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The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy

      Background

      Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight-adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy.

      Objective

      The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung.

      Study Design

      Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of betamethasone phosphate to target 12-hour fetal plasma betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2 ng/mL. In a subsequent experiment, fetal plasma betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (betamethasone phosphate + betamethasone acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses.

      Results

      The loading and maintenance doses were achieved and maintained the desired fetal plasma betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2 intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL betamethasone infusion group. Lambs from the 12-hour 2-ng/mL betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group.

      Conclusion

      In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose betamethasone phosphate infusion to achieve a fetal plasma betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy.

      Key words

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      References

        • Roberts D.
        • Brown J.
        • Medley N.
        • Dalzeil S.R.
        Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
        Cochrane Database Syst Rev. 2017; ([Epub ahead of print.])
        • Stoll B.J.
        • Hansen N.I.
        • Bell E.F.
        • et al.
        Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012.
        JAMA. 2015; 314: 1039-1051
        • Liggins G.C.
        • Howie R.N.
        A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
        Pediatrics. 1972; 50: 515-525
        • Newnham J.P.
        • White S.W.
        • Meharry S.
        • et al.
        Reducing preterm birth by a statewide multifaceted program: an implementation study.
        Am J Obstet Gynecol. 2017; 216: 434-442
        • Panel ACCPG
        Antenatal corticosteroids given to women prior to birth to improve fetal, infant, child and adult health: clinical practice guidelines.
        Liggins Institute, Auckland, New Zealand2015
        • Huang W.L.
        • Harper C.G.
        • Evans S.F.
        • Newnham J.P.
        • Dunlop S.A.
        Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep.
        Int J Dev Neurosci. 2001; 19: 415-425
        • Moss T.J.M.
        • Sloboda D.M.
        • Gurrin L.C.
        • Harding R.
        • Challis J.R.G.
        • Newnham J.P.
        Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure.
        Am J Physiol Regul Integr Comp Physiol. 2001; 281: R960-R970
        • Kutzler M.A.
        • Ruane E.K.
        • Coksaygan T.
        • Vincent S.E.
        • Nathanielsz P.W.
        Effects of three courses of maternally administered dexamethasone at 0.7, 0.75, and 0.8 of gestation on prenatal and postnatal growth in sheep.
        Pediatrics. 2004; 113: 313-319
        • Asztalos E.
        • Willan A.
        • Murphy K.
        • et al.
        Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5).
        BMC Pregnancy Childbirth. 2014; 14: 272
        • Asztalos E.V.
        • Murphy K.E.
        • Willan A.R.
        • et al.
        Multiple courses of antenatal corticosteroids for preterm Birth study outcomes in children at 5 years of age (MACS-5).
        JAMA Pediatr. 2013; 167: 1102-1110
        • Davis E.P.
        • Waffarn F.
        • Uy C.
        • Hobel C.J.
        • Glynn L.M.
        • Sandman C.A.
        Effect of prenatal glucocorticoid treatment on size at birth among infants born at term gestation.
        J Perinatol. 2009; 29: 731-737
        • Romejko-Wolniewicz E.
        • Teliga-Czajkowska J.
        • Czajkowski K.
        Antenatal steroids: can we optimize the dose?.
        Curr Opin Obstet Gynecol. 2014; 26: 77-82
        • Samtani M.N.
        • Lohle M.
        • Grant A.
        • Nathanielsz P.W.
        • Jusko W.J.
        Betamethasone pharmacokinetics after two prodrug formulations in sheep: implications for antenatal corticosteroid use.
        Drug Metab Dispos. 2005; 33: 1124-1130
        • Schmidt A.F.
        • Kemp M.W.
        • Kannan P.S.
        • et al.
        Antenatal dexamethasone vs betamethasone dosing for lung maturation in fetal sheep.
        Pediatr Res. 2017; 81: 496-503
        • Schmidt A.F.
        • Kemp M.W.
        • Rittenschober-Böhm J.
        • et al.
        Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep.
        Am J Obstet Gynecol. 2018; 218: 132.e1-132.e9
        • Notter R.H.
        • Egan E.A.
        • Kwong M.S.
        • Holm B.A.
        • Shapiro D.L.
        Lung surfactant replacement in premature lambs with extracted lipids from bovine lung lavage: effects of dose, dispersion technique, and gestational age.
        Pediatr Res. 1985; 19: 569-577
        • Kemp M.W.
        • Saito M.
        • Usuda H.
        • et al.
        Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate.
        Am J Obstet Gynecol. 2016; 215: 775.e1-775.e12
        • Zhang Y.
        • Huo M.
        • Zhou J.
        • Xie S.
        PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel.
        Comput Methods Programs Biomed. 2010; 99: 306-314
        • Kemp M.W.
        • Miura Y.
        • Payne M.S.
        • et al.
        Repeated maternal intramuscular or intraamniotic erythromycin incompletely resolves intrauterine Ureaplasma parvum infection in a sheep model of pregnancy.
        Am J Obstet Gynecol. 2014; 211: 134.e1-134.e9
        • Challis J.R.G.
        • Matthews S.G.
        • Gibb W.
        • Lye S.J.
        Endocrine and paracrine regulation of birth at term and preterm.
        Endocr Rev. 2000; 21: 514-550
        • Tello D.
        • Balsa E.
        • Acosta-Iborra B.
        • et al.
        Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting complex i activity.
        Cell Metab. 2011; 14: 768-779
        • Cruikshank W.W.
        • Kornfeld H.
        • Center D.M.
        Interleukin-16.
        J Leukoc Biol. 2000; 67: 757-766
        • Cote M.
        • Provost P.R.
        • Gerard-Hudon M.C.
        • Tremblay Y.
        Apolipoprotein C-II and lipoprotein lipase show a temporal and geographic correlation with surfactant lipid synthesis in preparation for birth.
        BMC Dev Biol. 2010; 10: 111
        • Echaide M.
        • Autilio C.
        • Arroyo R.
        • Perez-Gil J.
        Restoring pulmonary surfactant membranes and films at the respiratory surface.
        Biochim Biophys Acta. 2017; 1859: 1725-1739
        • Hanukoglu I.
        • Hanukoglu A.
        Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases.
        Gene. 2016; 579: 95-132
        • Ikegami M.
        • Jobe A.H.
        • Newnham J.
        • Polk D.H.
        • Willet K.E.
        • Sly P.
        Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs.
        Am J Respir Crit Care Med. 1997; 156: 178-184
        • Carlos R.Q.
        • Seidler F.J.
        • Slotkin T.A.
        Fetal dexamethasone exposure alters macromolecular characteristics of rat brain development: a critical period for regionally selective alterations?.
        Teratology. 1992; 46: 45-59
        • Christensen H.D.
        • Gonzalez C.L.
        • Stewart J.D.
        • Rayburn W.F.
        Multiple courses of antenatal betamethasone and cognitive development of mice offspring.
        J Matern Fetal Med. 2001; 10: 269-276
        • Cuffe J.S.M.
        • Dickinson H.
        • Simmons D.G.
        • Moritz K.M.
        Sex specific changes in placental growth and MAPK following short term maternal dexamethasone exposure in the mouse.
        Placenta. 2011; 32: 981-989
        • Murphy K.E.
        • Hannah M.E.
        • Willan A.R.
        • et al.
        Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
        Lancet. 2008; 372: 2143-2151
        • Gyamfi-Bannerman C.
        • Thom E.A.
        Antenatal betamethasone for women at risk for late preterm delivery.
        N Engl J Med. 2016; 375: 486-487
        • Della Torre M.
        • Hibbard J.U.
        • Jeong H.
        • Fischer J.H.
        Betamethasone in pregnancy: influence of maternal body weight and multiple gestation on pharmacokinetics.
        Am J Obstet Gynecol. 2010; 203: 254.e1-254.e12
        • Willet K.E.
        • Jobe A.H.
        • Ikegami M.
        • et al.
        Postnatal lung function after prenatal steroid treatment in sheep: effect of gender.
        Pediatr Res. 1997; 42: 885-892

      Linked Article

      • September 2018 (vol. 219, no. 3, page 301.e10)
        American Journal of Obstetrics & GynecologyVol. 220Issue 6
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          Kemp MW, Saito M, Usuda H, et al. The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy. Am J Obstet Gynecol 2018;219:301.e1-16.
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