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OPINION article

Front. Pediatr., 24 July 2023
Sec. Pediatric Oncology
Volume 11 - 2023 |

Synthesized evidence for childhood acute lymphoblastic leukemia

Felix M. Onyije* Ann Olsson Liacine Bouaoun Joachim Schüz
  • Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France

Childhood leukemia is the most common type of cancer among children globally (1). In this study, we evaluated the strength of evidence and magnitude of risk factors for childhood acute lymphoblastic leukemia (ALL) using relevant systematic reviews and pooled analyses that were not part of our previously published umbrella review (1). We also estimated the prevalence in the French population as an example of the relevance of different risk factors. The strength of the association was evaluated using the summary RR/OR values of the various meta-analyses and categorized as very strong (RR > 5), strong (RR > 2), moderate (RR > 1.5), modest (RR > 1.2), and weak (RR > 1). The strength of association, heterogeneity across studies, and number of studies were used to evaluate the strength of evidence. The evidence was categorized into “strong” (consistently strong or very strong risk estimates in quality systematic review and meta-analysis), “some” (consistently moderate risk estimates in quality systematic review and meta-analysis), “little” (consistently low risk estimates), “no” (consistently no association), and “conflicting.” The category of “conflicting” was used when systematic reviews on the same subject came to different conclusions (1). In this article, we provide an update on some of these risk factors strengthening our earlier findings and further promote the prevention of childhood ALL.

During the 70th World Health Assembly, the 2017 WHO cancer resolution adopted a global initiative for cancer prevention and control through an integrated approach (WHA70.12), which focused on reducing premature mortality from non-communicable diseases (NCDs) and achieving universal health coverage. Member states were strongly encouraged to promote the primary prevention of cancers (2). Identifying childhood ALL risk factors, especially modifiable risk factors, is crucial for the success of this campaign.

The first update is on maternal exposure to pesticides during preconception or pregnancy. A recently published systematic review (3) confirmed our previous assessment of convincing evidence of an increased ALL risk (1). In their systematic review and meta-analysis, the authors reported the strongest association in maternal outdoor exposure to pesticides during pregnancy, with more than a twofold increase in effect estimates (RR: 2.51, 95% CI: 1.39–4.55) based on three studies. The effect estimates for insecticides were 1.35 (95% CI: 0.91–2.01) based on four studies, while for herbicides, it was 1.19 (95% CI: 0.92–1.53) based on three studies. Paternal occupational exposure to pesticides at any time of the child's development was associated with childhood leukemia (OR: 1.20, 95% CI: 1.07–1.35) based on five studies. These findings were similar to the pooled summary estimates for general pesticide exposure during childhood and the risk of leukemia (OR: 1.82, 95% CI: 1.07–3.11), and for childhood exposure to insecticides and the risk of ALL (OR: 1.48, 95% CI: 1.17–1.86) based on five and two studies, respectively (Table 1). Some hypotheses suggest that childhood ALL associated with pesticide exposure may result from induced topoisomerase II inhibition leading to misrepaired DNA cleavage and further chromosomal aberrations in hematopoietic stem and/or progenitor cells (9). Greaves had earlier proposed the causal mechanism of childhood ALL to occur due to two genetic hits, with the first hit possibly being introduced by parental exposure to toxic substances during pregnancy (10).


Table 1. Recently published environmental risk factors for childhood acute lymphoblastic leukemia.

The second update is on childhood exposure to domestic radon and the risk of leukemia. In our previous review, we concluded “conflicting evidence” based on a meta-analysis of cohort studies (two studies; OR = 0.97, 95% CI: 0.81–1.15) and of case–control studies (eight studies; OR = 1.22, 95% CI: 1.01–1.42), with somewhat conflicting results. In recent systematic reviews and meta-analyses, Moon and Yoo (6) reported a summary risk estimate of 1.03 (95% CI: 1.01–1.06) per 100 Bq/m3 radon increase based on eight case–control studies with moderate heterogeneity across studies. Ngoc et al. evaluated eight case–control studies, yielding a summary risk estimate of 1.43 (95% CI: 1.19–1.72) (7). As the case–control studies included in those meta-analyses only partly overlapped with our previous review (1), we repeated our meta-analysis with 12 case–control studies, observing an increased summary risk estimate of 1.36 (95% CI: 1.11–1.66), with a heterogeneity of 52.8%, P-value = 0.02 (Table 1). Based on this finding, we upgraded radon to “little” evidence.

Further updates are on cesarean delivery and maternal diabetes. The evidence was categorized as “little” for cesarean delivery (OR: 1.18, 95% CI: 1.07–1.31) and “some” for maternal diabetes (OR: 1.46, 95% CI: 1.28–1.67), as reported in our previous review. These findings remained unchanged even after the addition of new studies (4, 5). In addition, with regard to exposure to extremely low-frequency magnetic fields (ELF-MF), the earlier evaluation of “some” evidence remained unchanged even after the inclusion of an additional systematic review (8). The prevalence of the highlighted risk factors in France varied from “common” to “high,” except for electromagnetic field exposure, which is rare (1116), confirming the importance of risk identification in any primary prevention.

Author contributions

FO was responsible for drafting and editing. AO, LB, and JS were involved in editing the manuscript. All authors contributed to the article and approved the submitted version.


This research was supported by the French National Cancer Institute (INCa:15670; PEDIAC Consortium).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

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Keywords: childhood leukemia, risk factors, environmental exposures, pesticides, radon, cesarean delivery

Citation: Onyije FM, Olsson A, Bouaoun L and Schüz J (2023) Synthesized evidence for childhood acute lymphoblastic leukemia. Front. Pediatr. 11:1209330. doi: 10.3389/fped.2023.1209330

Received: 20 April 2023; Accepted: 4 July 2023;
Published: 24 July 2023.

Edited by:

Marta Llop, Hospital Universitario y Politécnico La Fe, Spain

Reviewed by:

Ruth Etzel, U.S. Environmental Protection Agency, United States

© 2023 Onyije, Olsson, Bouaoun and Schüz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Felix M. Onyije