It has been proposed that children with acute lymphoblastic leukemia (ALL) are born with a dysregulated immune function that together with postnatal environmental exposures causes childhood ALL. Despite its importance for the understanding of ALL etiology, this hypothesis has been inadequately explored. In a population-based case-control study, we measured the concentrations of 10 cytokines and other inflammatory markers on neonatal dried blood spots from 178 children who at ages 1 to 9 years were diagnosed with B-cell precursor ALL and 178 matched controls. Through linkage with Danish nationwide registers, we also assessed whether neonatal inflammatory markers were associated with previously demonstrated risk factors for childhood ALL. Children who developed B-cell precursor ALL had significantly lower neonatal concentrations of IL8, soluble IL6 receptor (sIL6R) α, TGFβ1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP) and higher concentrations of IL6, IL17, and IL18 compared with matched controls. Concentrations of IL10 were below the detection level for both patients and controls. Birth order (IL18 and CRP), gestational age (sIL6Rα, TGFβ1, and CRP), and sex (sIL6Rα, IL8, and CRP), but not maternal age, infections during pregnancy, birth weight nor mode of delivery were significantly associated with the neonatal concentrations of inflammatory markers. Our findings support the hypothesis that children who later develop B-cell precursor ALL are born with a dysregulated immune function. Children who develop acute lymphoblastic leukemia are immunologically distinct at birth and could potentially react abnormally to infections in early childhood. .

Regardless that absolute ALL risk among offspring of women with diabetes remains low, our findings suggest that characteristics of the diabetic intrauterine environment promote ALL development. This offers a setting for future research into the biological mechanisms underlying childhood ALL.

The "delayed infection hypothesis" states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 10 person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77-0.99) and 0.85: (0.73-0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58-1.05 and 0.73: 0.52-1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06-0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.

Background It has been suggested that the transiently increased infection risk following childcare enrolment is compensated by decreased infection risk later in childhood and adolescence. We investigated how childcare enrolment affected rates of antimicrobial-treated infections during childhood and adolescence. Methods In a register-based cohort study of all children born in Denmark 1997–2014 with available exposure information (n = 1 007 448), we assessed the association between childcare enrolment before age 6 years and infection risks up to age 20 years, using antimicrobial exposure as proxy for infections. Nationwide childcare and prescription data were used. We estimated infection rates and the cumulative number of infections using adjusted Poisson regression models. Results We observed 4 599 993 independent episodes of infection (antimicrobial exposure) during follow-up. Childcare enrolment transiently increased infection rates; the younger the child, the greater the increase. The resulting increased cumulative number of infections associated with earlier age at childcare enrolment was not compensated by lower infection risk later in childhood or adolescence. Accordingly, children enrolled in childcare before age 12 months had experienced 0.5–0.7 more infections at age 6 years (in total 4.5–5.1 infections) than peers enrolled at age 3 years, differences that persisted throughout adolescence. The type of childcare had little impact on infection risks. Conclusions Early age at childcare enrolment is associated with a modest increase in the cumulative number of antimicrobial-treated infections at all ages through adolescence. Emphasis should be given to disrupting infectious disease transmission in childcare facilities through prevention strategies with particular focus on the youngest children.

Background The risk of infectious mononucleosis (IM) is affected both by crowding and by sibship structure, i.e., number and signed age differential between an index child and a sibling. Siblings provide protection against IM by pre-empting delayed primary Epstein-Barr virus infection with its associated high risk of IM. The association between childcare attendance and risk of IM, on the other hand, has never been studied in a large, well-characterized cohort. Methods Danish children born in July 1992 through 2016 with a completely known simple childcare attendance history before age 1.5 years (n = 908,866) were followed up for a hospital contact with an IM diagnosis at ages 1.5–26 years. Hazard ratios (HRs) of IM for an additional year of exposure were obtained from stratified Cox regression analyses, stratified by sex and year of birth, with age as the underlying time scale, adjusted for sibship structure, and sociodemographic variables including parental ethnicity and maternal age. Results An additional year of exclusively attending a daycare home (max 5 children) yielded HR = 0.90 (95% confidence interval 0.81–1.00), and similarly, each year of exclusively attending a childcare institution (e.g., crèche) yielded HR = 0.94 (0.84–1.06). Conclusions Forwarding enrollment in childcare by a year lowers the risk of IM later in life much less than having an additional sibling of comparable age and has no practical public health implications. We find our results suggestive of a random threshold for successful Epstein-Barr virus infection that is more easily reached by a sibling than the collective of playmates in daycare homes or childcare institutions.