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

Author:

He Jian-Rong12,Yu Yongfu3456,Fang Fang7,Gissler Mika891011,Magnus Per12,László Krisztina D.13,Ward Mary H.14,Paltiel Ora15,Tikellis Gabriella16,Maule Milena Maria1718,Qiu Xiu1,Du Jiangbo5619,Valdimarsdóttir Unnur Anna2021,Rahimi Kazem2,Wiemels Joseph L.22,Linet Martha S.23,Hirst Jane E.224,Li Jiong5,Dwyer Terence22526

Affiliation:

1. Division of Birth Cohort Study, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

2. Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom

3. Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China

4. Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, China

5. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

6. Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark

7. Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

8. Department of Molecular Medicine and Surgery, Karolinska Institute, Solna, Sweden

9. Academic Primary Health Care Centre, Region Stockholm, Sweden

10. Department of Child Psychiatry, Turku University Hospital, Turku University, Turku, Finland

11. Department of Knowledge Brokers, Finnish Institute for Health and Welfare, Helsinki, Finland

12. Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway

13. Department of Global Public Health, Karolinska Institute, Stockholm, Sweden

14. Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland

15. Braun School of Public Health and Community Medicine, Hadassah Medical Organization, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

16. Murdoch Children’s Research Institute, Royal Children’s Hospital, University of Melbourne, Melbourne, Australia

17. Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy

18. Azienda Ospedaliera Universitaria Città della Salute e della Scienza, Turin, Italy

19. Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China

20. Center of Public Health Sciences, University of Iceland, Reykjavik, Iceland

21. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

22. Center for Genetic Epidemiology, University of Southern California, Los Angeles

23. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

24. George Institute for Global Health, London, United Kingdom

25. Clinical Sciences Theme, Heart Group, Murdoch Children’s Research Institute, Melbourne, Australia

26. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia

Abstract

ImportanceMaternal 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.ObjectiveTo evaluate the association of maternal infection during pregnancy with childhood leukemia among offspring in a large study.Design, Setting, and ParticipantsThis 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.ExposuresMaternal infection during pregnancy categorized by anatomic locations identified from the Danish National Patient Registry.Main Outcomes and MeasuresThe 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.ResultsThis 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 RelevanceIn 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.

Publisher

American Medical Association (AMA)

Subject

General Medicine

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