Associations between multiple perinatal exposures and risk of childhood hospitalisation with infection: a registry-based study in two countries

doi:10.1007/s10654-025-01266-1

. 2025 Aug 13.

doi: 10.1007/s10654-025-01266-1. Online ahead of print.

Associations between multiple perinatal exposures and risk of childhood hospitalisation with infection: a registry-based study in two countries

Isobel M F Todd^{1

2}, Lars Henning Pedersen^{3

4}, Maria C Magnus⁵, Natasha Nassar^{6

7

8}, Jessica E Miller^#^{9

10

3}, David P Burgner^#^{9

10

11

12}

Affiliations

¹ Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, 50 Flemington Rd, Parkville, VIC, 3052, Australia. itodd@student.unimelb.edu.au.
² Murdoch Children's Research Institute, Parkville, VIC, Australia. itodd@student.unimelb.edu.au.
³ Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁴ Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.
⁵ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁶ Child Population and Translational Health Research, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
⁷ Leeder Centre for Health Policy, Economics and Data, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
⁸ Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia.
⁹ Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, 50 Flemington Rd, Parkville, VIC, 3052, Australia.
¹⁰ Murdoch Children's Research Institute, Parkville, VIC, Australia.
¹¹ Department of Infectious Diseases, Royal Children's Hospital Melbourne, Parkville, VIC, Australia.
¹² Faculty of Health, Deakin University, Burwood, VIC, Australia.

^# Contributed equally.

PMID: 40801990
DOI: 10.1007/s10654-025-01266-1

Associations between multiple perinatal exposures and risk of childhood hospitalisation with infection: a registry-based study in two countries

Isobel M F Todd et al. Eur J Epidemiol. 2025.

. 2025 Aug 13.

doi: 10.1007/s10654-025-01266-1. Online ahead of print.

Authors

Isobel M F Todd^{1

2}, Lars Henning Pedersen^{3

4}, Maria C Magnus⁵, Natasha Nassar^{6

7

8}, Jessica E Miller^#^{9

10

3}, David P Burgner^#^{9

10

11

12}

Affiliations

¹ Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, 50 Flemington Rd, Parkville, VIC, 3052, Australia. itodd@student.unimelb.edu.au.
² Murdoch Children's Research Institute, Parkville, VIC, Australia. itodd@student.unimelb.edu.au.
³ Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁴ Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.
⁵ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁶ Child Population and Translational Health Research, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
⁷ Leeder Centre for Health Policy, Economics and Data, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
⁸ Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia.
⁹ Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, 50 Flemington Rd, Parkville, VIC, 3052, Australia.
¹⁰ Murdoch Children's Research Institute, Parkville, VIC, Australia.
¹¹ Department of Infectious Diseases, Royal Children's Hospital Melbourne, Parkville, VIC, Australia.
¹² Faculty of Health, Deakin University, Burwood, VIC, Australia.

^# Contributed equally.

PMID: 40801990
DOI: 10.1007/s10654-025-01266-1

Abstract

Several perinatal exposures impact severe infection risk in offspring. However, most studies consider exposures in isolation rather than the impact of multiple co-occurring perinatal exposures. Here, we investigated the risk of hospitalised childhood infections associated with combinations of multiple perinatal exposures. We studied liveborn, singleton births in Denmark between 1997 and 2019 (n = 1,113,708) and Norway between 2008 and 2018 (n = 470,270) through national registry linkage. Seven perinatal exposures were evaluated including maternal antibiotic use during pregnancy, maternal smoking, maternal diabetes, hypertensive disorders of pregnancy, caesarean section birth, offspring being small for gestational age (SGA), and preterm birth. The outcome was hospitalised infections before 5 years age. Using Cox regression, we estimated hazard ratios (HR) of hospitalised infections for: (1) each exposure individually; (2) the cumulative number of exposures; (3) each unique combination of the seven exposures; (4) pairwise interactions between exposures. Results were combined through meta-analysis. Each exposure was individually associated with greater hospitalised infection risk with pooled HR estimates ranging from 1.08 (95% CI 1.08-1.09) for SGA to 1.45 (95% CI 1.43-1.46) for preterm birth. Cumulative risk was observed for increasing number of exposures from a pooled HR of 1.17 (95% CI 1.17-1.18) for one exposure to 1.88 (95% CI 1.78-1.99) for five or more exposures. Analyses of unique combinations of the exposures showed a particularly increased risk among preterm children with one or more additional exposures. Our findings can inform targeted strategies for the prevention and management of childhood infections. We highlight a simple, intuitive method for measuring risk associated with co-occurring exposures.

Keywords: Hospitalisation; Infection; Paediatric; Perinatal; Pregnancy.

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Conflict of interest statement

Declarations. Conflict of interest: All authors declare no financial relationships with any organisations that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work. Ethics approval: This study was exempted from the requirement for individual consent because of the registry-based nature of the study. The project was approved by the Regional Committee for Medical and Health Research Ethics of South/East Norway (Ref. 2018/24492/REK sør-øst), by the Danish Data Protection Agency (Aarhus University, journal number 2016051000001, serial number 2227), and by the Royal Children’s Hospital Melbourne Ethics Committee (Project ID 89792). Copyright statement: For the purposes of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

References

1. Hasegawa K, Tsugawa Y, Cohen A, Camargo CA Jr. Infectious disease-related emergency department visits among children in the US. Pediatr Infect Dis J. 2015;34(7):681–5. https://doi.org/10.1097/inf.0000000000000704 - DOI - PubMed
1. Baker MG, Barnard LT, Kvalsvig A, et al. Increasing incidence of serious infectious diseases and inequalities in new zealand: a National epidemiological study. Lancet. 2012;379(9821):1112–9. https://doi.org/10.1016/S0140-6736(11)61780-7 . - DOI - PubMed
1. Gehrt L, Laake I, Englund H, et al. Hospital contacts for infectious diseases among children in denmark, finland, norway, and sweden, 2008–2017. Clin Epidemiol. 2022;14:609–21. https://doi.org/10.2147/CLEP.S355193 . - DOI - PubMed
1. Hashimoto K, Maeda H, Iwasa H, et al. Tobacco exposure during pregnancy and infections in infants up to 1 year of age: the Japan environment and children’s study. J Epidemiol. 2023;33(10):489–97. https://doi.org/10.2188/jea.JE20210405 . - DOI - PubMed
1. Lawder R, Whyte B, Wood R, Fischbacher C, Tappin DM. Impact of maternal smoking on early childhood health: a retrospective cohort linked dataset analysis of 697 003 children born in Scotland 1997–2009. BMJ Open. 2019;9(3):e023213. https://doi.org/10.1136/bmjopen-2018-023213 . - DOI - PubMed

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[1] Hasegawa K, Tsugawa Y, Cohen A, Camargo CA Jr. Infectious disease-related emergency department visits among children in the US. Pediatr Infect Dis J. 2015;34(7):681–5. https://doi.org/10.1097/inf.0000000000000704 - DOI - PubMed

[2] Hasegawa K, Tsugawa Y, Cohen A, Camargo CA Jr. Infectious disease-related emergency department visits among children in the US. Pediatr Infect Dis J. 2015;34(7):681–5. https://doi.org/10.1097/inf.0000000000000704 - DOI - PubMed

[3] Baker MG, Barnard LT, Kvalsvig A, et al. Increasing incidence of serious infectious diseases and inequalities in new zealand: a National epidemiological study. Lancet. 2012;379(9821):1112–9. https://doi.org/10.1016/S0140-6736(11)61780-7 . - DOI - PubMed

[4] Baker MG, Barnard LT, Kvalsvig A, et al. Increasing incidence of serious infectious diseases and inequalities in new zealand: a National epidemiological study. Lancet. 2012;379(9821):1112–9. https://doi.org/10.1016/S0140-6736(11)61780-7 . - DOI - PubMed

[5] Gehrt L, Laake I, Englund H, et al. Hospital contacts for infectious diseases among children in denmark, finland, norway, and sweden, 2008–2017. Clin Epidemiol. 2022;14:609–21. https://doi.org/10.2147/CLEP.S355193 . - DOI - PubMed

[6] Gehrt L, Laake I, Englund H, et al. Hospital contacts for infectious diseases among children in denmark, finland, norway, and sweden, 2008–2017. Clin Epidemiol. 2022;14:609–21. https://doi.org/10.2147/CLEP.S355193 . - DOI - PubMed

[7] Hashimoto K, Maeda H, Iwasa H, et al. Tobacco exposure during pregnancy and infections in infants up to 1 year of age: the Japan environment and children’s study. J Epidemiol. 2023;33(10):489–97. https://doi.org/10.2188/jea.JE20210405 . - DOI - PubMed

[8] Hashimoto K, Maeda H, Iwasa H, et al. Tobacco exposure during pregnancy and infections in infants up to 1 year of age: the Japan environment and children’s study. J Epidemiol. 2023;33(10):489–97. https://doi.org/10.2188/jea.JE20210405 . - DOI - PubMed

[9] Lawder R, Whyte B, Wood R, Fischbacher C, Tappin DM. Impact of maternal smoking on early childhood health: a retrospective cohort linked dataset analysis of 697 003 children born in Scotland 1997–2009. BMJ Open. 2019;9(3):e023213. https://doi.org/10.1136/bmjopen-2018-023213 . - DOI - PubMed

[10] Lawder R, Whyte B, Wood R, Fischbacher C, Tappin DM. Impact of maternal smoking on early childhood health: a retrospective cohort linked dataset analysis of 697 003 children born in Scotland 1997–2009. BMJ Open. 2019;9(3):e023213. https://doi.org/10.1136/bmjopen-2018-023213 . - DOI - PubMed

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Associations between multiple perinatal exposures and risk of childhood hospitalisation with infection: a registry-based study in two countries

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Associations between multiple perinatal exposures and risk of childhood hospitalisation with infection: a registry-based study in two countries

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