Maternal infections during pregnancy and the risk of childhood leukaemia in the offspring: Evidence from large-scale cohort studies

Background: Leukaemia is the most common childhood cancer, but its aetiology remains unclear. Maternal infection during pregnancy might lead to chromosomal or immunological alterations in the fetus and could be a risk factor for childhood leukaemia. Clarifying the roles of maternal infections in the development of childhood leukaemia would be helpful for the prevention of this disease.
Objectives: This thesis aims to investigate the association of maternal infections during pregnancy with childhood leukaemia using data from different sources, including previously published reports, prospective cohort studies and population-based registries. Integrating results from different sources might enhance the robustness of the evidence.
Methods: Three analyses were conducted: (1) A systematic review and meta-analysis was firstly conducted to summarise findings in previous studies on maternal infections during pregnancy and childhood leukaemia. (2) Analyses using data on 312,879 mother-child pairs from the six prospective cohorts in the International Childhood Cancer Cohorts Consortium (I4C) was then performed to assess the association between self-reported maternal infections and childhood leukaemia. (3) A national registry-based investigation was further carried out among 4.9 million mother-child pairs in Denmark and Sweden to examine the association for hospital-diagnosed infections during pregnancy. A sibling analysis was also conducted to account for unmeasured familial confounders.
Results: In the systematic review and meta-analysis of previously published 32 articles from 20 studies (primarily case-control studies), I found that maternal influenza (pooled OR, 1.77; 95% CI, 1.01- 3.11), rubella (pooled OR, 2.79; 95% CI, 1.16-6.71) and varicella (pooled OR, 10.19; 95% CI, 1.98-52.39) during pregnancy, but not other infections, were associated with a higher risk of childhood leukaemia. In the I4C analysis, maternal urinary tract infection (HR, 1.68; 95% CI, 1.10-2.58) and respiratory tract infection (HR, 1.54; 95% CI, 1.05-2.26) were associated with increased risk of childhood leukaemia. Influenza-like illness showed a similar pattern but with less precise estimates (HR, 1.62; 95% CI, 0.76-3.42). The analysis based on Danish and Swedish registry data shows that urinary tract infection (HR, 1.55; 95% CI, 1.10-2.18), genital tract infection (HR, 2.32; 95% CI1.49-3.60) and influenza (HR, 4.42; 95% CI, 1.42-13.72) were associated with increased risk of childhood leukaemia. There is no evident association between other types of maternal infections during pregnancy and childhood leukaemia. A sibling analysis demonstrated similar results after controlling for familial confounding.
Conclusions: Maternal infections during pregnancy are associated with an increased risk of childhood leukaemia in the offspring. Maternal infections might be considered a candidate cause of childhood leukaemia in future aetiologic and mechanistic research.

Keywords: Cohort study
Maternal infection
Childhood leukaemia
Advisor: Dwyer , T
Hirst , J
Rahimi , K