorticoids on cerebral myelination in sheep. Obstet Gynecol 2009;113:142–51.
Dunlop SA, Archer MA, Quinlivan JA, Beazley LD, Newnham JP . Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med 1997;6:309–13.
Uno H, Lohmiller L, Thieme C, et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Res Dev Brain Res 1990;53:157–67.
Scheepens A, van de Waarenburg M, van den Hove D, Blanco CE . A single course of prenatal betamethasone in the rat alters postnatal brain cell proliferation but not apoptosis. J Physiol (Lond) 2003;552:163–75.
Antonow-Schlorke I, Schwab M, Li C, Nathanielsz PW . Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain. J Physiol (Lond) 2003;547:117–23.
Whitelaw A, Thoresen M . Antenatal steroids and the developing brain. Arch Dis Child Fetal Neonatal Ed 2000;83:F154–7.
Newnham JP, Moss TJ, Nitsos I, Sloboda DM . Antenatal corticosteroids: the good, the bad and the unknown. Curr Opin Obstet Gynecol 2002;14:607–12.
Coe CL, Lubach GR . Developmental consequences of antenatal dexamethasone treatment in nonhuman primates. Neurosci Biobehav Rev 2005;29:227–35.
Peltoniemi OM, Kari MA, Hallman M . Repeated antenatal corticosteroid treatment: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2011;90:719–27.
Rees SM, Camm EJ, Loeliger M, et al. Inhaled nitric oxide: effects on cerebral growth and injury in a baboon model of premature delivery. Pediatr Res 2007;61:552–8.
Loeliger M, Inder TE, Dalitz PA, et al. Developmental and neuropathological consequences of ductal ligation in the preterm baboon. Pediatr Res 2009;65:209–14.
Dieni S, Inder T, Yoder B, et al. The pattern of cerebral injury in a primate model of preterm birth and neonatal intensive care. J Neuropathol Exp Neurol 2004;63:1297–1309.
Gundersen HJ, Jensen EB . The efficiency of systematic sampling in stereology and its prediction. J Microsc 1987;147:229–63.
Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA . Neonatal chronic lung disease in extremely immature baboons. Am J Respir Crit Care Med 1999;160:1333–46.
Huang WL, Beazley LD, Quinlivan JA, Evans SF, Newnham JP, Dunlop SA . Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 1999;94:213–8.
Ligon KL, Alberta JA, Kho AT, et al. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J Neuropathol Exp Neurol 2004;63:499–509.
Bradl M, Lassmann H . Oligodendrocytes: biology and pathology. Acta Neuropathol 2010;119:37–53.
Waxman SG . Determinants of conduction velocity in myelinated nerve fibers. Muscle Nerve 1980;3:141–50.
Meister M, Wong RO, Baylor DA, Shatz CJ . Synchronous bursts of action potentials in ganglion cells of the developing mammalian retina. Science 1991;252:939–43.
Hagmann P, Sporns O, Madan N, et al. White matter maturation reshapes structural connectivity in the late developing human brain. Proc Natl Acad Sci USA 2010;107:19067–72.
Kumar S, Cole R, Chiappelli F, de Vellis J . Differential regulation of oligodendrocyte markers by glucocorticoids: post-transcriptional regulation of both proteolipid protein and myelin basic protein and transcriptional regulation of glycerol phosphate dehydrogenase. Proc Natl Acad Sci USA 1989;86:6807–11.
Tolcos M, Mallard C, McGregor H, Walker D, Rees S . Exposure to prenatal carbon monoxide and postnatal hyperthermia: short and long-term effects on neurochemicals and neuroglia in the developing brain. Exp Neurol 2000;162:235–46.
Acknowledgements
We acknowledge the major role that Terrie Inder has played in the premature baboon project. We are grateful to Rachael O’Dowd for her technical assistance and Michelle Loeliger for advice with tissue preparation and analysis.
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Shields, A., Thomson, M., Winter, V. et al. Repeated courses of antenatal corticosteroids have adverse effects on aspects of brain development in naturally delivered baboon infants. Pediatr Res 71, 661–667 (2012). https://doi.org/10.1038/pr.2012.18
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DOI: https://doi.org/10.1038/pr.2012.18


