title: Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC).
abstract: BACKGROUND
  Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery.
  
  
  METHODS
  We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis.
  
  
  RESULTS
  The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1·06 (95% CI 0·99-1·13), and was significant for prelabour caesarean delivery and ALL (1·23 [1·04-1·47]; p=0·018). Emergency caesarean delivery was not associated with ALL (OR 1·02 [95% CI 0·81-1·30]). AML was not associated with caesarean delivery (all indications OR 0·99 [95% CI 0·84-1·17]; prelabour caesarean delivery 0·83 [0·54-1·26]; and emergency caesarean delivery 1·05 [0·63-1·77]).
  
  
  CONCLUSIONS
  Our results suggest an increased risk of childhood ALL after prelabour caesarean delivery. If this association is causal, maladaptive immune activation due to an absence of stress response before birth in children born by prelabour caesarean delivery could be considered as a potential mechanism.
  
  
  BACKGROUND
  National Cancer Institute.
authors.affiliation: Department of Pediatrics, University of Minnesota, MN, USA. Electronic address: marcotte@umn.edu.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Marcotte
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Thomopoulos
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Claire
authors.initials: C
authors.lastname: Infante-Rivard
authors.affiliation: INSERM Unit 1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Epidemiology of Childhood and Adolescent Cancers Team, Villejuif, France; Paris-Descartes University, UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Clavel
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Eleni Th
authors.initials: ET
authors.lastname: Petridou
authors.affiliation: International Agency for Research on Cancer, Section of Environment and Radiation, Lyon, France.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schüz
authors.affiliation: National Liver Institute, Menoufia University, Menoufia, Egypt.
authors.forename: Sameera
authors.initials: S
authors.lastname: Ezzat
authors.affiliation: Dean's Department and Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Dockerty
authors.affiliation: University of California, School of Public Health, Berkeley, CA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Metayer
authors.affiliation: Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale, SCDU Epidemiologia dei Tumori, Novara, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Magnani
authors.affiliation: Baylor College of Medicine, Department of Pediatrics, Section of Hematology-Oncology, Houston, TX, USA; Texas Children's Cancer Center, Houston, TX, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Scheurer
authors.affiliation: Epidemiology Department, University of Washington School of Public Health, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Mueller
authors.affiliation: Central American Institute for Studies on Toxic Substances, Universidad Nacional, Heredia, Costa Rica; Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Mora
authors.affiliation: Central American Institute for Studies on Toxic Substances, Universidad Nacional, Heredia, Costa Rica.
authors.forename: Catharina
authors.initials: C
authors.lastname: Wesseling
authors.affiliation: Department of Women's and Children's Health, Obstetrics and Gynecology, Akademiska Sjukhuset, Uppsala, Sweden.
authors.forename: Alkistis
authors.initials: A
authors.lastname: Skalkidou
authors.affiliation: Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt.
authors.forename: Wafaa M
authors.initials: WM
authors.lastname: Rashed
authors.affiliation: University of California, School of Public Health, Berkeley, CA, USA; University of California, San Francisco, Neuro and Molecular Epidemiology Laboratory, San Francisco, CA, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Francis
authors.affiliation: INSERM Unit 1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Epidemiology of Childhood and Adolescent Cancers Team, Villejuif, France; Paris-Descartes University, UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Paris, France.
authors.forename: Roula
authors.initials: R
authors.lastname: Ajrouche
authors.affiliation: International Agency for Research on Cancer, Section of Environment and Radiation, Lyon, France.
authors.forename: Friederike
authors.initials: F
authors.lastname: Erdmann
authors.affiliation: INSERM Unit 1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Epidemiology of Childhood and Adolescent Cancers Team, Villejuif, France; Paris-Descartes University, UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Orsi
authors.affiliation: Department of Pediatrics, University of Minnesota, MN, USA.
authors.forename: Logan G
authors.initials: LG
authors.lastname: Spector
mesh_terms: D000293:Adolescent; D002170:Canada; D002585:Cesarean Section / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D003364:Costa Rica; D004534:Egypt; D005260:Female; D005602:France; D005858:Germany; D006115:Greece; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology*; D009520:New Zealand; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology*; D011247:Pregnancy; D012307:Risk Factors; D014481:United States