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The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use

Published:February 29, 2012DOI:https://doi.org/10.1016/j.ajog.2012.02.016

      Objective

      To determine the impact of maternal and fetal single nucleotide polymorphisms in key betamethasone pathways on neonatal outcomes.

      Study Design

      DNA was obtained from women given betamethasone and their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway single nucleotide polymorphisms. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis using relevant clinical variables and genotypes to model for associations with neonatal respiratory distress syndrome was performed.

      Results

      One hundred nine women delivering 117 infants were analyzed. Sixty-four infants (49%) developed respiratory distress syndrome. Multivariable analysis revealed that respiratory distress syndrome was associated with maternal single nucleotide polymorphisms in CYP3A5 (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.16–2.30) and the glucocorticoid resistance (OR, 0.28; 95% CI, 0.08–0.95) and fetal single nucleotide polymorphisms in ADCY9 (OR, 0.17; 95% CI, 0.03–0.80) and CYP3A7*1E (rs28451617; OR, 23.68; 95% CI, 1.33–420.6).

      Conclusion

      Maternal and fetal genotypes are independently associated with neonatal respiratory distress syndrome after treatment with betamethasone for preterm labor.

      Key words

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      References

        • American College of ObstetriciansGynecologists
        ACOG practice bulletin no. 43.
        Obstet Gynecol. 2003; 101: 1039-1047
        • Frisbie W.P.
        • Forbes D.
        • Pullum S.G.
        Compromised birth outcomes and infant mortality among racial and ethnic groups.
        Demography. 1996; 33: 469-481
        • Frisbie W.P.
        • Song S.E.
        • Powers D.A.
        • Street J.A.
        The increasing racial disparity in infant mortality: respiratory distress syndrome and other causes.
        Demography. 2004; 41: 773-800
        • Kavvadia V.
        • Greenough A.
        • Dimitriou G.
        • Hooper R.
        Influence of ethnic origin on respiratory distress syndrome in very premature infants.
        Arch Dis Child Fetal Neonatal Ed. 1998; 78: F25-F28
        • Ensom M.H.
        • Chang T.K.
        • Patel P.
        Pharmacogenetics: the therapeutic drug monitoring of the future?.
        Clin Pharmacokinet. 2001; 40: 783-802
        • Scott S.A.
        • Sangkuhl K.
        • Gardner E.E.
        • et al.
        Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy.
        Clin Pharmacol Ther. 2011; 90: 328-332
        • Grossniklaus D.
        Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing.
        PLoS Curr. 2010; 2
        • Crettol S.
        • Venetz J.P.
        • Fontana M.
        • Aubert J.D.
        • Pascual M.
        • Eap C.B.
        CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients.
        Ther Drug Monit. 2008; 30: 689-699
        • Perloff M.D.
        • von Moltke L.L.
        • Cotreau M.M.
        • Greenblatt D.J.
        Unchanged cytochrome P450 3A (CYP3A) expression and metabolism of midazolam, triazolam, and dexamethasone in mdr(−/−) mouse liver microsomes.
        Biochem Pharmacol. 1999; 57: 1227-1232
        • Hawkins G.A.
        • Lazarus R.
        • Smith R.S.
        • et al.
        The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids.
        J Allergy Clin Immunol. 2009; 123 (e7): 1376-1383
        • Tantisira K.G.
        • Lake S.
        • Silverman E.S.
        • et al.
        Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.
        Hum Mol Genet. 2004; 13: 1353-1359
        • Weiss S.T.
        • Lake S.L.
        • Silverman E.S.
        • et al.
        Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses.
        Proc Am Thorac Soc. 2004; 1: 364-367
        • Stoll B.J.
        • Hansen N.I.
        • Bell E.F.
        • et al.
        Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network.
        Pediatrics. 2010; 126: 443-456
        • Lehmann A.S.
        • Haas D.M.
        • McCormick C.L.
        • Skaar T.C.
        • Renbarger J.L.
        Collection of human genomic DNA from neonates: a comparison between umbilical cord blood and buccal swabs.
        Am J Obstet Gynecol. 2011; 204: 362e1-362e6
        • Raby B.A.
        • Van Steen K.
        • Lasky-Su J.
        • et al.
        Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma.
        Respir Res. 2009; 10: 67
        • Tantisira K.
        • Weiss S.
        • Tantisira K.
        • Weiss S.
        The pharmacogenetics of asthma treatment.
        Curr Allergy Asthma Rep. 2009; 9: 10-17
        • Lamba J.K.
        • Lin Y.S.
        • Schuetz E.G.
        • Thummel K.E.
        Genetic contribution to variable human CYP3A-mediated metabolism.
        Adv Drug Deliv Rev. 2002; 54: 1271-1294
        • Cholerton S.
        • Daly A.K.
        • Idle J.R.
        The role of individual human cytochromes P450 in drug metabolism and clinical response.
        Trends Pharmacol Sci. 1992; 13: 434-439
        • Thummel K.E.
        • Wilkinson G.R.
        In vitro and in vivo drug interactions involving human CYP3A.
        Annu Rev Pharmacol Toxicol. 1998; 38: 389-430
        • Hebert M.F.
        • Easterling T.R.
        • Kirby B.
        • et al.
        Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study.
        Clin Pharmacol Ther. 2008; 84: 248-253
        • Tracy T.S.
        • Venkataramanan R.
        • Glover D.D.
        • Caritis S.N.
        Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy.
        Am J Obstet Gynecol. 2005; 192: 633-639
        • Smit P.
        • van Schaik R.H.
        • van der Werf M.
        • et al.
        A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels.
        J Clin Endocrinol Metab. 2005; 90: 5313-5316
        • Leeder J.S.
        • Gaedigk R.
        • Marcucci K.A.
        • et al.
        Variability of CYP3A7 expression in human fetal liver.
        J Pharmacol Exp Ther. 2005; 314: 626-635
        • Kalabis G.M.
        • Petropoulos S.
        • Gibb W.
        • Matthews S.G.
        Multidrug resistance phosphoglycoprotein (ABCB1) expression in the guinea pig placenta: developmental changes and regulation by betamethasone.
        Can J Physiol Pharmacol. 2009; 87: 973-978
        • Leschziner G.D.
        • Andrew T.
        • Pirmohamed M.
        • Johnson M.R.
        ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research.
        Pharmacogenomics J. 2006; 7: 154-179
        • van Rossum E.F.
        • van den Akker E.L.
        Glucocorticoid resistance.
        Endocr Dev. 2011; 20: 127-136
        • Tantisira K.G.
        • Small K.M.
        • Litonjua A.A.
        • Weiss S.T.
        • Liggett S.B.
        Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways.
        Hum Mol Genet. 2005; 14: 1671-1677
        • Jobe A.H.
        • Soll R.F.
        Choice and dose of corticosteroid for antenatal treatments.
        Am J Obstet Gynecol. 2004; 190: 878-881
        • Haas D.M.
        • McCullough W.
        • Olsen C.H.
        • et al.
        Neonatal outcomes with different betamethasone dosing regimens: a comparison.
        J Reprod Med. 2005; 50: 915-922
        • Ballard P.L.
        • Granberg P.
        • Ballard R.A.
        Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.
        J Clin Invest. 1975; 56: 1548-1554
        • Hebert M.F.
        • Ma X.
        • Naraharisetti S.B.
        • et al.
        Are we optimizing gestational diabetes treatment with glyburide?.
        Clin Pharmacol Ther. 2009; 85: 607-614