Birthweight
Birthweight is one of the most commonly studied perinatal risk factor of childhood cancer. High birthweight as a proxy of fetal macrosomia has been found to increase the risk of several cancers, including leukemia, CNS tumors, neuroblastoma, colorectal and breast cancer. Both genetics/epigenetics and environmental factors have been proposed to underlie these associations, whereas growth factors (IGF-1 and IGF-2) seem to play a crucial role in carcinogenesis by stimulating mitogenesis and cell cycle progression, while inhibiting apoptosis. Thus, IGFs can lead to an increase in the number of hematopoietic stem cells and to the promotion of malignant transformation of some of them, which may subsequently expand to pre-leukemic and then to overt leukemic. Moreover, it is well known that fetal macrosomia is associated with increased rates of cesarean delivery. An increased risk of leukemia in children born by cesarean section has been reported after controlling for birthweight, which has been attributed to altered microbiota colonization or/and to the lack of increased cortisol levels that could eliminate preleukemic and leukemic cells (the “adrenal hypothesis”). Furthermore, given the global increase in the incidence of obesity and the effect of overweight/obesity during pregnancy on high birthweight, the potential association between fetal macrosomia and childhood cancer risk merits further investigation. It would be interesting to explore whether primary prevention of overweight/obesity may indirectly reduce the incidence of childhood cancer.