By Sarah Brandt
Principal supervisor: Professor Jakob Stokholm, COPSAC
Co-supervisor: Senior Researcher Astrid Sevelsted, COPSAC
Chairperson: Professor Anne Amalie Elgaard Thorup, University of Copenhagen, Denmark
Opponent: Professor Lars Christian Mørch Stene, Norwegian Institute of Public Health, Norway
Opponent: Associate Professor Signe Voss Vahlkvist, Sygehus Lillebælt, Kolding, Denmark
Summary
This thesis investigates the influence of early-life environmental exposures, collectively referred to as the exposome, on the development of immune-mediated diseases (IMDs) such as asthma, allergies, eczema, celiac disease, juvenile arthritis, type 1 diabetes, and overweight in children and adolescents. Affecting millions worldwide, these diseases burden individuals and healthcare systems. While genetic predisposition plays an important role, environmental exposures during critical developmental windows are increasingly recognized for their role in shaping immune function and determining disease susceptibility.
Exposomic risk factors – including the external environment, such as pollutants and living conditions, as well as internal biological processes, like microbial composition and inflammation – are thought to disrupt immune system maturation in various ways; early-life exposures, such as antibiotic use or medical interventions, may alter microbial composition, provoke chronic inflammation, and impair immune regulatory pathways. These disruptions, during infancy and early childhood, may predispose individuals to IMDs by creating an imbalance between immune tolerance and activation, leading to chronic inflammation.
This research focuses on two exposomic risk factors:
- Systemic antibiotic use during infancy and
- Labor induction in pregnancy
Associations between these risk factors and IMDs in childhood and adolescence are examined using Denmark’s extensive nationwide registries, providing longitudinal data on individuals from birth onwards. By linking multiple registries, including the Civil Registration System, the Danish National Patient Registry, and the Danish National Prescription Registry, this thesis employs a cohort study design to examine early-life exposures and their subsequent impact on IMD development. Population-based data ensures real-world applicability, and Cox proportional hazard models evaluate associations between exposures and outcomes while adjusting for confounders.
Paper I examines the association between systemic antibiotic use during infancy and the risk of asthma, allergies, celiac disease, eczema, juvenile arthritis, T1D, and overweight. The results indicate significant associations between early antibiotic use and increased risks for these conditions, suggesting that early-life antibiotic use may influence immune development. However, sibling-based analyses indicate that familial factors partially influence these associations, underscoring the complexity of isolating the direct impact of antibiotic use from other contributing factors.
Paper II explores labor induction and childhood asthma. The results identify a consistent association across gestational ages. Importantly, this association is also observed in healthy pregnancies carried to term and post-term, raising questions about the potential long-term effects of labor induction during childbirth on disease development later in life.
This thesis adds to the growing body of evidence on the role of early-life exposures in IMD development while contributing novel findings not previously reported. By leveraging Denmark’s robust epidemiological resources, it addresses critical gaps in our understanding of the environmental drivers of IMDs and lays the groundwork for future studies. Specifically, the results emphasize the importance of considering modifiable factors such as antibiotic stewardship and labor induction practices to mitigate disease risk.
