Age-, sex- and disease subtype–related foetal growth differentials in childhood acute myeloid leukaemia risk: A Childhood Leukemia International Consortium analysis


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Aim: Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases. Methods: Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed. Results: A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03–2.14), reduced to 34% in boys aged <2 years (OR: 1.34, 95% CI: 1.05–1.71) and 25% in boys aged 0–14 years (OR: 1.25, 95% CI: 1.06–1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15–2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00–1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers. Conclusions: Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalEuropean Journal of Cancer
StatePublished - May 2020

Bibliographical note

Funding Information:
Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) was partially supported by the Hellenic Society for Social Pediatrics and Health Promotion. The Brazilian study has been supported by CNPq research scholarships (# 301594/2015-5 ) and FAPERJ (# E026/102.337/2013 ). The Danish study was supported by the US National Institutes of Health ( R21CA175959 , R03ES021643 ). The Taiwanese study was supported by Alex's Lemonade Stand Foundation grant number 17–01882 ), and P.-C.L. is supported in part by the Taiwan Ministry of Science and Technology ( MOST 107-2314-B-227-009-MY3 ); Taipei City Hospital (grant no. 10801-62-008 ); The Data Coordination Center at the IARC is supported by a grant from Children with Cancer UK for which we are grateful. The German case-control study was funded by the German Federal Ministry of the Environment, Nature Conservation and Nuclear Safety . The COG-AE24 study was supported by the Children's Oncology Group and the National Institutes of Health Grantsgrants: R01 CA79940 , U10 CA13539 , U10 CA98543 and U10CA180886 ) and the Children's Cancer Research Fund , Minneapolis, MN. Regarding the French studies, funding support was as follows: ADELE: INSERM , the French Ministère de l’Environnement , the Association pour la Recherche contre le Cancer , the Fondation de France , the Fondation Jeanne Liot , the Fondation Weisbrem-Berenson , the Ligue Contre le Cancer du Val de Marne and the Ligue Nationale Contre le Cancer ; ELECTRE: INSERM , the French Ministère de l’Environnement , the Association pour la Recherche sur le Cancer (ARC) , the Fondation de France , the Fondation pour la Recherche Médicale , Institut Electricité Santé ; ESCALE: Fondation de France , ARC , AFSSAPS , Cent pour Sang la Vie , Inserm , AFSSET , ANR (Grantgrant ID: ANR-10-COHO-0009 ), INCA , Cancéropôle Ile de France ; ESTELLE: INCa , Ligue Nationale contre le Cancer , association Enfants et Santé , ANSES, the Agence Nationale de Sécurité Sanitaire de l'alimentation, de l’Environnement et du Travail (PNREST Anses, Cancer TMOI AVIESAN, 2013/1/248), INCa-DHOS , Cancéropôle Ile de France , ANR (Grantgrant ID: ANR-10-COHO-0009 ). The cancer registry data in Washington are supported by the National Cancer Institute # HHSN261201300012I with additional support from the Fred Hutchinson Cancer Research Center and the Centers for Disease Control and Prevention 's National Program of Central Cancer Registries. The funding source of the Costa Rica study was the Universidad Nacional, Costa Rica and the Research Department of the Swedish International Development Cooperation Agency (Sida/SAREC) . The Italian SETIL study was financially supported by research grants received by AIRC (the Italian Association on Research on Cancer), MIUR (the Ministry for Instruction, University and Research, PRIN Program), the Ministry of Health (Ricerca Sanitaria Finalizzata Program) , the Ministry of Labour and Welfare, Associazione Neuroblastoma, Piemonte Region (Ricerca Sanitaria Finalizzata Regione Piemonte Program), Liguria Region , Comitato per la vita ‘Daniele Chianelli’-Associazione per la Ricerca e la Cura delle Leucemie , Linfomi e Tumori di Adulti e Bambini (Perugia) .

Funding Information:
Administration, annual meetings, and pooled analyses were partially supported by the National Cancer Institute (NCI) , USA ( R03CA132172 , Cancer Epidemiology Consortia), National Institute of Environmental Health Sciences (NIEHS) , USA ( P01ES018172 , R01ES009137 , R13ES021145 , R13ES022868 , R13ES024632 and U13ES026496 ), the US Environmental Protection Agency (USEPA) , USA ( RD83451101 ), CHILDREN with CANCER UK, Alex's Lemonade Stand Foundation (ALSF) , São Paulo Research Foundation (FAPESP) , Northwestern Mutual (NM) , Texas Children's Hospital (TCH) , Childhood Cancer Research Fund (CCRF) and individual member study institutions. The content is solely the responsibility of the authors and does not necessarily represent the official views of the aforementioned institutions. The authors thank the Brazilian Collaborative Study Group of Infant Leukemia that notified cases for the epidemiological studies. The authors thank the research investigators Julie Ross and Erin Marcotte (University of Minnesota) and clinical investigators at the Children's Oncology Group (COG) principal and affiliate member institutions of the COG-AE24study. The authors thank Costa Rica CRCLS staff, especially Costa Rican Childhood Leukemia Study (CRCLS) participants and their families, and Noemy Gomez for her support during the data cleaning process. The authors thank Dr. Peter Kaatsch, Dr. Rolf Meinert, Dr. Uwe Kaletsch and Dr. Jörg Michaelis for their work in the German GCCR study. The authors thank the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST): Collaborative Study Group and complimentary sources for the nationwide collection of cases and Panagiota Bouka, field coordinator. The authors thank Veronique Luzon (IARC) for data management of the CLIC Data Coordination Center. The authors thank Dr. Laurent Orsi (Inserm) for his work in the French studies (ADELE, ELECTRE, ESCALE, ESTELLE) and the Société Française de lutte contre les Cancers de l’Enfant et de l’Adolescent (SFCE) principal investigators and heads of paediatric haematology departments.


  • Acute myeloid leukaemia
  • Birth length
  • Birthweight for gestational age
  • Childhood
  • Foetal growth
  • Weight-for-length ratio

PubMed: MeSH publication types

  • Clinical Conference
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

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