Abstract
Introduction:
Intrauterine growth restriction (IUGR) is associated with high rates of neonatal morbidity. IUGR babies are often born preterm and are, therefore, exposed to antenatal glucocorticoids. Antenatal glucocorticoids significantly improve overall survival rates of preterm infants, but there is a paucity of information about their effects on IUGR Infants.
Methods:
We induced IUGR in sheep by single umbilical artery ligation (SUAL), or sham in control fetuses. To half the ewes, we administered betamethasone (BM) on d 5 (BM1) and 6 (BM2) following surgery, and collected fetal lung tissue on d 7.
Results:
SUAL alone was associated with higher circulating fetal cortisol levels (2.8 ± 0.4 vs. 1.0 ± 0.4, P = 0.001) as compared with controls but not with changes in lung morphology or surfactant protein (SP) gene expression. BM was associated with a significant reduction in lung tissue density (P = 0.048). There were no significant differences between groups in lung DNA concentration or septal crest density. SP-A, SP-B, and SP-C gene expressions were significantly increased in control and SUAL fetuses that were administered BM.
Discussion:
These results show that in SUAL fetuses, maternal BM is associated with acceleration of fetal lung structure, as occurs in normally grown fetuses, and that BM induces SP production, an effect not observed in SUAL-induced IUGR fetuses alone.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Beck S, Wojdyla D, Say L, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ 2010;88:31–8.
NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. Effect of corticosteroids for fetal maturation on perinatal outcomes: NIH consensus development panel on the effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995;273:413–8.
Crowley PA . Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995;173:322–35.
Liggins GC . The role of cortisol in preparing the fetus for birth. Reprod Fertil Dev 1994;6:141–50.
Willet KE, Jobe AH, Ikegami M, Newnham J, Brennan S, Sly PD . Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs. Pediatr Res 2000;48:782–8.
Coalson JJ . Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73–81.
Gilbert WM, Danielsen B . Pregnancy outcomes associated with intrauterine growth restriction. Am J Obstet Gynecol 2003;188:1596–9.
Greenough A, Yuksel B, Cheeseman P . Effect of in utero growth retardation on lung function at follow-up of prematurely born infants. Eur Respir J 2004;24:731–3.
Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO . Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. BMJ 1991;303:671–5.
Maritz GS, Cock ML, Louey S, Joyce BJ, Albuquerque CA, Harding R . Effects of fetal growth restriction on lung development before and after birth: a morphometric analysis. Pediatr Pulmonol 2001;32:201–10.
Maritz GS, Cock ML, Louey S, Suzuki K, Harding R . Fetal growth restriction has long-term effects on postnatal lung structure in sheep. Pediatr Res 2004;55:287–95.
Joyce BJ, Louey S, Davey MG, Cock ML, Hooper SB, Harding R . Compromised respiratory function in postnatal lambs after placental insufficiency and intrauterine growth restriction. Pediatr Res 2001;50:641–9.
Mericq V, Medina P, Kakarieka E, Márquez L, Johnson MC, Iñiguez G . Differences in expression and activity of 11β-hydroxysteroid dehydrogenase type 1 and 2 in human placentas of term pregnancies according to birth weight and gender. Eur J Endocrinol 2009;161:419–25.
Torrance HL, Derks JB, Scherjon SA, Wijnberger LD, Visser GH . Is antenatal steroid treatment effective in preterm IUGR fetuses? Acta Obstet Gynecol Scand 2009;88:1068–73.
Miller SL, Chai M, Loose J, et al. The effects of maternal betamethasone administration on the intrauterine growth-restricted fetus. Endocrinology 2007;148:1288–95.
Miller SL, Supramaniam VG, Jenkin G, Walker DW, Wallace EM . Cardiovascular responses to maternal betamethasone administration in the intrauterine growth-restricted ovine fetus. Am J Obstet Gynecol 2009;201:613.e1–8.
Supramaniam VG, Jenkin G, Loose J, Wallace EM, Miller SL . Chronic fetal hypoxia increases activin A concentrations in the late-pregnant sheep. BJOG 2006;113:102–9.
Cock ML, Albuquerque CA, Joyce BJ, Hooper SB, Harding R . Effects of intrauterine growth restriction on lung liquid dynamics and lung development in fetal sheep. Am J Obstet Gynecol 2001;184:209–16.
Gagnon R, Langridge J, Inchley K, Murotsuki J, Possmayer F . Changes in surfactant-associated protein mRNA profile in growth-restricted fetal sheep. Am J Physiol 1999;276(3 Pt 1):L459–65.
Orgeig S, Crittenden TA, Marchant C, McMillen IC, Morrison JL . Intrauterine growth restriction delays surfactant protein maturation in the sheep fetus. Am J Physiol Lung Cell Mol Physiol 2010;298:L575–83.
Ballard PL, Ning Y, Polk D, Ikegami M, Jobe AH . Glucocorticoid regulation of surfactant components in immature lambs. Am J Physiol 1997;273(5 Pt 1):L1048–57.
Jobe AH, Nitsos I, Pillow JJ, Polglase GR, Kallapur SG, Newnham JP . Betamethasone dose and formulation for induced lung maturation in fetal sheep. Am J Obstet Gynecol 2009;201:611.e1–7.
Braems GA, Yao LJ, Inchley K, et al. Ovine surfactant protein cDNAs: use in studies on fetal lung growth and maturation after prolonged hypoxemia. Am J Physiol Lung Cell Mol Physiol 2000;278:L754–64.
Polglase GR, Nitsos I, Jobe AH, Newnham JP, Moss TJ . Maternal and intra-amniotic corticosteroid effects on lung morphometry in preterm lambs. Pediatr Res 2007;62:32–6.
Pringle KC . Human fetal lung development and related animal models. Clin Obstet Gynecol 1986;29:502–13.
Kotecha S . Lung growth for beginners. Paediatr Respir Rev 2000;1:308–13.
Quiros I, Mayo JC, Garcia-Suarez O, et al. Melatonin prevents glucocorticoid inhibition of cell proliferation and toxicity in hippocampal cells by reducing glucocorticoid receptor nuclear translocation. J Steroid Biochem Mol Biol 2008;110:116–24.
Oshika E, Liu S, Ung LP, et al. Glucocorticoid-induced effects on pattern formation and epithelial cell differentiation in early embryonic rat lungs. Pediatr Res 1998;43:305–14.
Vyas J, Kotecha S . Effects of antenatal and postnatal corticosteroids on the preterm lung. Arch Dis Child Fetal Neonatal Ed 1997;77:F147–50.
Pinkerton KE, Willet KE, Peake JL, Sly PD, Jobe AH, Ikegami M . Prenatal glucocorticoid and T4 effects on lung morphology in preterm lambs. Am J Respir Crit Care Med 1997;156(2 Pt 1):624–30.
McCallum J, Smith N, MacLachlan JN, et al. Effects of antenatal glucocorticoids on cerebral protein synthesis in the preterm ovine fetus. Am J Obstet Gynecol 2008;198:103.e1–6.
Shelton SD, Boggess KA, Smith T, Herbert WN . Effect of betamethasone on maternal glucose. J Matern Fetal Neonatal Med 2002;12:191–5.
Foglia LM, Deering SH, Lim E, Landy H . Maternal glucose levels after dexamethasone for fetal lung development in twin vs singleton pregnancies. Am J Obstet Gynecol 2008;199:380.e1–4.
Magnusson AL, Powell T, Wennergren M, Jansson T . Glucose metabolism in the human preterm and term placenta of IUGR fetuses. Placenta 2004;25:337–46.
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(1 Pt 1):114–21.
Jenkin G, Jorgensen G, Thorburn GD, Buster JE, Nathanielsz PW . Induction of premature delivery in sheep following infusion of cortisol to the fetus. I. The effect of maternal administration of progestagens. Can J Physiol Pharmacol 1985;63:500–8.
Robertson MC, Murila F, Tong S, Baker LS, Yu VY, Wallace EM . Predicting perinatal outcome through changes in umbilical artery Doppler studies after antenatal corticosteroids in the growth-restricted fetus. Obstet Gynecol 2009;113:636–40.
Wallace EM, Baker LS . Effect of antenatal betamethasone administration on placental vascular resistance. Lancet 1999;353:1404–7.
Allison BJ, Crossley KJ, Flecknoe SJ, Davis PG, Morley CJ, Hooper SB . Ventilation and oxygen: dose-related effects of oxygen on ventilation-induced lung injury. Pediatr Res 2010;67:238–43.
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H . Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984;133:1710–5.
Bocking AD, McMillen IC, Harding R, Thorburn GD . Effect of reduced uterine blood flow on fetal and maternal cortisol. J Dev Physiol 1986;8:237–45.
Acknowledgements
We thank Alex Satragno for his surgical assistance and Tharani Sabaretnam and Jan Loose for technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sutherland, A., Crossley, K., Allison, B. et al. The effects of intrauterine growth restriction and antenatal glucocorticoids on ovine fetal lung development. Pediatr Res 71, 689–696 (2012). https://doi.org/10.1038/pr.2012.19
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2012.19
This article is cited by
-
Mortality and neurological outcomes in extremely and very preterm infants born to mothers with hypertensive disorders of pregnancy
Scientific Reports (2021)
-
Antenatal corticosteroids and preterm offspring outcomes in hypertensive disorders of pregnancy: A Japanese cohort study
Scientific Reports (2020)
-
Fetal growth restriction is associated with an altered cardiopulmonary and cerebral hemodynamic response to surfactant therapy in preterm lambs
Pediatric Research (2019)
-
Altered cardiovascular function at birth in growth-restricted preterm lambs
Pediatric Research (2016)


