Risk for childhood leukemia associated with maternal and paternal age

Abstract

The role of reproductive factors, such as parental age, in the pathogenesis of childhood leukemias is being intensively examined; the results of individual studies are controversial. This meta-analysis aims to quantitatively synthesize the published data on the association between parental age and risk of two major distinct childhood leukemia types in the offspring. Eligible studies were identified and pooled relative risk (RR) estimates were calculated using random-effects models, separately for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Subgroup analyses were performed by study design, geographical region, adjustment factors; sensitivity analyses and meta-regression analyses were also undertaken. 77 studies (69 case-control and eight cohort) were deemed eligible. Older maternal and paternal age were associated with increased risk for childhood ALL (pooled RR = 1.05, 95 % CI 1.01-1.10; pooled RR = 1.04, 95 % CI 1.00-1.08, per 5 year increments, respectively). The association between maternal age and risk of childhood AML showed a U-shaped pattern, with symmetrically associated increased risk in the oldest (pooled RR = 1.23, 95 % CI 1.06-1.43) and the youngest (pooled RR = 1.23, 95 % CI 1.07-1.40) extremes. Lastly, only younger fathers were at increased risk of having a child with AML (pooled RR = 1.28, 95 % CI 1.04-1.59). In conclusion, maternal and paternal age represents a meaningful risk factor for childhood leukemia, albeit of different effect size by leukemia subtype. Genetic and socio-economic factors may underlie the observed associations. Well-adjusted studies, scheduled by large consortia, are anticipated to satisfactorily address methodological issues, whereas the potential underlying genetic mechanisms should be elucidated by basic research studies.

Parental age and childhood cancer risk: A Danish population-based registry study

“…Our findings for ALL largely affirm the results of previous studies which reported an increased risk of ALL with older maternal age [7–9, 16, 19]. However, our results contradict the strong association between older paternal age (45+) and ALL that persisted with adjustment for maternal age in a recent registry-based Danish cohort study [10].…”

“…In terms of acute myeloid leukemia (AML), there was a U-shaped risk with maternal age and the risk of AML was increased only in offspring born to younger fathers. Only 4 of the 77 studies included in this analysis examined the impact of mutual adjustment for maternal and paternal age, and the only notable association that persisted with mutual adjustment was an increased risk of AML with younger maternal age [7]. …”

Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium

“…In the context of the current CLIC study, a meta-analysis was undertaken [22] showing positive associations of advanced age of both parents at birth of the index child with ALL in the offspring irrespective of study design. Subsequently, registry-based, record-linkage nested case-control (NCC) studies from the US and Denmark also reported an increased ALL risk with advanced maternal age, whereas the positive associations with older paternal age were marginally significant [23–26].…”

Advanced paternal age and childhood cancer in offspring: A nationwide register-based cohort study

“…The association between maternal age and risk of childhood leukemia has been studied in several studies over more than half a century, but the results are inconsistent. A recent meta‐analysis found that the mother's age is a risk factor for childhood leukemia . The association between paternal age and risk of childhood leukemia has also been studied, yet to a much more limited extent and mostly over the last two decades.…”