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Am J Perinatol 2024; 41(04): 395-404
DOI: 10.1055/s-0042-1760386
Review Article

Long-Term Outcomes of Multiple versus a Single Course of Antenatal Steroids: A Systematic Review

Kiran Ninan 
1   Department of Obstetrics and Gynecology, McMaster University, Ontario, Canada
2   Department of Health Research Methods, Evidence, and Impact, McMaster University, Ontario, Canada
,
Sugee K. Liyanage
1   Department of Obstetrics and Gynecology, McMaster University, Ontario, Canada
,
Kellie E. Murphy
3   Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Toronto, Toronto, Ontario, Canada
,
Elizabeth V. Asztalos 
4   Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
,
Sarah D. McDonald 
1   Department of Obstetrics and Gynecology, McMaster University, Ontario, Canada
2   Department of Health Research Methods, Evidence, and Impact, McMaster University, Ontario, Canada
5   Department of Radiology, McMaster University, Ontario, Canada
6   Division of Maternal-Fetal Medicine, McMaster University, Ontario, Canada
› Author Affiliations Funding S.D.M. is supported by a Tier II Canadian Institutes of Health Research (CIHR) Canada Research Chair (grant number: 950-229920). CIHR was not involved in any aspect of this study and the authors declare no sources of financial support or competing interests for this project.
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Abstract

Multiple courses versus a single course of antenatal corticosteroids (ACS) have been associated with mild respiratory benefits but also adverse outcomes like smaller head circumference and birth weight. Long-term effects warrant study. We systematically reviewed long-term outcomes (≥1 year) in both preterm and term birth after exposure to preterm multiple courses (including a rescue dose or course) versus a single course. We searched seven databases from January 2000 to October 2021. We included follow-up studies of randomized controlled trials (RCTs) and cohort studies with births occurring in/after the year 2000, given advances in perinatal care. Two reviewers assessed titles/abstracts, articles, quality, and outcomes including psychological disorders, neurodevelopment, and anthropometry. Six follow-up studies of three RCTs and two cohort studies (over 2,860 children total) met inclusion criteria. Among children born preterm, randomization to multiple courses versus a single course of ACS was not associated with adjusted beneficial or adverse neurodevelopmental/psychological or other outcomes, but data are scant after a rescue dose (120 and 139 children, respectively, low certainty) and nonexistent after a rescue course. For children born at term (i.e., 27% of the multiple courses of ACS 5-year follow-up study of 1,728 preterm/term born children), preterm randomization to multiple courses (at least one additional course) versus a single course was significantly associated with elevated odds of neurosensory impairment (adjusted odds ratio = 3.70, 95% confidence interval: 1.57–8.75; 212 and 247 children, respectively, moderate certainty). In this systematic review of long-term outcomes after multiple courses versus a single course of ACS, there were no significant benefits or risks regarding neurodevelopment in children born preterm but little data after one rescue dose and none after a rescue course. However, multiple courses (i.e., at least one additional course) should be considered cautiously: after term birth, there are no long-term benefits but neurosensory harms.

Key Points

  • We systematically reviewed the long-term impact of multiple versus a single course of ACS.

  • Long-term follow-up data were scant after a rescue dose and absent after one rescue course of ACS.

  • In children born preterm, multiple courses of ACS were not associated with long-term benefits/harms.

  • In children born at term, multiple courses of ACS were associated with neurosensory impairment.

  • Preterm administration of multiple courses of ACS should be considered cautiously.

Keywords

antenatal corticosteroids - long-term outcomes - neurodevelopment - systematic review

Supplementary Material



Publication History

Received: 24 March 2022

Accepted: 25 October 2022

Article published online:
01 February 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Committee on Obstetric Practice. Committee opinion no. 713: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2017; 130 (02) e102-e109
    CrossrefPubMedGoogle Scholar
  • 2 World Health Organization. WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Geneva, Switzerland: WHO publication; 2015
    Google Scholar
  • 3 Skoll A, Boutin A, Bujold E. et al. No. 364-antenatal corticosteroid therapy for improving neonatal outcomes. J Obstet Gynaecol Can 2018; 40 (09) 1219-1239
    CrossrefPubMedGoogle Scholar
  • 4 Razaz N, Skoll A, Fahey J, Allen VM, Joseph KS. Trends in optimal, suboptimal, and questionably appropriate receipt of antenatal corticosteroid prophylaxis. Obstet Gynecol 2015; 125 (02) 288-296
    CrossrefPubMedGoogle Scholar
  • 5 Adams TM, Kinzler WL, Chavez MR, Vintzileos AM. The timing of administration of antenatal corticosteroids in women with indicated preterm birth. Am J Obstet Gynecol 2015; 212 (05) 645.e1-645.e4
    CrossrefPubMedGoogle Scholar
  • 6 Vis JY, Wilms FF, Kuin RA. et al. Time to delivery after the first course of antenatal corticosteroids: a cohort study. Am J Perinatol 2011; 28 (09) 683-688
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Adams TM, Kinzler WL, Chavez MR, Fazzari MJ, Vintzileos AM. Practice patterns in the timing of antenatal corticosteroids for fetal lung maturity. J Matern Fetal Neonatal Med 2015; 28 (13) 1598-1601
    CrossrefPubMedGoogle Scholar
  • 8 Crowther CA, McKinlay CJ, Middleton P, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev 2015; (07) CD003935
    PubMedGoogle Scholar
  • 9 Antenatal Corticosteroid Clinical Practice Guidelines Panel. Antenatal corticosteroids given to women prior to birth to improve fetal, infant, child and adult health: New Zealand and Australian clinical practice guidelines 2015. Accessed December 9, 2022 at: https://www.ligginstrials.org/ANC_CPG/downloads/Antenatal_Corticosteroid_Clinical_Practice_Guidelines.pdf
    PubMed
  • 10 Abbasi S, Hirsch D, Davis J. et al. Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome. Am J Obstet Gynecol 2000; 182 (05) 1243-1249
    CrossrefPubMedGoogle Scholar
  • 11 Wapner RJ, Sorokin Y, Thom EA. et al; National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol 2006; 195 (03) 633-642
    CrossrefPubMedGoogle Scholar
  • 12 Murphy KE, Willan AR, Hannah ME. et al; Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study Collaborative Group. Effect of antenatal corticosteroids on fetal growth and gestational age at birth. Obstet Gynecol 2012; 119 (05) 917-923
    CrossrefPubMedGoogle Scholar
  • 13 Shields A, Thomson M, Winter V, Coalson J, Rees S. Repeated courses of antenatal corticosteroids have adverse effects on aspects of brain development in naturally delivered baboon infants. Pediatr Res 2012; 71 (06) 661-667
    CrossrefPubMedGoogle Scholar
  • 14 Uno H, Lohmiller L, Thieme C. et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Res Dev Brain Res 1990; 53 (02) 157-167
    CrossrefPubMedGoogle Scholar
  • 15 Huang WL, Harper CG, Evans SF, Newnham JP, Dunlop SA. Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. Int J Dev Neurosci 2001; 19 (04) 415-425
    CrossrefPubMedGoogle Scholar
  • 16 Dunlop SA, Archer MA, Quinlivan JA, Beazley LD, Newnham JP. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med 1997; 6 (06) 309-313
    PubMedGoogle Scholar
  • 17 Doyle LW, Cheong JL, Ehrenkranz RA, Halliday HL. Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev 2017; 10 (10) CD001146
    PubMedGoogle Scholar
  • 18 Higgins JP, Thomas J, Chandler J. et al, eds. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. Chichester, United Kingdom: John Wiley & Sons; 2019
    CrossrefGoogle Scholar
  • 19 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
    CrossrefPubMedGoogle Scholar
  • 20 Shah V, Warre R, Lee SK. Quality improvement initiatives in neonatal intensive care unit networks: achievements and challenges. Acad Pediatr 2013; 13 (suppl 6): S75-S83
    CrossrefPubMedGoogle Scholar
  • 21 Horbar JD, Edwards EM, Greenberg LT. et al. Variation in performance of neonatal intensive care units in the United States. JAMA Pediatr 2017; 171 (03) e164396
    CrossrefPubMedGoogle Scholar
  • 22 Wells G, Shea B, O'Connell D. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed June 25, 2020 at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
    PubMedGoogle Scholar
  • 23 Review Manager (RevMan) Version 5.4. The Cochrane Collaboration; 2020
    PubMed
  • 24 Asztalos E, Willan A, Murphy K. et al; MACS-5 Collaborative Group. 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 (01) 272
    CrossrefPubMedGoogle Scholar
  • 25 Asztalos EV, Murphy KE, Hannah ME. et al; Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study Collaborative Group. Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes. Pediatrics 2010; 126 (05) e1045-e1055
    CrossrefPubMedGoogle Scholar
  • 26 Asztalos EV, Murphy KE, Willan AR. et al; MACS-5 Collaborative Group. Multiple courses of antenatal corticosteroids for preterm birth study: outcomes in children at 5 years of age (MACS-5). JAMA Pediatr 2013; 167 (12) 1102-1110
    PubMedGoogle Scholar
  • 27 Vanda R. Comparison of the effect of corticosteroid therapy and pre-natal single-period treatment on birth size and neuronal development in preterm infants with one year follow up in Yasuj hospitals in 2015–2017. Rev Latinoam Hipertens 2018; 13 (06) 567-572
    PubMedGoogle Scholar
  • 28 Sandesh Kiran PS, Dutta S, Narang A, Bhansali A, Malhi P. Multiple courses of antenatal steroids. Indian J Pediatr 2007; 74 (05) 463-469
    CrossrefPubMedGoogle Scholar
  • 29 Wapner RJ, Sorokin Y, Mele L. et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007; 357 (12) 1190-1198
    CrossrefPubMedGoogle Scholar
  • 30 Pesonen A-K, Räikkönen K, Lano A, Peltoniemi O, Hallman M, Kari MA. Antenatal betamethasone and fetal growth in prematurely born children: implications for temperament traits at the age of 2 years. Pediatrics 2009; 123 (01) e31-e37
    CrossrefPubMedGoogle Scholar
  • 31 Peltoniemi OM, Kari MA, Lano A. et al; Repeat Antenatal Betamethasone (RepeatBM) Follow-Up Study Group. Two-year follow-up of a randomised trial with repeated antenatal betamethasone. Arch Dis Child Fetal Neonatal Ed 2009; 94 (06) F402-F406
    CrossrefPubMedGoogle Scholar
  • 32 Räikkönen K, Gissler M, Kajantie E. Associations between maternal antenatal corticosteroid treatment and mental and behavioral disorders in children. JAMA 2020; 323 (19) 1924-1933
    CrossrefPubMedGoogle Scholar
  • 33 Carson R, Monaghan-Nichols AP, DeFranco DB, Rudine AC. Effects of antenatal glucocorticoids on the developing brain. Steroids 2016; 114: 25-32
    CrossrefPubMedGoogle Scholar
  • 34 Kapoor A, Dunn E, Kostaki A, Andrews MH, Matthews SG. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol 2006; 572 (Pt 1): 31-44
    CrossrefPubMedGoogle Scholar
  • 35 Jobe AH, Goldenberg RL. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. Am J Obstet Gynecol 2018; 219 (01) 62-74
    CrossrefPubMedGoogle Scholar
  • 36 Walters A, McKinlay C, Middleton P, Harding JE, Crowther CA. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev 2022; 4 (07) CD003935
    PubMedGoogle Scholar
  • 37 Shah PS, Sankaran K, Aziz K. et al; Canadian Neonatal Network. Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: a cause for concern?. J Perinatol 2012; 32 (02) 132-138
    CrossrefPubMedGoogle Scholar
  • 38 Zeitlin J, Manktelow BN, Piedvache A. et al; EPICE Research Group. Use of evidence based practices to improve survival without severe morbidity for very preterm infants: results from the EPICE population based cohort. BMJ 2016; 354: i2976
    CrossrefPubMedGoogle Scholar
  • 39 Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006; 117 (04) 1253-1261
    CrossrefPubMedGoogle Scholar
  • 40 Lechner BE, Vohr BR. Neurodevelopmental outcomes of preterm infants fed human milk: a systematic review. Clin Perinatol 2017; 44 (01) 69-83
    CrossrefPubMedGoogle Scholar
  • 41 Schmölzer GM, Kumar M, Pichler G, Aziz K, O'Reilly M, Cheung P-Y. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 2013; 347: f5980
    CrossrefPubMedGoogle Scholar
  • 42 Doyle LW, Anderson PJ. Long-term outcomes of bronchopulmonary dysplasia. Semin Fetal Neonatal Med 2009; 14 (06) 391-395
    CrossrefPubMedGoogle Scholar