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

Purpose: 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.