Methodological considerations
We acknowledge that the present study integrated data from different
systematic reviews and meta-analyses that used non-uniform literature
search criteria and different analytical approaches; thus, the potential
of missing some studies cannot be excluded. In addition, an inherent
limitation of the present umbrella review, as of any review, is that it
is liable to become out of date almost as soon as it is finished; of
note is that eight systematic reviews and meta-analyses have been
published after the end of the literature search up to the submission of
the present study . To overcome this limitation, we are planning to
develop our work to a living umbrella review. Moreover, summarizing the
evidence from large pooled analyses and several large cohort studies on
environmental risk factors and childhood cancer was beyond the scope of
the present umbrella review, which integrated data only on systematic
reviews and meta-analyses. The combination of systematic reviews,
meta-analyses, pooled analyses and cohort studies under the scope of a
future “umbrella review” is being planned. In addition, though we
included all study-specific associations reported in each meta-analysis,
we have missed some additional subgroup meta-analyses due to
insufficient study-specific estimates. Of note is that age-specific or
sex-specific subgroup meta-analyses (i.e. sub-analyses on infant
leukemia) were not retrieved due to the lack of study-specific effect
estimates. The only available age-specific meta-analyses examined the
association of environmental risk factors with early-onset leukemia
(<5 years) and CNS tumors (<10 years). Thus, we
could not further address at this stage the potentially differential
effect of these factors in males and females, or the differential effect
of these factors on infant leukemia, which is a distinct disease entity.
Moreover, the assessment of the quality of the primary studies included
in each meta-analysis was beyond the scope of this study; however, the
AMSTAR tool allowed us to assess some trajectories of the quality of
primary studies. However, though the fully adjusted
meta-analysis-specific effect estimates were used whenever available,
some meta-analyses were based on unadjusted primary study-specific
estimates; the definition of the fully adjusted model also varied
greatly from study to study and from exposure to exposure. Thus, issues
of confounding may have hampered the results presented herein. In
addition, owing to the rarity of childhood cancer, primary cohort
studies represented a minority of this literature with case-control
studies accounting for the overwhelming majority of primary studies
included in each meta-analysis. Case-control evidence is prone to
selection bias and is thus less robust to provide support to the
causality of associations. Indeed, sensitivity analyses including only
cohort or nested case-control studies provided weak level of evidence
about specific exposures and childhood cancer risk. Moreover, though we
examined the presence and extent of biases, the statistical tests
implemented were not definitive in determining the exact source of these
biases . Lastly, some inherent limitations of these tests, i.e., the
possibility of false-positive results from the Egger’s test, should be
taken account, although the effect magnitude is usually not substantial
and the primary studies are not randomized controlled trials of
interventions.