Cancer Causes & Control

, Volume 25, Issue 10, pp 1283–1293 | Cite as

Maternal reproductive history, fertility treatments and folic acid supplementation in the risk of childhood acute leukemia: the ESTELLE Study

  • Roula Ajrouche
  • Jérémie Rudant
  • Laurent Orsi
  • Arnaud Petit
  • André Baruchel
  • Brigitte Nelken
  • Marlène Pasquet
  • Gérard Michel
  • Christophe Bergeron
  • Stéphane Ducassou
  • Virginie Gandemer
  • Patrick Lutz
  • Laure Saumet
  • Xavier Rialland
  • Denis Hémon
  • Jacqueline Clavel
Original paper



To investigate the potential involvement of fertility treatments and other conditions of becoming pregnant (infertility, getting pregnant on birth control, maternal history of fetal loss) and folic acid supplements in the etiology of childhood leukemia (CL).


The ESTELLE study included 747 cases of CL [636 cases of acute lymphoblastic leukemia (ALL) and 100 of acute myeloblastic leukemia (AML)] diagnosed in France in 2010–2011 and 1,421 population controls frequency-matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. The odds ratios (OR) and their 95 % confidence intervals were estimated using unconditional regression models adjusted for potential confounders.


CL was not associated with difficulty in becoming pregnant [OR 0.9 (0.7–1.2)], in vitro fertilisation [OR 0.6 (0.3–1.5)] or the use of any fertility treatment [OR 0.8 (0.5–1.1)] for the index pregnancy. CL was not significantly associated with becoming pregnant on contraception [OR 1.2 (0.8–1.8)], but a positive association was observed for third generation oral contraception [OR 4.3 (1.2–16.2)]; however, the result is based on small numbers. Folic acid supplementation during pregnancy was not associated with CL, but an inverse borderline association was observed for supplementation initiated in the 3 months preceding pregnancy [OR 0.7 (0.5–1.0)]. In addition, maternal histories of stillbirth and miscarriage were associated with ALL [OR 2.6 (1.1–5.9)] and AML [OR 1.8 (1.1–2.8)], respectively.


The findings do not suggest that infertility and fertility treatments are risk factors for CL. They suggest that maternal histories of stillbirth and miscarriage may be more frequent among mothers of CL cases and that folic acid supplementation during preconception may reduce the risk of CL.


Infertility Fertility treatments Contraception Folic acid Fetal loss Childhood leukemia 



Acute leukemia


Acute lymphocytic leukemia


Acute myeloblastic leukemia


Artificial insemination


Assisted reproductive technologies


Childhood acute leukemia


Combined oral contraceptives


Computer-assisted telephone interviewing


Gamete intrafallopian transfer


Intracytoplasmic sperm injection


In vitro fertilization


National Registry of Childhood Hematopoietic Malignancies


National Registry of Childhood Solid Tumors


Odds ratios


Zygote intrafallopian transfer



The authors are grateful to: Noureddine Balegroune, Sofiène Ben salha and the team of clinical research associates who contributed to the recruitment of the cases; Laure Faure and the staff of the French National Registry of Childhood Blood Malignancies, who contributed to case detection and verification; Christophe David and the team of interviewers (Institut IPSOS), who recruited the controls and interviewed the cases and controls. The authors would like to thank all of the Société Française de lutte contre les Cancers de l’Enfant et de l’Adolescent (SFCE) principal investigators: André Baruchel (Hôpital Saint-Louis/Hôpital Robert Debré, Paris), Claire Berger (Centre Hospitalier Universitaire, Saint-Etienne), Christophe Bergeron (Centre Léon Bérard, Lyon), Gerard Michel (Hôpital La Timone, Marseille), Yves Bertrand (Hôpital Debrousse, Lyon), Pascal Chastagner (Centre Hospitalier Universitaire, Nancy), Patrick Boutard (Centre Hospitalier Régional Universitaire, Caen), Gérard Couillault (Hôpital d’Enfants, Dijon), Christophe Piguet (Centre Hospitalier Régional Universitaire, Limoges), Anne-Sophie Defachelles (Centre Oscar Lambret, Lille), François Demeocq (Hôpital Hôtel-Dieu, Clermont-Ferrand), Alain Fischer (Hôpital des Enfants Malades, Paris), Virginie Gandemer (Centre Hospitalier Universitaire – Hôpital Sud, Rennes), Dominique Valteau-Couanet (Institut Gustave Roussy, Villejuif), Philippe Colombat (Centre Gatien de Clocheville, Tours), Frederic Millot (Centre Hospitalier Universitaire Jean Bernard, Poitiers), Guy Leverger (Hôpital Armand-Trousseau, Paris), Patrick Lutz (Hôpital de Hautepierre, Strasbourg), Nicolas Sirvent (Hôpital Arnaud de Villeneuve, Montpellier), Xavier Rialland (Hôpital Mère et Enfants, Nantes), Martine Münzer (American Memorial Hospital, Reims), Brigitte Nelken (Hôpital Jeanne de Flandre, Lille), François Doz (Institut Curie, Paris), Brigitte Pautard (Centre Hospitalier Universitaire, Amiens), Yves Perel (Hôpital Pellegrin Tripode, Bordeaux), Alain Pierre-Kahn (Hôpital Enfants Malades, Paris), Emmanuel Plouvier (Centre Hospitalier Régional, Besançon), Xavier Rialland (Centre Hospitalier Universitaire, Angers), Alain Robert (Hôpital des Enfants, Toulouse), Hervé Rubie (Hôpital des Enfants, Toulouse), Nicolas Sirvent (L’Archet, Nice), Marilyne Poiree (Fondation Lenval, Nice), Jean-Pierre Vannier (Hôpital Charles Nicolle, Rouen), Dominique Plantaz (Centre Hospitalier Universitaire, Grenoble), Philippe le moine (Hôpital Morvan, Brest) and Christian Sainte Rose (Centre Hospitalier Universitaire Necker, Paris). The authors would like also to thank all of the Lebanese university. This work was supported by grants from the Ligue Nationale Contre le Cancer (LNCC), the Agence Nationale de Sécurité Sanitaire de l’alimentation, de l’Environnement et du Travail (ANSES), the Institut National du Cancer (INCa) and the association Enfants et santé.

Conflict of interest

We declare that we have no conflict of interest.


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Roula Ajrouche
    • 1
    • 2
  • Jérémie Rudant
    • 1
    • 2
    • 3
  • Laurent Orsi
    • 1
    • 2
  • Arnaud Petit
    • 4
    • 5
  • André Baruchel
    • 6
    • 7
  • Brigitte Nelken
    • 8
  • Marlène Pasquet
    • 9
  • Gérard Michel
    • 10
  • Christophe Bergeron
    • 11
  • Stéphane Ducassou
    • 12
  • Virginie Gandemer
    • 13
  • Patrick Lutz
    • 14
  • Laure Saumet
    • 15
  • Xavier Rialland
    • 16
    • 17
  • Denis Hémon
    • 1
    • 2
  • Jacqueline Clavel
    • 1
    • 2
    • 3
  1. 1.Department of Environmental Epidemiology of CancersINSERMVillejuifFrance
  2. 2.Department of Environmental Epidemiology of Cancers, Research Centre for Epidemiology and Population HealthParis-Sud UniversityVillejuifFrance
  3. 3.RNHE - National Registry of Childhood Hematopoietic MalignanciesVillejuifFrance
  4. 4.Service onco-hématologie pédiatriqueAP-HP, Hôpital Armand TrousseauParisFrance
  5. 5.Université Paris 6 Pierre et Marie CurieParisFrance
  6. 6.Service hématologie pédiatriqueAP-HP, Hôpital Robert DebréParisFrance
  7. 7.Université Paris 7ParisFrance
  8. 8.Service hématologie pédiatrique, Hôpital Jeanne de FlandreCHRULilleFrance
  9. 9.Service oncologie pédiatriqueHôpital des EnfantsToulouseFrance
  10. 10.Service hémato-oncologie pédiatriqueAP-HM, Hôpital la TimoneMarseilleFrance
  11. 11.Bureau d’Etude CliniqueInstitut d’Hématologie et d’Oncologie PédiatriqueLyonFrance
  12. 12.Service onco-hématologie pédiatriqueHôpital Pellegrin TripodeBordeauxFrance
  13. 13.Unité onco-hématologie pédiatriqueCHU Hôpital SudRennesFrance
  14. 14.Service de pédiatrie 3Hôpital de HautepierreStrasbourgFrance
  15. 15.Service hémato-oncologie pédiatriqueHôpital Arnaud de VilleneuveMontpellierFrance
  16. 16.Unité d’onco-hématologie pédiatrique, Hôpital Mère-EnfantCHU-NantesNantesFrance
  17. 17.Unité d’oncologie pédiatriqueCHU d’AngersAngersFrance

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