Grading the evidence
We graded the evidence regarding the association of environmental risk
factors and childhood cancer accounting for the above criteria, namely
the p -value of the significant associations, the presence and
extent of heterogeneity, as well as the presence of small study effects
and excess significance bias (Table 2). Overall, 40% of the 509
meta-analyses were nominally statistically significant, and were
thereafter evaluated for strong, highly suggestive, suggestive or weak
evidence. A hundred sixty-six of the 509 reported meta-analyses (32.5%)
presented weak evidence (p <0.05 for the summary random
effects).
We found no association supported by strong evidence. Of note is that
the association of isolated cryptorchidism with testicular cancer
fulfilled all criteria of strong evidence with the exception of
considerable heterogeneity (I2>50%), and
was thus considered as highly suggestive (Table 2).
Overall, 12 meta-analyses (2.4%) were supported by highly suggestive
evidence (Figure 2). Among these meta-analyses, two showed a decreased
risk, by approximately 20%, of ALL in relation to maternal vitamin
supplementation during pregnancy (summary OR: 0.81, 95% CI: 0.74-0.88)
and breastfeeding for more than 6 months (summary OR: 0.76, 95% CI:
0.68-0.84). Four meta-analyses supported by highly suggestive evidence
found an increased risk for overall leukemia, especially ALL, in
relation to paternal smoking during pregnancy , as well as residential
exposure to pesticides, especially insecticides during pregnancy or
childhood . There was also highly suggestive evidence for the
association between high or increased birthweight and overall leukemia,
particularly ALL . The remaining 4 out of 12 highly suggestive
associations showed increased risk, by 14-22%, for childhood CNS
tumors, and especially astrocytoma in relation to high birthweight
(>4000 grams), as well as increased risk for testicular
cancer in relation to testicular microlithiasis (summary OR: 15.46, 95%
CI: 6.93-34.47) and isolated cryptorchidism (summary OR: 2.90, 95% CI:
2.21-3.82; Figure 2).
A total of 26 meta-analyses (5.1%) were supported by suggestive
evidence (Figure 2). Three associations showed a significant inverse
association of maternal folic acid supplementation during pregnancy and
daycare attendance with ALL, as well as between breastfeeding for more
than 6 months and overall acute leukemia. The remaining 23 associations
showed increased risk for childhood hematological malignancies related
to various exposures (use of assisted reproductive technologies, alcohol
and coffee consumption during pregnancy, home exposure to pesticides,
especially herbicides and insecticides during childhood, high exposure
to traffic density, high benzene exposure, petrol station/repair garage
proximity, fetal loss history, paternal ever smoking, birthweight
increase and preterm birth) , as well as increased risk for CNS tumors
in relation to birthweight increase and indoor pesticide exposure during
preconception or childhood .
Sensitivity analyses including only systematic reviews and meta-analyses
with ≥4 cohort or nested-case-control studies (n=28 meta-analyses)
yielded statistically significant results for nine (32.1%) associations
which were all supported by weak evidence. These associations concerned
medically assisted reproduction, high birthweight and advanced paternal
age in relation to increased risk of hematological and other solid
cancers (results not shown).