Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Antenatal corticosteroid administration is associated with decreased growth of the fetal thymus: a prospective cohort study

Abstract

Objective

To examine the effect of antenatal corticosteroid administration (ACS) on fetal thymus growth in women who received ACS compared with gestational-age-matched controls.

Study design

Fetal thymus size and growth were measured in women at risk for preterm delivery who received ACS and compared with a matched cohort of women who were at low risk for preterm delivery and did not receive ACS. Fetal thymus perimeter and diameter were measured by 2-D ultrasound at baseline and every 2 weeks until delivery.

Results

After adjusting for confounders, ACS exposure was associated with a significant reduction in thymus perimeter size (−0.70; 95% CI: −1.33, −0.07; P = 0.03). For every additional week of exposure, thymus growth trajectory was significantly decreased in ACS-exposed fetuses (P = 0.04).

Conclusion

The association between ACS and reduced fetal thymus growth should be further examined to establish the impact of ACS on childhood thymus development and immune programming.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Committee on Obstetric Practice. Committee opinion no. 713: antenatal corticosteroid therapy for fetal maturation. Obstet Cynecol. 2017;2:e102–9.

    Google Scholar 

  2. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;19:CD004454.

  3. Melamed N, Shah J, Soraisham A, Yoon EW, Lee SK, Shah PS, et al. Association between antenatal corticosteroid administration-to-birth interval and outcomes of preterm neonates. Obstet Gynecol. 2015;125:1377–84.

    CAS  PubMed  Google Scholar 

  4. Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, et al. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med. 2016;374:1311–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Andrews M, Matthews S. Antenatal glucocorticoids: is there cause for concern? Fetal Matern Med Rev. 2003;14:329–54.

    Google Scholar 

  6. Erni K, Shaqiri-Emini L, La Marca R, Zimmermann R, Ehlert U. Psychobiological effects of prenatal glucocorticoid exposure in 10-year-old-children. Front Psychiatry. 2012;3:104.

    PubMed  PubMed Central  Google Scholar 

  7. Aghajafari Murphy FK, Matthews S, Ohlsson A, Amankwah K, Hannah M. Repeated doses of antenatal corticosteroids in animals: a systematic review. Am J Obstet Gynecol. 2002;186:843–9.

    PubMed  Google Scholar 

  8. Braun T, Challis JR, Newnham JP, Sloboda DM. Early-life glucocorticoid exposure: the hypothalamic-pituitary-adrenal axis, placental function, and long-term disease risk. Endocr Rev. 2013;34:885–916.

    CAS  PubMed  Google Scholar 

  9. Chabra S, Cottrill C, Rayens MK, Cross R, Lipke D, Bruce M. Lymphocyte subsets in cord blood of preterm infants: effect of antenatal steroids. Biol Neonate. 1998;74:200–7.

    CAS  PubMed  Google Scholar 

  10. Kavelaars A, van der Pompe G, Bakker JM, van Hasselt PM, Cats B, Visser GH, et al. Altered immune function in human newborns after prenatal administration of betamethasone: enhanced natural killer cell activity and decreased T cell proliferation in cord blood. Pediatr Res. 1999;45:306–12.

    CAS  PubMed  Google Scholar 

  11. Cohen JJ, Duke RC. Glucocorticoid activation of a calcium dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol. 1984;132:38–42.

    CAS  PubMed  Google Scholar 

  12. Diemert A, Hartwig I, Pagenkemper M, Mehnert R, Hansen G, Tolosa E, et al. Fetal thymus size in human pregnancies reveals inverse association with regulatory T cell frequencies in cord blood. J Reprod Immunol. 2016;113:76–82.

    CAS  PubMed  Google Scholar 

  13. Cho JY, Min JY, Lee YH, McCrindle B, Hornberger LK, Yoo SJ. Diameter of the normal fetal thymus on ultrasound. Ultrasound Obstet Gynecol. 2007;29:634–8.

    CAS  PubMed  Google Scholar 

  14. Zalel Y, Gamzu R, Mashiach S, Achiron R. The development of the fetal thymus: an in utero sonographic evaluation. Prenat Diagn. 2002;22:114–7.

    PubMed  Google Scholar 

  15. Streiner DL, Norman GR. Correction for multiple testing: is there a resolution? Chest. 2011;140:16–8.

    PubMed  Google Scholar 

  16. Li L, Bahtiyar MO, Buhimschi CS, Zou L, Zhou QC, Copel JA. Assessment of the fetal thymus by two- and three-dimensional ultrasound during normal human gestation and in fetuses with congenital heart defects. Ultrasound Obstet Gynecol. 2011;37:404–9.

    CAS  PubMed  Google Scholar 

  17. Peelen MJ, Kazemier BM, Ravelli AC, De Groot CJ, Van Der Post JA, Mol BW, et al. Impact of fetal gender on the risk of preterm birth, a national cohort study. Acta Obstet Gynecol Scand. 2016;95:1034–41.

    PubMed  Google Scholar 

  18. Hertz-Picciotto I, Park HY, Dostal M, Kocan A, Trnovec T, Sram R. Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development. Basic Clin Pharm Toxicol. 2008;102:146–54.

    CAS  Google Scholar 

  19. Morrissey PJ, Charrier K, Alpert A, Bressler L. In vivo administration of IL-1 induces thymic hypoplasia and increased levels of serum corticosterone. J Immunol. 1988;141:1456–63.

    CAS  PubMed  Google Scholar 

  20. Vacchio MS, Ashwell JD, King LB. A positive role for thymus-derived steroids in formation of the T-cell repertoire. Ann N Y Acad Sci. 1998;840:317–27.

    CAS  PubMed  Google Scholar 

  21. Alexander N, Rosenlocher F, Stalder T, Linke J, Distler W, Morgner J, et al. Impact of antenatal synthetic glucocorticoid exposure on endocrine stress reactivity in term-born children. J Clin Endocrinol Metab. 2012;97:3538–44.

    CAS  PubMed  Google Scholar 

  22. Iqbal M, Audette MC, Petropoulos S, Gibb SW, Matthews SG. Placental drug transporters and their role in fetal protection. Placenta. 2012;33:137–42.

    CAS  PubMed  Google Scholar 

  23. Bale TL. Lifetime stress experience: transgenerational epigenetics and germ cell programming. Dialogues Clin Neurosci. 2014;16:297–305.

    PubMed  PubMed Central  Google Scholar 

  24. Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet. 2005;365:1856–62.

    CAS  PubMed  Google Scholar 

  25. Schaffer L, Luzi F, Burkhardt T, Rauh M, Beinder E. Antenatal betamethasone administration alters stress physiology in healthy neonates. Obstet Gynecol. 2009;113:1082–8.

    CAS  PubMed  Google Scholar 

  26. Diepenbruck I, Much CC, Krumbholz A, Kolster M, Thieme R, Thieme D, et al. Effect of prenatal steroid treatment on the developing immune system. J Mol Med. 2013;91:1293–302.

    CAS  PubMed  Google Scholar 

  27. Kuypers E, Collins JJ, Jellema RK, Wolfs TG, Kemp MW, Nitsos I, et al. Ovine fetal thymus response to lipopolysaccharide-induced chorioamnionitis and antenatal corticosteroids. PLoS One. 2012;7:e38257.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kunzmann S, Glogger K, Been JV, Kallapur SG, Nitsos I, Moss TJ, et al. Thymic changes after chorioamnionitis induced by intraamniotic lipopolysaccharide in fetal sheep. Am J Obstet Gynecol. 2010;202:476 e471–9.

    Google Scholar 

  29. Yinon Y, Zalel Y, Weisz B, Mazaki-Tovi S, Sivan E, Schiff E, et al. Fetal thymus size as a predictor of chorioamnionitis in women with preterm premature rupture of membranes. Ultrasound Obstet Gynecol. 2007;29:639–43.

    CAS  PubMed  Google Scholar 

  30. Olearo E, Oberto M, Ogge G, Botta G, Pace C, Gaglioti P, et al. Thymic volume in healthy, small for gestational age and growth restricted fetuses. Prenat Diagn. 2012;32:662–7.

    PubMed  Google Scholar 

  31. Cromi A, Ghezzi F, Raffaelli R, Bergamini V, Siesto G, Bolis P. Ultrasonographic measurement of thymus size in IUGR fetuses: a marker of the fetal immunoendocrine response to malnutrition. Ultrasound Obstet Gynecol. 2009;33:421–6.

    CAS  PubMed  Google Scholar 

  32. Mohamed N, Eviston DP, Quinton AE, Benzie RJ, Kirby AC, Peek MJ, et al. Smaller fetal thymuses in pre-eclampsia: a prospective cross-sectional study. Ultrasound Obstet Gynecol. 2011;37:410–5.

    CAS  PubMed  Google Scholar 

  33. El-Haieg DO, Zidan AA, El-Nemr MM. The relationship between sonographic fetal thymus size and the components of the systemic fetal inflammatory response syndrome in women with preterm prelabour rupture of membranes. BJOG. 2008;115:836–41.

    CAS  PubMed  Google Scholar 

  34. Basu S, Dewangan S, Shukla RC, Anupurva S, Kumar A. Thymic involution as a predictor of early-onset neonatal sepsis. Paediatr Int Child Health. 2012;32:147–51.

    PubMed  Google Scholar 

  35. Aksakal SE, Kandemir O, Altinbas S, Esin S, Muftuoglu KH. Fetal thymus size as a predictor of histological chorioamnionitis in preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2014;27:1118–22.

    PubMed  Google Scholar 

  36. Jeppesen DL, Ersboll AK, Nielsen SD, Hoppe TU, Valerius NH. Low thymic size in preterm infants in the neonatal intensive care unit, a possible marker of infection? A prospective study from birth to 1 year of age. Acta Paediatr. 2011;100:1319–25.

    CAS  PubMed  Google Scholar 

  37. Kolte L, Rosenfeldt V, Vang L, Jeppesen D, Karlsson I, Ryder LP, et al. Reduced thymic size but no evidence of impaired thymic function in uninfected children born to human immunodeficiency virus-infected mothers. Pediatr Infect Dis J. 2011;30:325–30.

    PubMed  Google Scholar 

  38. Garly ML, Trautner SL, Marx C, Danebod K, Nielsen J, Ravn H, et al. Thymus size at 6 months of age and subsequent child mortality. J Pediatr. 2008;153:683–8. 688 e1–3

    PubMed  Google Scholar 

  39. Moore SE, Fulford AJ, Wagatsuma Y, Persson LA, Arifeen SE, Prentice AM. Thymus development and infant and child mortality in rural Bangladesh. Int J Epidemiol. 2014;43:216–23.

    PubMed  Google Scholar 

  40. Airo P, Scarsi M, Brucato A, Benicchi T, Malacarne F, Cavazzana I, et al. Characterization of T-cell population in children with prolonged fetal exposure to dexamethasone for anti-Ro/SS-A antibodies associated congenital heart block. Lupus. 2006;15:553–61.

    CAS  PubMed  Google Scholar 

  41. Namazy JA, Chambers C, Schatz M. Safety of therapeutic options for treating asthma in pregnancy. Expert Opin Drug Saf. 2014;13:1613–21.

    CAS  PubMed  Google Scholar 

  42. Magu S, Gathwala G, Agarwal S, Parihar A. Sonographic measurement of thymic size in preterm infants: prediction model for thymic size in the Indian subcontinent. Indian J Pediatr. 2012;79:764–8.

    PubMed  Google Scholar 

  43. Gamez F, De Leon-Luis J, Pintado P, Perez R, Robinson JN, Antolin E, et al. Fetal thymus size in uncomplicated twin and singleton pregnancies. Ultrasound Obstet Gynecol. 2010;36:302–7.

    CAS  PubMed  Google Scholar 

  44. De Leon-Luis J, Gamez F, Pintado P, Antolin E, Perez R, Ortiz-Quintana L, et al. Sonographic measurements of the thymus in male and female fetuses. J Ultrasound Med. 2009;28:43–8.

    PubMed  Google Scholar 

  45. Gur EB, Gur MS, Ince O, Kasap E, Genc M, Tatar S, et al. Vitamin D deficiency in pregnancy may affect fetal thymus development. Ginekol Pol. 2016;87:378–83.

    PubMed  Google Scholar 

  46. Michie CA, Hasson N, Tulloh R. The neonatal thymus and antenatal steroids. Arch Dis Child Fetal Neonatal Ed. 1998;79:F159.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. C. Society for Maternal-Fetal Medicine Publications. Implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery. Am J Obstet Gynecol. 2016;215:B13–5.

    Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Sharon Adams (SA), Meredith Hood (MH), Caroline Crerar (CC), and Louisa Loizides (LL), sonographers employed at St. Michaels Hospital, for performing the ultrasounds for this study. The authors would also like to thank Kate Besel, research assistant at St. Michaels Hospital, and David Gurau, resident in Obstetrics and Gynaecology at the University of Toronto, for helping with study recruitment and recording study data.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Howard Berger.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jones, C.A., Nisenbaum, R., De Souza, L.R. et al. Antenatal corticosteroid administration is associated with decreased growth of the fetal thymus: a prospective cohort study. J Perinatol 40, 30–38 (2020). https://doi.org/10.1038/s41372-019-0554-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-019-0554-z

This article is cited by

Search

Quick links