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. 2023 Feb 1;6(2):e230133.
doi: 10.1001/jamanetworkopen.2023.0133.

Evaluation of Maternal Infection During Pregnancy and Childhood Leukemia Among Offspring in Denmark

Jian-Rong He  1   2 , Yongfu Yu  3   4   5   6 , Fang Fang  7 , Mika Gissler  8   9   10   11 , Per Magnus  12 , Krisztina D László  13 , Mary H Ward  14 , Ora Paltiel  15 , Gabriella Tikellis  16 , Milena Maria Maule  17   18 , Xiu Qiu  1 , Jiangbo Du  5   6   19 , Unnur Anna Valdimarsdóttir  20   21 , Kazem Rahimi  2 , Joseph L Wiemels  22 , Martha S Linet  23 , Jane E Hirst  2   24 , Jiong Li  5 , Terence Dwyer  2   25   26
Affiliations

Evaluation of Maternal Infection During Pregnancy and Childhood Leukemia Among Offspring in Denmark

Jian-Rong He et al. JAMA Netw Open. .

Abstract

Importance: Maternal infection is common during pregnancy and is an important potential cause of fetal genetic and immunological abnormalities. Maternal infection has been reported to be associated with childhood leukemia in previous case-control or small cohort studies.

Objective: To evaluate the association of maternal infection during pregnancy with childhood leukemia among offspring in a large study.

Design, setting, and participants: This population-based cohort study used data from 7 Danish national registries (including the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Cancer Registry, and others) for all live births in Denmark between 1978 and 2015. Swedish registry data for all live births between 1988 and 2014 were used to validate the findings for the Danish cohort. Data were analyzed from December 2019 to December 2021.

Exposures: Maternal infection during pregnancy categorized by anatomic locations identified from the Danish National Patient Registry.

Main outcomes and measures: The primary outcome was any leukemia; secondary outcomes were acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Offspring childhood leukemia was identified in the Danish National Cancer Registry. Associations were first assessed in the whole cohort using Cox proportional hazards regression models, adjusted for potential confounders. A sibling analysis was performed to account for unmeasured familial confounding.

Results: This study included 2 222 797 children, 51.3% of whom were boys. During the approximately 27 million person-years of follow-up (mean [SD], 12.0 [4.6] years per person), 1307 children were diagnosed with leukemia (ALL, 1050; AML, 165; or other, 92). Children born to mothers with infection during pregnancy had a 35% increased risk of leukemia (adjusted hazard ratio [HR], 1.35 [95% CI, 1.04-1.77]) compared with offspring of mothers without infection. Maternal genital and urinary tract infections were associated with a 142% and 65% increased risk of childhood leukemia, with HRs of 2.42 (95% CI, 1.50-3.92) and 1.65 (95% CI, 1.15-2.36), respectively. No association was observed for respiratory tract, digestive, or other infections. The sibling analysis showed comparable estimates to the whole-cohort analysis. The association patterns for ALL and AML were similar to that for any leukemia. No association was observed for maternal infection and brain tumors, lymphoma, or other childhood cancers.

Conclusions and relevance: In this cohort study of approximately 2.2 million children, maternal genitourinary tract infection during pregnancy was associated with childhood leukemia among offspring. If confirmed in future studies, our findings may have implications for understanding the etiology and developing preventive measures for childhood leukemia.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr He reported receiving a PhD scholarship from the China Scholarship Council during the conduct of the study. Dr László reported receiving grants from Forte, the Heart and Lung Foundation, and the Karolinska Institutet Research Foundation during the conduct of the study. Dr Rahimi reported receiving grants from the Oxford Martin School of the University of Oxford, the British Heart Foundation, the UK Research and Innovation (UKRI) Global Challenge Research Fund, and the Oxford Biomedical Research Centre as well as personal fees from BMJ Heart Journal for associate editorship outside the submitted work. Dr Hirst reported receiving a UKRI Future Leaders Fellowship outside the submitted work. Dr Li reported receiving grants from the Danish Council for Independent Research, the Nordic Cancer Union, and Novo Nordisk Fonden during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of Any Maternal Infection and Specific Infection Types During Pregnancy With Any Childhood Leukemia in Offspring
All models were adjusted for maternal age, educational level, parity, cohabitation during pregnancy, any diabetes during pregnancy, birth year, and birth season. All hazard ratios (HRs) were calculated by comparing children with each type of maternal infection exposure vs children without any maternal infection exposure.
Figure 2.
Figure 2.. Stratified Association of Maternal Infection for Any Childhood Leukemia by Diagnosis Age
All models were adjusted for maternal age, educational level, parity, cohabitation during pregnancy, any diabetes during pregnancy, birth year, and birth season. HR indicates hazard ratio.
See this image and copyright information in PMC

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