title: Maternal fetal loss history and increased acute leukemia subtype risk in subsequent offspring: a systematic review and meta-analysis.
abstract: OBJECTIVE
  History of fetal loss including miscarriage and stillbirth has been inconsistently associated with childhood (0-14 years) leukemia in subsequent offspring. A quantitative synthesis of the inconclusive literature by leukemia subtype was therefore conducted.
  
  
  METHODS
  Eligible studies (N = 32) were identified through the screening of over 3500 publications. Random-effects meta-analyses were conducted on the association of miscarriage/stillbirth history with overall (AL; 18,868 cases/35,685 controls), acute lymphoblastic (ALL; 16,150 cases/38,655 controls), and myeloid (AML; 3042 cases/32,997 controls) leukemia. Sensitivity and subgroup analyses by age and ALL subtype, as well as meta-regression were undertaken.
  
  
  RESULTS
  Fetal loss history was associated with increased AL risk [Odds Ratio (OR) 1.10, 95% Confidence Intervals (CI) 1.04-1.18]. The positive association was seen for ALL (OR 1.12, 95%CI 1.05-1.19) and for AML (OR 1.13, 95%CI 0.91-1.41); for the latter the OR increased in sensitivity analyses. Notably, stillbirth history was significantly linked to ALL risk (OR 1.33, 95%CI 1.02-1.74), but not AML. By contrast, the association of ALL and AML with previous miscarriage reached marginal significance. The association of miscarriage history was strongest in infant ALL (OR 2.34, 95%CI 1.19-4.60).
  
  
  CONCLUSIONS
  In this meta-analysis involving >50,000 children, we found noteworthy associations by indices of fetal loss, age at diagnosis, and leukemia type; namely, of stillbirth with ALL and miscarriage history with infant ALL. Elucidation of plausible underlying mechanisms may provide insight into leukemia pathogenesis and indicate monitoring interventions prior to and during pregnancy.
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece.
authors.forename: M A
authors.initials: MA
authors.lastname: Karalexi
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Dessypris
authors.affiliation: Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Skalkidou
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece.
authors.forename: S -I
authors.initials: S-
authors.lastname: Biniaris-Georgallis
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece.
authors.forename: Ε Ι
authors.initials: ΕΙ
authors.lastname: Kalogirou
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece.
authors.forename: T P
authors.initials: TP
authors.lastname: Thomopoulos
authors.affiliation: Department of Women's and Children׳s Health, Karolinska Institutet and Karolinska University Hospital, 17176, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Herlenius
authors.affiliation: Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Spector
authors.affiliation: First Department of Obstetrics and Gynecology of the University of Athens, Alexandra Hospital, Athens, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Loutradis
authors.affiliation: First Department of Pediatrics, University of Athens, Medical School, Aghia Sophia Children's Hospital, Athens, Greece.
authors.forename: G P
authors.initials: GP
authors.lastname: Chrousos
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece. epetrid@med.uoa.gr.
authors.forename: E Th
authors.initials: ET
authors.lastname: Petridou
mesh_terms: D000022:Abortion, Spontaneous; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D011247:Pregnancy; D012307:Risk Factors; D050497:Stillbirth
keywords: Childhood acute lymphoblastic leukemia; Childhood acute myeloid leukemia; Meta-analysis; Meta-regression; Miscarriage; Stillbirth