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Cancer Causes Control. 2017 Jun;28(6):599-624. doi: 10.1007/s10552-017-0890-2. Epub 2017 Apr 11.

Maternal fetal loss history and increased acute leukemia subtype risk in subsequent offspring: a systematic review and meta-analysis.

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Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece.
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
Department of Women's and Children׳s Health, Karolinska Institutet and Karolinska University Hospital, 17176, Stockholm, Sweden.
Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
First Department of Obstetrics and Gynecology of the University of Athens, Alexandra Hospital, Athens, Greece.
First Department of Pediatrics, University of Athens, Medical School, Aghia Sophia Children's Hospital, Athens, Greece.
Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, 75 Mikras Asias Str, 11527, Athens, Greece.



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.


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.


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).


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.


Childhood acute lymphoblastic leukemia; Childhood acute myeloid leukemia; Meta-analysis; Meta-regression; Miscarriage; Stillbirth

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