Download PDF
Am J Perinatol 2024; 41(S 01): e2919-e2926
DOI: 10.1055/s-0043-1776348
Original Article

The Impact of Infant Sex on Multiple Courses versus a Single Course of Antenatal Corticosteroids: A Secondary Analysis of a Randomized Controlled Trial

Kiran Ninan 
1   Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
2   Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
,
Kellie E. Murphy
3   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
,
Elizabeth V. Asztalos 
4   Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
,
Yidi Jiang
5   Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada
,
Ella Huszti
5   Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada
,
Stephen G. Matthews
6   Department of Physiology, University of Toronto, Toronto, Ontario, Canada
,
Pasqualina Santaguida
1   Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
2   Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
,
Amit Mukerji
7   Division of Neonatology, Department of Pediatrics, McMaster University, Ontario, Canada
,
Sarah D. McDonald 
1   Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
2   Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
8   Department of Radiology, McMaster University, Hamilton, Ontario, Canada
9   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations Funding S.D.M. is supported by a Tier II Canadian Institutes of Health Research (CIHR) Canada Research Chair (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.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Objective Animal literature has suggested that the impact of antenatal corticosteroids (ACS) may vary by infant sex. Our objective was to assess the impact of infant sex on the use of multiple courses versus a single course of ACS and perinatal outcomes.

Study Design We conducted a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth trial, which randomly allocated pregnant people to multiple courses versus a single course of ACS. Our primary outcome was a composite of perinatal mortality or clinically significant neonatal morbidity (including neonatal death, stillbirth, severe respiratory distress syndrome, intraventricular hemorrhage [grade III or IV], cystic periventricular leukomalacia, and necrotizing enterocolitis [stage II or III]). Secondary outcomes included individual components of the primary outcome as well as anthropometric measures. Baseline characteristics were compared between participants who received multiple courses versus a single course of ACS. An interaction between exposure to ACS and infant sex was assessed for significance and multivariable regression analyses were conducted with adjustment for predefined covariates, when feasible.

Results Data on 2,300 infants were analyzed. The interaction term between treatment status (multiple courses vs. a single course of ACS) and infant sex was not significant for the primary outcome (p = 0.86), nor for any of the secondary outcomes (p > 0.05).

Conclusion Infant sex did not modify the association between exposure to ACS and perinatal outcomes including perinatal mortality or neonatal morbidity or anthropometric outcomes. However, animal literature indicates that sex-specific differences after exposure to ACS may emerge over time and thus investigating long-term sex-specific outcomes warrants further attention.

Key Points

  • We explored the impact of infant sex on perinatal outcomes after multiple versus a single course of ACS.

  • Infant sex was not a significant effect modifier of ACS exposure and perinatal outcomes.

  • Animal literature indicates that sex-specific differences after ACS exposure may emerge over time.

  • Further investigation of long-term sex-specific outcomes is warranted.

Keywords

antenatal corticosteroids - neonatal morbidity - perinatal mortality - secondary analysis of RCT - sex-specific effects

Supplementary Material



Publication History

Received: 17 April 2023

Accepted: 27 September 2023

Article published online:
07 November 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • 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 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
  • 3 McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2020; 12 (12) CD004454
    CrossrefPubMedGoogle Scholar
  • 4 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
    PubMedGoogle Scholar
  • 5 Willet KE, Jobe AH, Ikegami M. et al. Postnatal lung function after prenatal steroid treatment in sheep: effect of gender. Pediatr Res 1997; 42 (06) 885-892
    CrossrefPubMedGoogle Scholar
  • 6 Ishak N, Sozo F, Harding R, De Matteo R. Does lung development differ in male and female fetuses?. Exp Lung Res 2014; 40 (01) 30-39
    CrossrefPubMedGoogle Scholar
  • 7 Kemp MW, Newnham JP, Challis JG, Jobe AH, Stock SJ. The clinical use of corticosteroids in pregnancy. Hum Reprod Update 2016; 22 (02) 240-259
    PubMedGoogle Scholar
  • 8 McGowan PO, Matthews SG. Prenatal stress, glucocorticoids, and developmental programming of the stress response. Endocrinology 2018; 159 (01) 69-82
    CrossrefPubMedGoogle Scholar
  • 9 Moisiadis VG, Constantinof A, Kostaki A, Szyf M, Matthews SG. Prenatal glucocorticoid exposure modifies endocrine function and behaviour for 3 generations following maternal and paternal transmission. Sci Rep 2017; 7 (01) 11814
    CrossrefPubMedGoogle Scholar
  • 10 Owen D, Matthews SG. Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function in juvenile guinea pigs. J Neuroendocrinol 2007; 19 (03) 172-180
    CrossrefPubMedGoogle Scholar
  • 11 Liu L, Li A, Matthews SG. Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects. Am J Physiol Endocrinol Metab 2001; 280 (05) E729-E739
    CrossrefPubMedGoogle Scholar
  • 12 Aghajafari F, Murphy K, Matthews S, Ohlsson A, Amankwah K, Hannah M. Repeated doses of antenatal corticosteroids in animals: a systematic review. Am J Obstet Gynecol 2002; 186 (04) 843-849
    CrossrefPubMedGoogle Scholar
  • 13 van der Merwe JL, Sacco A, Toelen J, Deprest J. Long-term neuropathological and/or neurobehavioral effects of antenatal corticosteroid therapy in animal models: a systematic review. Pediatr Res 2020; 87 (07) 1157-1170
    CrossrefPubMedGoogle Scholar
  • 14 Wood CE, Keller-Wood M. The critical importance of the fetal hypothalamus-pituitary-adrenal axis. F1000 Res 2016; 5: 115
    CrossrefPubMedGoogle Scholar
  • 15 Moisiadis VG, Matthews SG. Glucocorticoids and fetal programming part 1: outcomes. Nat Rev Endocrinol 2014; 10 (07) 391-402
    CrossrefPubMedGoogle Scholar
  • 16 Murphy KE, Hannah ME, Willan AR. et al; MACS Collaborative Group. Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 2008; 372 (9656) 2143-2151
    CrossrefPubMedGoogle Scholar
  • 17 Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol 2007; 165 (06) 710-718
    CrossrefPubMedGoogle Scholar
  • 18 Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat 1979; 6 (02) 65-70
    PubMedGoogle Scholar
  • 19 R: A Language and Environment for Statistical Computing. Version 4.0.3. R Foundation for Statistical Computing; 2020 Accessed May 1, 2022 at: https://www.R-project.org
    PubMedGoogle Scholar
  • 20 Ramos-Navarro C, Sánchez-Luna M, Zeballos-Sarrato S, Pescador-Chamorro I. Antenatal corticosteroids and the influence of sex on morbidity and mortality of preterm infants. J Matern Fetal Neonatal Med 2022; 35 (18) 3438-3445
    CrossrefPubMedGoogle Scholar
  • 21 Battarbee AN, Glover AV, Vladutiu CJ. et al. Sex-specific differences in late preterm neonatal outcomes. Am J Perinatol 2019; 36 (12) 1223-1228
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Roberge S, Lacasse Y, Tapp S. et al. Role of fetal sex in the outcome of antenatal glucocorticoid treatment to prevent respiratory distress syndrome: systematic review and meta-analysis. J Obstet Gynaecol Can 2011; 33 (03) 216-226
    CrossrefPubMedGoogle Scholar
  • 23 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
  • 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 Clifton VL. Review: sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 2010; 31 (Suppl): S33-S39
    CrossrefPubMedGoogle Scholar
  • 26 Hauser J, Feldon J, Pryce CR. Direct and dam-mediated effects of prenatal dexamethasone on emotionality, cognition and HPA axis in adult Wistar rats. Horm Behav 2009; 56 (04) 364-375
    CrossrefPubMedGoogle Scholar
  • 27 Battarbee AN, Ros ST, Esplin MS. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR). Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes. Am J Obstet Gynecol MFM 2020; 2 (01) 100077
    CrossrefPubMedGoogle Scholar
  • 28 Gyamfi-Bannerman C. Antenatal corticosteroids: it's all about timing. BJOG 2017; 124 (10) 1575
    CrossrefPubMedGoogle Scholar
  • 29 Jobe AH, Kemp M, Schmidt A, Takahashi T, Newnham J, Milad M. Antenatal corticosteroids: a reappraisal of the drug formulation and dose. Pediatr Res 2021; 89 (02) 318-325
    CrossrefPubMedGoogle Scholar
  • 30 Lee JY, Yun HJ, Kim CY, Cho YW, Lee Y, Kim MH. Prenatal exposure to dexamethasone in the mouse induces sex-specific differences in placental gene expression. Dev Growth Differ 2017; 59 (06) 515-525
    CrossrefPubMedGoogle Scholar
  • 31 Guo J, Fang M, Zhuang S. et al. Prenatal dexamethasone exposure exerts sex-specific effect on placental oxygen and nutrient transport ascribed to the differential expression of IGF2. Ann Transl Med 2020; 8 (05) 233
    CrossrefPubMedGoogle Scholar
  • 32 Wieczorek A, Perani CV, Nixon M. et al. Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta. Am J Physiol Endocrinol Metab 2019; 317 (01) E109-E120
    CrossrefPubMedGoogle Scholar