Association of childhood obesity with risk of early all-cause and cause-specific mortality: A Swedish prospective cohort study

Background Pediatric obesity is associated with increased risk of premature death from middle age onward, but whether the risk is already increased in young adulthood is unclear. The aim was to investigate whether individuals who had obesity in childhood have an increased mortality risk in young adulthood, compared with a population-based comparison group. Methods and findings In this prospective cohort study, we linked nationwide registers and collected data on 41,359 individuals. Individuals enrolled at age 3–17.9 years in the Swedish Childhood Obesity Treatment Register (BORIS) and living in Sweden on their 18th birthday (start of follow-up) were included. A comparison group was matched by year of birth, sex, and area of residence. We analyzed all-cause mortality and cause-specific mortality using Cox proportional hazards models, adjusted according to group, sex, Nordic origin, and parental socioeconomic status (SES). Over 190,752 person-years of follow-up (median follow-up time 3.6 years), 104 deaths were recorded. Median (IQR) age at death was 22.0 (20.0–24.5) years. In the childhood obesity cohort, 0.55% (n = 39) died during the follow-up period, compared to 0.19% (n = 65) in the comparison group (p < 0.001). More than a quarter of the deaths among individuals in the childhood obesity cohort had obesity recorded as a primary or contributing cause of death. Male sex and low parental SES were associated with premature all-cause mortality. Suicide and self-harm with undetermined intent were the main cause of death in both groups. The largest difference between the groups lay within endogenous causes of death, where children who had undergone obesity treatment had an adjusted mortality rate ratio of 4.04 (95% CI 2.00–8.17, p < 0.001) compared with the comparison group. The main study limitation was the lack of anthropometric data in the comparison group. Conclusions Our study shows that the risk of mortality in early adulthood may be higher for individuals who had obesity in childhood compared to a population-based comparison group.


Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported Stated in the introduction "Overweight and obesity under 18 years of age has also been linked to an increased risk of premature mortality from middle adulthood onward. A limited number of studies, conducted before the obesity epidemic, with baseline data collected during the period , have investigated the association between measured BMI in adolescence and risk of mortality in young adulthood." "To our knowledge, there are no current studies on risk of mortality in young adulthood in relation to measured height and weight in childhood." Objectives 3 State specific objectives, including any prespecified hypotheses Introduction, last sentence "Therefore, the aim was to examine whether individuals who had obesity in childhood have an increased risk of mortality in young adulthood, compared with a population-based comparison group."

Study design 4
Present key elements of study design early in the paper Methods, paragraph 1-2 "Individuals were included if they were enrolled in the Swedish Childhood Obesity Treatment Register (BORIS) at age 3-17.9 years, and alive and living in Sweden on their 18th birthday (start of follow-up, n = 7,049)." "Using a personal identification number, unique to each resident in Sweden, a comparison group from the Total Population Register was historically (year of entrance in BORIS) matched …" Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection "The main exposure was obesity in childhood, defined using the International Obesity Task Force sex-and age-adjusted cut-offs for body mass index standard deviation score (BMI SDS)." "Mortality was assessed using all-cause mortality and cause-specific mortality." " Cause-specific mortality was categorized into three groups;…" "Parental socioeconomic status (SES) was estimated based on parental education, occupation, and income,…" "Covariates included were sex, Nordic origin, and age and BMI SDS at start of obesity treatment." "…those with a diagnosis of genetic syndromes and/or malignant tumors (including malignant and benign brain tumors) were identified… "Genetic syndromes included Fragile X, Klinefelter, Laurence-Moon-Bardet-Biedl, Down, Noonan, Prader-Willi, Silver Russell, and Turner." Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group Methods, paragraph 3-4 "Information on date of death and primary cause and contributing causes of death was retrieved from the Cause of Death Register." "Information on weight, height, and age at initiation of pediatric obesity treatment was retrieved from BORIS. Information on parental education, occupation, and income was collected from the Longitudinal Integration Database for Health Insurance and Labour Market Studies. Information on country of birth and emigration was retrieved from the Swedish Total Population Register" "…a diagnosis of a genetic syndrome and/or malignant tumors (including malignant and benign brain tumors) were identified in the National Patient Register…" Bias 9 Describe any efforts to address potential sources of bias Methods, paragraph 2 & 5 "Using a personal identification number, unique to each resident in Sweden, a comparison group from the Total Population Register was historically (year of entrance in BORIS) matched …" "The National Board for Health and Welfare (www.socialstyrelsen.se/en) and Statistics Sweden (www.scb.se/en), both governmental agencies, are responsible for all the national registries mentioned above…" Study size 10 Explain how the study size was arrived at Methods, paragraph 1-2 "Individuals were included if they were enrolled in the Swedish Childhood Obesity Treatment Register (BORIS) at age 3-17.9 years, and alive and living in Sweden on their 18th birthday (start of follow-up, n = 7,049). No exclusion criteria were applied." "a comparison group from the Total Population Register was historically (year of entrance in BORIS) matched with a ratio of 1:5 by sex, year of birth, and area of residence (n=34,310)." Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why Methods, paragraph 3 & 7 "Information on weight, height, and age at initiation of pediatric obesity treatment was retrieved from BORIS" "The mean maternal and paternal SES score was calculated and divided into four categories; low SES (0-1.5 points), medium-low SES (2-3 points), medium-high SES (3.5-4.5 points), and high SES (5-6 points)." Statistical methods

12
(a) Describe all statistical methods, including those used to control for confounding Methods, paragraph 9 "Power analyses were performed using the score test for Cox proportional hazards regression. To examine if the risk of all-cause mortality differed between groups, crude and adjusted Cox proportional hazard models were used to calculate mortality rate ratios (MRRs) and 95% confidence intervals (CIs). Adjusted models were controlled according to…" "Kaplan-Meier analysis was used to investigate whether there was a difference in crude probability of survival between the groups." (b) Describe any methods used to examine subgroups and interactions Methods, paragraph 10 "In analyses including individuals in the childhood obesity cohort only, the potential impact of obesity severity (BMI SDS) and age at obesity treatment initiation was investigated." (c) Explain how missing data were addressed Methods, paragraph 9 "As parental SES was missing for only a limited number of individuals (childhood obesity cohort, 0.4% [n = 28]; comparison group, 0.9% [n = 308]), complete case analyses were done." (d) Cohort study-If applicable, explain how loss to follow-up was addressed N/A Case-control study-If applicable, explain how matching of cases and controls was addressed Cross-sectional study-If applicable, describe analytical methods taking account of sampling strategy (e) Describe any sensitivity analyses Methods, paragraph 9 "As post hoc analyses, sensitivity analyses were performed excluding individuals with genetic syndromes and malignant tumors in childhood."

Results
Participants 13* (a) Report numbers of individuals at each stage of study-eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed Results, paragraph 1 & 6 "In total 41,359 individuals were included." "Information on cause-specific mortality was available for 97% (n=38) of the deceased in the childhood obesity cohort and 95% (n=62) of the deceased in the comparison group." (b) Give reasons for non-participation at each stage Methods, paragraph 9 and Discussion paragraph 13 "As parental SES was missing for only a limited number of individuals (childhood obesity cohort, 0.4% [n = 28]; comparison group, 0.9% [n = 308]), complete case analyses were done." "Four of the deceased had an unknown cause of death and were thus not included in the cause-specific analyses. The reasons for this might include declining rates of autopsy, or death abroad with inability to determine cause of death." (c) Consider use of a flow diagram Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders Results, paragraph 1, Table 1 and S1 Table   "Since the groups were matched on sex and age, there was an even distribution between groups with respect to sex (46% females) and age at end of follow-up (median age 21.6 years, IQR 19.6-24.7, maximum age 38.8 years)." "Further, they were more likely to be of non-Nordic origin, have low parental SES, genetic syndromes, and tumors before 18 years of age than individuals from the comparison group." (b) Indicate number of participants with missing data for each variable of interest Methods, paragraph 9 "As parental SES was missing for only a limited number of individuals (childhood obesity cohort, 0.4% [n = 28]; comparison group, 0.9% [n = 308]), complete case analyses were done." (c) Cohort study-Summarise follow-up time (eg, average and total amount) Results, paragraph 1-2 "Individuals who had been referred to obesity treatment in childhood were followed on average 9.5 (SD 4.0) years from start of treatment to end of follow-up (maximum 23.0 years)." "During a total of 190,752 person-years of follow-up,…" Outcome data 15* Cohort study-Report numbers of outcome events or summary measures over time  Table 2 &  Table 3 "All-cause mortality was overall higher for individuals in the childhood obesity cohort compared to the comparison group (Fig 1)" "Individuals in the childhood obesity cohort had an almost three times greater risk of all-cause mortality compared to individuals in the comparison group..." "In analyses mutually adjusted according to group (childhood obesity cohort vs. comparison group), sex, Nordic origin, and parental SES, the results were only mildly attenuated, and remained statistically significant (Table 2)." "Suicide and self-harm were the most common cause of death in both groups (Table 3)…" "Death due to endogenous causes showed the most pronounced difference in the childhood obesity cohort compared to the comparison group…" (b) Report category boundaries when continuous variables were categorized Methods, paragraph 7 "The mean maternal and paternal SES score was calculated and divided into four categories; low SES (0-1.5 points), medium-low SES (2-3 points), medium-high SES (3.5-4.5 points), and high SES (5-6 points)." (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses Results, paragraph 5 & 8 "In sensitivity analyses, individuals with genetic syndromes (n=155) and malignant tumors (n=167) in childhood were excluded (childhood obesity cohort=1.77%, comparison group=0.57%)." "In analyses adjusted for age at start of obesity treatment, Nordic origin, sex, and parental SES, the severity of obesity at the start of treatment was associated with premature death (MRR per 0.5-unit increase in BMI SDS 1.79 [95% CI 1.29-2.48]; p = 0.001). Age at start of obesity treatment did not influence the outcome..."

Discussion
Key results 18 Summarise key results with reference to study objectives Discussion, paragraph 1-2 "This study found that individuals who had obesity in childhood had a 3 times higher risk of all-cause mortality in early adulthood compared with a populationbased comparison group." "Suicide and self-harm were the most common cause of death in both groups. The largest difference in cause-specific death between the groups was for endogenous causes, where the MRR was 4 times higher in the childhood obesity cohort compared to the comparison group. Furthermore, 1 in 4 deaths among individuals who had obesity in childhood had obesity recorded as a primary or contributing cause of death." Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias Discussion, paragraph 9-13 "…it has been questioned whether it is possible to study associations between BMI and mortality under the age of 30 years because of the very low mortality rate." "…we did not apply any exclusion criteria, e.g. genetics syndromes." "Weight and height were measured for all individuals in the obesity cohort, however, these data were not available in the comparison group." "…it is possible that the relationship between obesity in childhood and mortality risk in early adulthood is confounded by unmeasured factors,…" "Four of the deceased individuals had an unknown cause of death and were thus not included in the cause-specific analyses." Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence Discussion, paragraph 3-8 "In the present study the mortality rate in the childhood obesity cohort was 12.0 per 10,000 person-years, while the expected mortality rate (from the comparison group) was 4.1 deaths per 10,000 person-years. Previous estimated risks of premature death in young adulthood are based on data collected roughly 50-70 years ago…" "…being of non-Nordic origin did not predict risk of all-cause mortality in early adulthood. In contrast, a U.S. based study, …showed associations between mortality and different ethnic groups, demonstrating a higher mortality risk among ethnic minorities" "Family conditions, such as parental working status and education, …are associated with mortality risk in adulthood… In the current study, low parental SES, compared to high, was associated with risk of all-cause mortality in young adulthood almost to the same extent as pediatric obesity." "Several forms of cancer have also been associated with obesity in adults. However, in our study we did not see a significant influence of cancer during follow-up on the observed mortality..." "The severity of obesity at the start of obesity treatment was a risk factor for premature death. This has to our knowledge not been demonstrated previously." "The association between obesity and risk of premature mortality could be explained by several mediating factors of both somatic and non-somatic origin..." "…overweight and obesity have been associated with depression, discrimination, and bullying …both somatic and psychological factors may play a role in the increased risk of mortality observed in individuals with obesity." Generalisability 21 Discuss the generalisability (external validity) of the study results Discussion, paragraph 9 & 13 "Despite the many relationships between obesity and severe morbidities, it has been questioned whether it is possible to study associations between BMI and mortality under the age of 30 years because of the very low mortality rate. A reverse power analysis showed that our study had a large enough study sample for the actual number of events. It has also been argued that a long follow-up time is necessary to investigate deaths due to illness influenced by BMI." "…the Cause of Death Register is a high-quality, virtually complete register of all deaths in Sweden since 1952 and contains both primary and contributing causes of death, indicating a potential chain that led to death."

Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based