Is early life antibiotic-use a risk factor for the development of Type 1 diabetes? : a longitudinal data linkage study : a thesis with publications presented in partial fulfillment to the requirements for the degree of Doctor of Philosophy in Public Health (Epidemiology), Massey University, Wellington, New Zealand

Abstract

Introduction: Early-life antibiotic-use may disrupt the gut microbiota, potentially increasing the risk of Type 1 diabetes (T1D). This thesis assessed associations between prenatal and early childhood antibiotic exposure and T1D. Methods: A meta-analysis of 14 studies (2006-2020), encompassing 3,066,063 participants, assessed associations between early-life antibiotic-use and T1D. Subsequently, a longitudinal nation-wide linkage study examined this association in 315,789 New Zealand children born between 2005-2010 and followed until 2021, using Cox proportional hazards regression controlled for potential confounders. Patterns of antibiotic-use during pregnancy and early childhood were also analysed across demographic characteristics. Associations between both pre and post natal antibiotic exposure were assessed, including analyses by antibiotic class and spectrum, and stratification by delivery mode. T1D was identified using insulin dispensing and hospitalisation records. Results: The meta-analysis, showed a pooled risk estimates for prenatal exposure of 1.10 (95% CI: 1.00–1.21); for postnatal antibiotic-use a pooled risk estimate of 1.11 (95%CI 1.04–1.18) was found, with ≥5 courses resulting in a pooled estimate of 1.36 (95%CI 1.15–1.61). Broad-spectrum antibiotics were associated with higher risk (HR: 1.13, 95% CI: 1.03–1.23). In New Zealand, 30% of pregnant women received antibiotics, predominantly penicillin (73.7%). Higher usage was observed among Pacific (38.7%) and Māori (35.7%) women, those most deprived (i.e. those from the lowest socio-economic group) (39.5%). Those who had caesarean deliveries had higher rates of antibiotic use, with incidence rate ratios (IRRs) of 1.27 for elective and 1.09 for emergency procedures. By age five, 96% of children had received antibiotics, with similar subgroup patterns as observed for pregnant women. Prenatal antibiotic-use was associated with an increased T1D risk in a dose-dependent fashion (≥3 courses, HR 1.86; 95%CI:1.44–2.39), with the highest risk for broad-spectrum antibiotics (HR: 1.30; 95%CI: 1.12–1.57). Postnatal antibiotic-use was associated, also in a dose-dependent way, with T1D (≥13 courses, HR 1.93; 95%CI 1.18–3.17; broad-spectrum antibiotics, HR 1.74; 95%CI 1.10-2.78). Stratified analyses by delivery mode resulted in mixed results across different analyses. Conclusion: These findings show high antibiotic-use in New Zealand and among specific ethnic and socio-economic subgroups. It also showed clear associations with the development of childhood T1D, which is consistent with international studies as shown in the meta-analysis, underscoring the need for judicious antibiotic stewardship