Associations of Antenatal Corticosteroids With Neurodevelopment in Children Aged 27-30 Months: A Population-Based Cohort Study

doi:10.1111/1471-0528.18101

. 2025 Jun;132(7):902-915.

doi: 10.1111/1471-0528.18101. Epub 2025 Feb 19.

Associations of Antenatal Corticosteroids With Neurodevelopment in Children Aged 27-30 Months: A Population-Based Cohort Study

Emily M Frier¹, Marius Lahti-Pulkkinen^{2

3}, Chun Lin⁴, Fabienne Decrue³, Helga Zoega^{5

6}, Karel Allegaert^{7

8}, Jasper V Been^{9

10}, David Burgner^{11

12}, Kate Duhig¹³, Kristjana Einarsdóttir^{6

14}, Lani Florian¹⁵, Abigail Fraser¹⁶, Mika Gissler^{17

18}, Cynthia Gyamfi-Bannerman¹⁹, Lars Henning Pedersen^{20

21}, Jessica E Miller^{11

12}, Ben W Mol^{22

23}, Sarah R Murray¹, Jane Norman²⁴, Devender Roberts²⁵, Ewoud Schuit²⁶, Ting Shi⁴, Aziz Sheikh⁴, Joshua P Vogel²⁷, Rachael Wood^{4

28}, Emma McGoldrick²⁵, Bo Jacobsson^{29

30}, Eyal Krispin³¹, Rebecca M Reynolds^{1

3}, Sarah J Stock^{1

4}; Co‐OPT Collaboration

Collaborators, Affiliations

Collaborators

Co‐OPT Collaboration:
Karel Allegaert, Jasper Been, David Burgner, Kate Duhig, Kristjana Einarsdóttir, John Fahey, Lani Florian, Abigail Fraser, Mika Gissler, Cynthia Gyamfi-Bannerman, Bo Jacobsson, Eyal Krispin, Stefan Kuhle, Marius Lahti-Pulkkinen, Jessica Miller, Ben Mol, Sarah Murray, Jane Norman, Lars Henning Pedersen, Richard Riley, Devender Roberts, Ewoud Schuit, Aziz Sheikh, Ting Shi, Claire Tochel, Joshua Vogel, Rachael Wood, John Wright, Helga Zoega, Karel Allegaert, Jasper Been, David Burgner, Kate Duhig, Kristjana Einarsdóttir, John Fahey, Lani Florian, Abigail Fraser, Mika Gissler, Cynthia Gyamfi-Bannerman, Bo Jacobsson, Eyal Krispin, Stefan Kuhle, Marius Lahti-Pulkkinen, Jessica Miller, Ben Mol, Sarah Murray, Jane Norman, Lars Henning Pedersen, Richard Riley, Devender Roberts, Ewoud Schuit, Aziz Sheikh, Ting Shi, Claire Tochel, Joshua Vogel, Rachael Wood, John Wright, Helga Zoega

Affiliations

¹ MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
² Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
³ Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
⁴ Usher Institute, The University of Edinburgh, Edinburgh, UK.
⁵ Faculty of Medicine and Health, School of Population Health, UNSW Sydney, Sydney, New South Wales, Australia.
⁶ Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁷ Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
⁸ Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands.
⁹ Department of Neonatal and Paediatric Intensive Care, Division of Neonatology, Erasmus MC Sophia Children's Hospital, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
¹⁰ Department of Obstetrics and Gynaecology, Erasmus MC Sophia Children's Hospital, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
¹¹ Department of Paediatrics, Melbourne University, Parkville, Victoria, Australia.
¹² Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
¹³ Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK.
¹⁴ Faculty of Health Sciences, Curtin University, Bentley, Western Australia, Australia.
¹⁵ Moray House School of Education and Sport, University of Edinburgh, Edinburgh, UK.
¹⁶ Population Health Sciences, Bristol Medical School and MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
¹⁷ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹⁸ Knowledge Brokers, Finnish Institute for Health and Welfare, Helsinki, Finland.
¹⁹ Department of Obstetrics, Gynaecology, and Reproductive Sciences, University of California, San Diego, La Jolla, California, USA.
²⁰ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²¹ Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, Denmark.
²² Ritchie Centre, Monash University, Clayton, Australia.
²³ Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
²⁴ University of Nottingham, Nottingham, UK.
²⁵ Family Health Division, Liverpool Women's Hospital, Liverpool, UK.
²⁶ Department of Epidemiology & Health Economics, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
²⁷ Maternal, Child and Adolescent Health Program, Burnet Institute, Melbourne, Victoria, Australia.
²⁸ Public Health Scotland, Edinburgh, UK.
²⁹ Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³⁰ Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
³¹ Maternal Fetal Care Center, Boston Children's Hospital, Boston, Massachusetts, USA.

PMID: 39971868
PMCID: PMC12051224
DOI: 10.1111/1471-0528.18101

Associations of Antenatal Corticosteroids With Neurodevelopment in Children Aged 27-30 Months: A Population-Based Cohort Study

Emily M Frier et al. BJOG. 2025 Jun.

. 2025 Jun;132(7):902-915.

doi: 10.1111/1471-0528.18101. Epub 2025 Feb 19.

Authors

Collaborators

Co‐OPT Collaboration:
Karel Allegaert, Jasper Been, David Burgner, Kate Duhig, Kristjana Einarsdóttir, John Fahey, Lani Florian, Abigail Fraser, Mika Gissler, Cynthia Gyamfi-Bannerman, Bo Jacobsson, Eyal Krispin, Stefan Kuhle, Marius Lahti-Pulkkinen, Jessica Miller, Ben Mol, Sarah Murray, Jane Norman, Lars Henning Pedersen, Richard Riley, Devender Roberts, Ewoud Schuit, Aziz Sheikh, Ting Shi, Claire Tochel, Joshua Vogel, Rachael Wood, John Wright, Helga Zoega, Karel Allegaert, Jasper Been, David Burgner, Kate Duhig, Kristjana Einarsdóttir, John Fahey, Lani Florian, Abigail Fraser, Mika Gissler, Cynthia Gyamfi-Bannerman, Bo Jacobsson, Eyal Krispin, Stefan Kuhle, Marius Lahti-Pulkkinen, Jessica Miller, Ben Mol, Sarah Murray, Jane Norman, Lars Henning Pedersen, Richard Riley, Devender Roberts, Ewoud Schuit, Aziz Sheikh, Ting Shi, Claire Tochel, Joshua Vogel, Rachael Wood, John Wright, Helga Zoega

Affiliations

¹ MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
² Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
³ Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
⁴ Usher Institute, The University of Edinburgh, Edinburgh, UK.
⁵ Faculty of Medicine and Health, School of Population Health, UNSW Sydney, Sydney, New South Wales, Australia.
⁶ Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁷ Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
⁸ Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands.
⁹ Department of Neonatal and Paediatric Intensive Care, Division of Neonatology, Erasmus MC Sophia Children's Hospital, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
¹⁰ Department of Obstetrics and Gynaecology, Erasmus MC Sophia Children's Hospital, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
¹¹ Department of Paediatrics, Melbourne University, Parkville, Victoria, Australia.
¹² Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
¹³ Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK.
¹⁴ Faculty of Health Sciences, Curtin University, Bentley, Western Australia, Australia.
¹⁵ Moray House School of Education and Sport, University of Edinburgh, Edinburgh, UK.
¹⁶ Population Health Sciences, Bristol Medical School and MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
¹⁷ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹⁸ Knowledge Brokers, Finnish Institute for Health and Welfare, Helsinki, Finland.
¹⁹ Department of Obstetrics, Gynaecology, and Reproductive Sciences, University of California, San Diego, La Jolla, California, USA.
²⁰ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²¹ Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, Denmark.
²² Ritchie Centre, Monash University, Clayton, Australia.
²³ Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
²⁴ University of Nottingham, Nottingham, UK.
²⁵ Family Health Division, Liverpool Women's Hospital, Liverpool, UK.
²⁶ Department of Epidemiology & Health Economics, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
²⁷ Maternal, Child and Adolescent Health Program, Burnet Institute, Melbourne, Victoria, Australia.
²⁸ Public Health Scotland, Edinburgh, UK.
²⁹ Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³⁰ Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
³¹ Maternal Fetal Care Center, Boston Children's Hospital, Boston, Massachusetts, USA.

PMID: 39971868
PMCID: PMC12051224
DOI: 10.1111/1471-0528.18101

Abstract

Objective: To examine the associations of antenatal corticosteroid (ACS) exposure with neurodevelopment in early childhood, and how these vary with gestational age at birth.

Design: Population-based cohort study.

Setting: Scotland, UK.

Population: 285 637 singleton children born at 28-41 weeks' gestation, between 1st January 2011 and 31st December 2017, who underwent health reviews at 27-30 months of age.

Methods: Logistic and linear regression analyses, stratified by gestation at birth (28-33, 34-36, 37-38 and 39-41 weeks' gestation), were used to evaluate the associations between ACS exposure and neurodevelopmental outcomes, and adjusted for maternal age, body mass index, diabetes, antenatal smoking, parity, neighbourhood deprivation, birth year, child sex and age at review.

Main outcome measures: Practitioner-identified concerns about any neurodevelopmental domain, and the average of five domain scores on neurodevelopmental milestones from the parent-rated Ages and Stages Questionnaire (ASQ-3).

Results: After adjustment for covariates, ACS exposure was associated with reduced neurodevelopmental concerns in children born at 28-33 weeks' gestation (OR = 0.79, 95% CI = 0.62-0.999) and with increased neurodevelopmental concerns in children born at 34-36 weeks' gestation (OR = 1.11, 95% CI = 1.01-1.21). No independent associations emerged in children born at later gestations. ACS exposure was not associated with ASQ-3 scores in any gestational age group.

Conclusions: In early childhood, ACS exposure was associated with statistically significantly reduced neurodevelopmental concerns in children born at 28-33 weeks' gestation, and with statistically significantly increased neurodevelopment concerns in children born at 34-36 weeks' gestation. However, the effect sizes of these associations were small. No independent associations were found between ACS exposure and neurodevelopment in term-born children.

Keywords: antenatal corticosteroids; neurodevelopment; preterm birth.

PubMed Disclaimer

Conflict of interest statement

The Co‐OPT ACS study is funded through a Wellcome Trust Clinical Career Development Fellowship grant (Funding Reference number 209560/Z/17) awarded to SJS. ML‐P is supported by grants from the Academy of Finland (330206). FD is supported by the Swiss National Science Foundation (P500PM_206634) and the Bangeter‐Rhyner Foundation. HZ is supported by a UNSW Scientia Program Award. DB is supported by a National Health and Medical Research Council Investigator Grant (GTN1175744). Research at Murdoch Children's Research Institute (DB, JEM) is supported by the Victorian Government's Operational Infrastructure Program. KD is funded by Health Education England (HEE)/NIHR. CG‐B is supported by research grants from NHLBI, NICHD and NIHMD, and has received research funding from HealthCore Inc/SERA Prognostics Inc. and MIRVIE Inc. LHP is supported by a Borregaard Clinical Ascending Investigator Grant from the Novo Nordisk Foundation (NNF18OC0054457). JPV is supported by an Australian National Health and Medical Research Council (NHMRC) Investigator grant (GNT1194248). EMcG acknowledges support of the NIHR North West Coast Scholars' Programme. RMR acknowledges the support of the British Heart Foundation (RE/18/5/34216). The remaining authors declare no conflicts of interest.

Figures

**FIGURE 1**
Derivation of the study cohort. “Practitioner‐assessed ND” refers to children with complete outcome data on practitioner concern about neurodevelopment and “ASQ‐3 ND score” refers to children with complete data on ASQ‐3 neurodevelopment score. ACS, antenatal corticosteroids; ASQ‐3, Ages and Stages Questionnaire Third Edition; n = number of children; ND, neurodevelopment.

See this image and copyright information in PMC

References

1. McGoldrick E., Stewart F., Parker R., and Dalziel S. R., “Antenatal Corticosteroids for Accelerating Fetal Lung Maturation for Women at Risk of Preterm Birth,” Cochrane Database of Systematic Reviews 12 (2020): CD004454, 10.1002/14651858.CD004454.pub4. - DOI - PMC - PubMed
1. Frier E. M., Lin C., Reynolds R. M., et al., “Consortium for the Study of Pregnancy Treatments (Co‐OPT): An International Birth Cohort to Study the Effects of Antenatal Corticosteroids,” PLoS One 18, no. 3 (2023): e0282477, 10.1371/journal.pone.0282477. - DOI - PMC - PubMed
1. Ninan K., Gojic A., Wang Y., et al., “The Proportions of Term or Late Preterm Births After Exposure to Early Antenatal Corticosteroids, and Outcomes: Systematic Review and Meta‐Analysis of 1.6 Million Infants,” BMJ 382 (2023): e076035, 10.1136/bmj-2023-076035. - DOI - PMC - PubMed
1. Jobe A. H., “Antenatal Corticosteroids‐A Concern for Lifelong Outcomes,” Journal of Pediatrics 217 (2020): 184–188, 10.1016/j.jpeds.2019.09.015. - DOI - PubMed
1. Reynolds R. M., “Glucocorticoid Excess and the Developmental Origins of Disease: Two Decades of Testing the Hypothesis – 2012 Curt Richter Award Winner,” Psychoneuroendocrinology 38, no. 1 (2013): 1–11, 10.1016/j.psyneuen.2012.08.012. - DOI - PubMed

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[1] McGoldrick E., Stewart F., Parker R., and Dalziel S. R., “Antenatal Corticosteroids for Accelerating Fetal Lung Maturation for Women at Risk of Preterm Birth,” Cochrane Database of Systematic Reviews 12 (2020): CD004454, 10.1002/14651858.CD004454.pub4. - DOI - PMC - PubMed

[2] McGoldrick E., Stewart F., Parker R., and Dalziel S. R., “Antenatal Corticosteroids for Accelerating Fetal Lung Maturation for Women at Risk of Preterm Birth,” Cochrane Database of Systematic Reviews 12 (2020): CD004454, 10.1002/14651858.CD004454.pub4. - DOI - PMC - PubMed

[3] Frier E. M., Lin C., Reynolds R. M., et al., “Consortium for the Study of Pregnancy Treatments (Co‐OPT): An International Birth Cohort to Study the Effects of Antenatal Corticosteroids,” PLoS One 18, no. 3 (2023): e0282477, 10.1371/journal.pone.0282477. - DOI - PMC - PubMed

[4] Frier E. M., Lin C., Reynolds R. M., et al., “Consortium for the Study of Pregnancy Treatments (Co‐OPT): An International Birth Cohort to Study the Effects of Antenatal Corticosteroids,” PLoS One 18, no. 3 (2023): e0282477, 10.1371/journal.pone.0282477. - DOI - PMC - PubMed

[5] Ninan K., Gojic A., Wang Y., et al., “The Proportions of Term or Late Preterm Births After Exposure to Early Antenatal Corticosteroids, and Outcomes: Systematic Review and Meta‐Analysis of 1.6 Million Infants,” BMJ 382 (2023): e076035, 10.1136/bmj-2023-076035. - DOI - PMC - PubMed

[6] Ninan K., Gojic A., Wang Y., et al., “The Proportions of Term or Late Preterm Births After Exposure to Early Antenatal Corticosteroids, and Outcomes: Systematic Review and Meta‐Analysis of 1.6 Million Infants,” BMJ 382 (2023): e076035, 10.1136/bmj-2023-076035. - DOI - PMC - PubMed

[7] Jobe A. H., “Antenatal Corticosteroids‐A Concern for Lifelong Outcomes,” Journal of Pediatrics 217 (2020): 184–188, 10.1016/j.jpeds.2019.09.015. - DOI - PubMed

[8] Jobe A. H., “Antenatal Corticosteroids‐A Concern for Lifelong Outcomes,” Journal of Pediatrics 217 (2020): 184–188, 10.1016/j.jpeds.2019.09.015. - DOI - PubMed

[9] Reynolds R. M., “Glucocorticoid Excess and the Developmental Origins of Disease: Two Decades of Testing the Hypothesis – 2012 Curt Richter Award Winner,” Psychoneuroendocrinology 38, no. 1 (2013): 1–11, 10.1016/j.psyneuen.2012.08.012. - DOI - PubMed

[10] Reynolds R. M., “Glucocorticoid Excess and the Developmental Origins of Disease: Two Decades of Testing the Hypothesis – 2012 Curt Richter Award Winner,” Psychoneuroendocrinology 38, no. 1 (2013): 1–11, 10.1016/j.psyneuen.2012.08.012. - DOI - PubMed

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Associations of Antenatal Corticosteroids With Neurodevelopment in Children Aged 27-30 Months: A Population-Based Cohort Study

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Associations of Antenatal Corticosteroids With Neurodevelopment in Children Aged 27-30 Months: A Population-Based Cohort Study

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