Metabolic syndrome as a late effect of childhood hematopoietic stem cell transplantation – A thorough statistical evaluation of putative risk factors

Background: Metabolic syndrome (MetS) is frequent among survivors of childhood hematopoietic stem-cell transplantation (HSCT), but assessment of risk factors is challenged by survivor and participation bias in long-term follow-up studies. Methods: A cohort of 395 pediatric patients transplanted between 1980 and 2018 was investigated. MetS was assessed at follow-up between December 2018 and March 2020. Two composite outcomes ((a) combining MetS and death, (b) combining MetS, death, and nonparticipation) were considered to address the risk of selection bias. Results: Among 234 survivors invited to the follow-up, 96 individuals (median age 27 years) participated. MetS prevalence was 30% among participants. The only significant HSCT risk factor was a variable combining HSCT indication and conditioning with total-body irradiation (TBI) (p =.0011). Compared to acute leukemias (AL) treated with high-grade TBI (8–12 Gy), a lower MetS prevalence was seen for nonmalignant diseases treated with no/low-grade TBI (0–4.5 Gy) (OR = 0.04, 95% confidence interval (CI): 0.00–0.23). Analyses of the composite outcomes indicated overestimation of the effect of high-grade TBI due to selection bias. Scrutiny showed strong residual confounding between HSCT indication and high-grade TBI within AL-patients. The HSCT effect on MetS reflected HSCT effects on high-density-lipoprotein (HDL) and triglycerides. Compared to AL treated with high-grade TBI, nonmalignant diagnoses treated with no/low-grade TBI had higher HDL (+40%, 95% CI: +21% to +62%) and lower triglyceride (−59%, 95% CI: −71% to −42%). Conclusion: The TBI effect on MetS may be overestimated in follow-up studies due to selection bias and confounding. The TBI effect was confined to the potentially modifiable MetS criteria HDL and triglyceride.