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Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data

Pediatric Researchvolume 84pages458465 (2018) | Download Citation




Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.


We used preterm baboons, mice, and humans (≤276/7 weeks gestation) to examine betamethasone’s effects on ductus gene expression and constriction both in vitro and in vivo.


In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone’s effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone’s contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26–27 weeks gestation, betamethasone’s contractile effects were apparent even in the absence of prostaglandin inhibitors.


We speculate that betamethasone’s contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone’s effects vary according to the infant’s developmental age at birth.

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  1. 1.

    Clyman, R. in Fetal and Neonatal Physiology 5th edn (ed Polin, R. et al.) 592–598 (Elsevier, Philadelphia, PA, 2017).

  2. 2.

    Clyman, R. I. et al. Effects of antenatal glucocorticoid administration on the ductus arteriosus of preterm lambs. Am. J. Physiol. 241, H415–H420 (1981).

  3. 3.

    Momma, K., Nishihara, S. & Ota, Y. Constriction of the fetal ductus arteriosus by glucocorticoid hormones. Pediatr. Res. 15, 19–21 (1981).

  4. 4.

    Wasserstrum, N. et al. Betamethasone and the human fetal ductus arteriosis. Obstet. Gynecol. 74, 897–900 (1989).

  5. 5.

    Kahler, C., Schleussner, E., Moller, A. & Seewald, H. J. Doppler measurements in fetoplacental vessels after maternal betamethasone administration. Fetal Diagn. Ther. 19, 52–57 (2004).

  6. 6.

    Clyman, R. I. et al. Prenatal administration of betamethasone for prevention of patient ductus arteriosus. J. Pediatr. 98, 123–126 (1981).

  7. 7.

    Doyle, L. W. et al. Effects of antenatal steroid therapy on mortality and morbidity in very low birth weight infants. J. Pediatr. 108, 287–292 (1986).

  8. 8.

    Waffarn, F., Siassi, B., Cabal, L. & Schmidt, P. L. Effect of antenatal glucocorticoids on clinical closure of the ductus arteriosus. Am. J. Dis. Child 137, 336–338 (1983).

  9. 9.

    Eronen, M., Kari, A., Pesonen, E. & Hallman, M. The effect of antenatal dexamethasone administration on the fetal and neonatal ductus arteriosus. A randomized double-blind study. Am. J. Dis. Child. 147, 187–192 (1993).

  10. 10.

    Park, H. W., Choi, Y. S., Kim, K. S. & Kim, S. N. Chorioamnionitis and patent ductus arteriosus: a systematic review and meta-analysis. PLoS ONE 10, e0138114 (2015).

  11. 11.

    Onland, W., de Laat, M. W., Mol, B. W. & Offringa, M. Effects of antenatal corticosteroids given prior to 26 weeks’ gestation: a systematic review of randomized controlled trials. Am. J. Perinatol. 28, 33–44 (2011).

  12. 12.

    Crowley, P. A. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am. J. Obstet. Gynecol. 173, 322–335 (1995).

  13. 13.

    Liebowitz, M. & Clyman, R. I. Prophylactic indomethacin compared with delayed conservative management of the patent ductus arteriosus in extremely preterm infants: effects on neonatal outcomes. J. Pediatr. 187, 119–126 (2017).

  14. 14.

    Vidaeff, A. C., Ramin, S. M., Gilstrap, L. C. 3rd & Alcorn, J. L. Characterization of corticosteroid redosing in an in vitro cell line model. Am. J. Obstet. Gynecol. 191, 1403–1408 (2004).

  15. 15.

    Ring, A. M. et al. The effect of a prolonged time interval between antenatal corticosteroid administration and delivery on outcomes in preterm neonates: a cohort study. Am. J. Obstet. Gynecol. 196, 457 e451–456 (2007).

  16. 16.

    Costa, S., Zecca, E., De Luca, D., De Carolis, M. P. & Romagnoli, C. Efficacy of a single dose of antenatal corticosteroids on morbidity and mortality of preterm infants. Eur. J. Obstet. Gynecol. Reprod. Biol. 131, 154–157 (2007).

  17. 17.

    Liebowitz, M. & Clyman, R. I. Antenatal betamethasone: a prolonged time interval from administration to delivery is associated with an increased incidence of severe intraventricular hemorrhage in infants born before 28 weeks gestation. J. Pediatr. 177, 114–120.e111 (2016).

  18. 18.

    Coalson, J. J., Winter, V. T., Siler-Khodr, T. & Yoder, B. A. Neonatal chronic lung disease in extremely immature baboons. Am. J. Respir. Crit. Care Med. 160, 1333–1346 (1999).

  19. 19.

    Waleh, N. et al. Patterns of gene expression in the ductus arteriosus are related to environmental and genetic risk factors for persistent ductus patency. Pediatr. Res. 68, 292–297 (2010).

  20. 20.

    Stewart, J. D., Gonzalez, C. L., Christensen, H. D. & Rayburn, W. F. Impact of multiple antenatal doses of betamethasone on growth and development of mice offspring. Am. J. Obstet. Gynecol. 177, 1138–1144 (1997).

  21. 21.

    Ozdemir, H., Guvenal, T., Cetin, M., Kaya, T. & Cetin, A. A placebo-controlled comparison of effects of repetitive doses of betamethasone and dexamethasone on lung maturation and lung, liver, and body weights of mouse pups. Pediatr. Res. 53, 98–103 (2003).

  22. 22.

    Plosa, E. J. et al. Epithelial beta1 integrin is required for lung branching morphogenesis and alveolarization. Development 141, 4751–4762 (2014).

  23. 23.

    Gonzales, L. W., Guttentag, S. H., Wade, K. C., Postle, A. D. & Ballard, P. L. Differentiation of human pulmonary type II cells in vitro by glucocorticoid plus cAMP. Am. J. Physiol. Lung. Cell Mol. Physiol. 283, L940–L951 (2002).

  24. 24.

    Waleh, N. et al. Effects of advancing gestation and non-caucasian race on ductus arteriosus gene expression. J. Pediatr. 167, 1033–1041 e1032 (2015).

  25. 25.

    Shelton, E. L. et al. Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone. Physiol. Genom. 46, 457–466 (2014).

  26. 26.

    Reese, J. et al. Chronic in utero cyclooxygenase inhibition alters PGE2-regulated ductus arteriosus contractile pathways and prevents postnatal closure. Pediatr. Res. 66, 155–161 (2009).

  27. 27.

    El-Khuffash, A. et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr. Res. 76, 238–244 (2014).

  28. 28.

    Coceani, F. & Baragatti, B. Mechanisms for ductus arteriosus closure. Semin. Perinatol. 36, 92–97 (2012).

  29. 29.

    Doyle L. W., Ehrenkranz R. A., & Halliday H. L. Early (8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2014:CD001146.

  30. 30.

    Schena, F. et al. Association between hemodynamically significant patent ductus arteriosus and bronchopulmonary dysplasia. J. Pediatr. 166, 1488–1492 (2015).

  31. 31.

    Schmidt, B. et al. Effects of prophylactic indomethacin in extremely low-birth-weight infants with and without adequate exposure to antenatal corticosteroids. Arch. Pediatr. Adolesc. Med. 165, 642–646 (2011).

  32. 32.

    Peltoniemi, O. M., Kari, M. A. & Hallman, M. Repeated antenatal corticosteroid treatment: a systematic review and meta-analysis. Acta Obstet. Gynecol. Scand. 90, 719–727 (2011).

  33. 33.

    Liu, H., Manganiello, V. C. & Clyman, R. I. Expression, activity and function of cAMP and cGMP phosphodiesterases in the mature and immature ductus arteriosus. Pediatr. Res. 64, 477–481 (2008).

  34. 34.

    Toyoshima, K., Momma, K., Imamura, S. & Nakanishi, T. In vivo dilatation of the fetal and postnatal ductus arteriosus by inhibition of phosphodiesterase 3 in rats. Biol. Neonate. 89, 251–256 (2006).

  35. 35.

    Ichikawa, Y. et al. Inhibition of phosphodiesterase type 3 dilates the rat ductus arteriosus without inducing intimal thickening. Circ. J. 76, 2456–2464 (2012).

  36. 36.

    Waleh, N. et al. Oxygen-induced tension in the sheep ductus arteriosus: effects of gestation on potassium and calcium channel regulation. Pediatr. Res. 65, 285–290 (2009).

  37. 37.

    Michelakis, E. et al. Voltage-gated potassium channels in human ductus arteriosus. Lancet 356, 134–137 (2000).

  38. 38.

    Thebaud, B. et al. Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus. Circulation 110, 1372–1379 (2004).

  39. 39.

    Roghair, R. D. et al. Late-gestation betamethasone enhances coronary artery responsiveness to angiotensin II in fetal sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R80–R88 (2004).

  40. 40.

    Pagni, E., Baragatti, B., Scebba, F. & Coceani, F. Functional closure of the ductus arteriosus at birth: evidence against an intermediary role of angiotensin II. Pharmacology 93, 120–125 (2014).

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This work was supported by a grant from U.S. Public Health Service NHLBI (HL109199, HL46691, HL56061, HL132805, HL52636 BPD Resource Center, and P51RR13986 Primate Center facility support) and by a gift from the Jamie and Bobby Gates Foundation.

Author information


  1. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    • Elaine L. Shelton
    • , Erin J. Plosa
    • , John T. Benjamin
    • , Christopher W. Hooper
    • , Noah J. Ehinger
    • , Stanley Poole
    • , Naoko Brown
    •  & Jeff Reese
  2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    • Elaine L. Shelton
  3. Biosciences Division, SRI International, Menlo Park, CA, USA

    • Nahid Waleh
  4. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    • Ginger L. Milne
  5. Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA

    • Steven Seidner
    •  & Donald McCurnin
  6. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    • Jeff Reese
  7. Departments of Pediatrics and Cardiovascular Research Center, University of California San Francisco, San Francisco, CA, USA

    • Ronald I. Clyman


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The authors declare no competing interests.

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Correspondence to Ronald I. Clyman.

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