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Am J Physiol Endocrinol Metab 295: E170-E178, 2008. First published May 20, 2008; doi:10.1152/ajpendo.00047.2008
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Repeated betamethasone treatment of pregnant sheep programs persistent reductions in circulating IGF-I and IGF-binding proteins in progeny

Kathryn L. Gatford,1 Julie A. Owens,1 Shaofu Li,2 Timothy J. M. Moss,2,3 John P. Newnham,2,3 John R. G. Challis,4 and Deborah M. Sloboda2,3

1Research Centre for Early Origins of Adult Disease, Discipline of Obstetrics and Gynecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide; 2School of Women's and Infant's Health, The University of Western Australia, Perth; 3Women and Infants Research Foundation of Western Australia, Subiaco, Perth, Australia; and 4Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Ontario, Canada

Submitted 24 January 2008 ; accepted in final form 15 May 2008

Exposure to synthetic glucocorticoids in utero markedly improves survival after preterm birth, but repeated exposures impair fetal and postnatal growth and are associated with evidence of insulin resistance in later life. The insulin-like growth factor (IGF) axis is an important regulator of growth and metabolism before and after birth. We have therefore investigated the effects of repeated maternal betamethasone injections on plasma IGF-I, IGF-II, and IGF-binding proteins (IGFBP) in fetal and postnatal progeny in the sheep. Pregnant sheep carrying male fetuses were injected with saline or betamethasone at 104, 111, and 118 days of gestation (dG, term ~150 dG). Plasma samples were collected postmortem from fetuses before (75, 84, 101 dG) or after one (109 dG), two (116 dG), or three (121–122, 132–133, 145–147 dG) doses of saline or betamethasone and from progeny at 42 and 84 days of age. Fetal weight was reduced after two or more maternal betamethasone injections, and this effect persisted to term. Repeated betamethasone exposures reduced plasma IGF-I and total IGFBP in fetuses at 133 dG and progeny at 84 days, and reduced plasma IGFBP-3 at 84 days. Fetal plasma IGF-II tended to increase transiently at 109 dG following the first betamethasone injection. Fetal, placental, and/or postnatal weights correlated positively with concomitant plasma IGF-I, IGF-II, and total IGFBP. We conclude that repeated exposure to synthetic glucocorticoids in utero programs the IGF axis before and after birth, which may contribute to the adverse effects of betamethasone exposure on growth and metabolism.

antenatal glucocorticoids; pregnancy; programming; insulin-like growth factor-binding protein


Address for reprint requests and other correspondence: K. L. Gatford, Research Centre for Early Origins of Adult Disease, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Univ. of Adelaide SA 5005, Australia (e-mail: kathy.gatford{at}adelaide.edu.au)






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