Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations.

OBJECTIVES: To determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed between carriers and noncarriers. METHODS: Using target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment. RESULTS: Of 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5-4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017). CONCLUSION: Among Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype.

Childhood height and risk of testicular germ cell tumors in adulthood.

Increased adult stature has been associated with risk of testicular germ cell tumors (TGCT) in a number of studies. Whether childhood stature is also associated with TGCT is unclear as no studies of measured childhood height and TGCT have been reported. Thus, associations between TGCT in adulthood and childhood height and growth between ages 7 and 13 years were examined in a cohort from the Copenhagen School Health Records Register. Analyses included 162,607 boys born during the years 1930-1989. Development of TGCT was determined via linkage to the Danish Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression. Between 1968 and 2014, 782 TGCT were diagnosed. Childhood height, per one unit increase in z-score, was associated with risk of TGCT, with HRs ranging from 1.11 (95%CI 1.03-1.20) at age 7 to 1.09 (95%CI = 1.01-1.18) at age 13. In a categorical analysis, the shortest boys were at the lowest risk of developing TGCT. Results varied little by TGCT histology (seminoma and nonseminoma). Growth between ages 7 and 13 years was not associated with risk. These findings suggest that risk of TGCT in adulthood was already determined by age 7 years. Although the mechanism requires further investigation, these results provide additional evidence that risk of TGCT is determined at a young age, thus suggesting that additional investigation of early life factors is warranted.

Childhood body mass index in relation to subsequent risk of type 1 diabetes-A Danish cohort study.

The incidence of type 1 diabetes (T1D) is increasing, and obesity may be a contributing factor by increasing the risk and accelerating the onset. We investigated the relation between childhood body mass index z-scores (BMIz) and the later risk of T1D, including association with age at onset of T1D. The study included 238 cases and 10 147 controls selected from the Copenhagen School Health Record Register (CSHRR). Cases of T1D were identified in the Danish Registry of Childhood and Adolescent Diabetes and 2 regional studies and linked to CSHRR. Using conditional logistic regression models, the association of childhood prediagnostic BMIz at 7 and 13 years of age and changes between these ages with subsequent risk (odds ratio, OR) of T1D was estimated. A greater BMIz at 7 and 13 years of age was associated with increased risk of T1D with OR of 1.23 (confidence interval, CI 1.09-1.37; P = .0001) and 1.20 (CI 1.04-1.40; P = .016), respectively. The risk was increased by upward changes in z-scores from birth to 7 years (OR=1.21, P = .003) and from 7 to 13 years of age (OR=1.95, P = .023), but in the latter age interval also by a decline in BMIz (OR = 1.91, P = .034). There were no associations between BMIz at 7 and 13 years of age and the age of onset (P = .34 and P = .42, respectively). Increased BMIz is associated with a moderate increase in risk of T1D, but with no relation to age at onset within the analyzed age range. Increased BMIz over time is unlikely to explain the rising incidence of T1D.

The effect of impaired glucose metabolism on weight loss in multidisciplinary childhood obesity treatment.

OBJECTIVE: To investigate whether children and adolescents exhibiting an impaired glucose metabolism are more obese at treatment entry and less likely to reduce their degree of obesity during treatment. METHODS: The present study is a longitudinal observational study, including children and adolescents from the Children's Obesity Clinic, Holbaek, Denmark. Anthropometrics, pubertal development, socioeconomic status (SES), and fasting concentrations of plasma glucose, serum insulin, serum C-peptide, and whole blood glycosylated hemoglobin (HbA1c) were collected at treatment entry and at follow-up. Proxies of Homeostasis Model Assessment 2-insulin sensitivity (HOMA2-IS) and Homeostasis Model Assessment 2-ß-cell function (HOMA2-B) were calculated with the Homeostasis Model Assessment 2 program. RESULTS: In total, 569 (333 boys) patients, median 11.5 years of age (range 6-22 years), and median body mass index (BMI) z-score 2.94 (range 1.34-5.54) were included. The mean BMI z-score reduction was 0.31 (±0.46) after 13 months (range 6-18) of treatment. At treatment entry, patients with impaired estimates of glucose metabolism were more obese than normoglycemic patients. Baseline concentration of C-peptide was associated with a lower weight loss during treatment in girls (P = .02). Reduction in the insulin concentrations was associated with reduction in BMI z-score in both sexes (P < .0001, P = .0005). During treatment, values of glucose, HbA1c, HOMA2-IS, and HOMA2-B did not change or impact the treatment outcome, regardless of age, sex, SES, or degree of obesity at treatment entry. CONCLUSION: The capability to reduce weight during multidisciplinary treatment in children and adolescents with overweight/obesity is not influenced by an impaired glucose metabolism at study entry or during the course of treatment.

Childhood body mass index growth trajectories and endometrial cancer risk.

Previously, we found that excess weight already in childhood has positive associations with endometrial cancer; however, associations with changes in body mass index (BMI) during childhood are not well understood. Therefore, we examined whether growth in childhood BMI is associated with endometrial cancer and its sub-types. A cohort of 155,505 girls from the Copenhagen School Health Records Register with measured weights and heights at the ages of 6-14 years and born 1930-1989 formed the analytical population. BMI was transformed to age-specific z scores. Using linear spline multilevel models, each girl's BMI growth trajectory was estimated as the deviance from the average trajectory for three different growth periods (6.25-7.99, 8.0-10.99, 11.0-14.0 years). Via a link to health registers, 1,020 endometrial cancer cases were identified, and Cox regressions were performed. A greater gain in BMI during childhood was positively associated with endometrial cancer but no differences between the different growth periods were detected in models adjusted for baseline BMI. The hazard ratios for the associations with overall growth during childhood per 0.1 z score increase were 1.15 (95% confidence interval [CI]: 1.07-1.24) for all endometrial cancers, 1.12 (95% CI: 1.04-1.21) for estrogen-dependent cancers, 1.16 (95% CI: 1.06-1.26) for endometrioid adenocarcinomas and 1.46 (95% CI: 1.16-1.84) for non-estrogen-dependent cancers. Growth in BMI in early life is positively linked to later endometrial cancer risk. We did not identify any sensitive childhood growth period, which suggests that excess gain in BMI during the entire childhood period should be avoided.

Childhood Body Size and the Risk of Malignant Melanoma in Adulthood.

Malignant melanoma (MM) is the most aggressive form of skin cancer. Adult anthropometry influences MM development; however, associations between childhood body size and future melanomagenesis are largely unknown. We investigated whether height, body mass index (BMI; weight (kg)/height (m)2), and body surface area (BSA) at ages 7-13 years and birth weight are associated with adult MM. Data from the Copenhagen School Health Records Register, containing annual height and weight measurements of 372,636 Danish children born in 1930-1989, were linked with the Danish Cancer Registry. Cox regression analyses were performed. During follow-up, 2,329 MM cases occurred. Height at ages 7-13 years was significantly associated with MM, even after BMI and BSA adjustments. No significant BMI-MM or BSA-MM associations were detected when adjusting for height. Children who were persistently tall at both age 7 years and age 13 years had a significantly increased MM risk compared with children who grew taller between those ages. Birth weight was positively associated with MM. We conclude that associations between body size and MM originate early in life and are driven largely by height and birth weight, without any comparable influence of BMI or BSA. Melanoma transformation is unlikely to be due to height per se; however, height-regulating processes in childhood present new areas for mechanistic explorations of this disease.

Childhood body mass index and height in relation to site-specific risks of colorectal cancers in adult life.

As colorectal cancers have a long latency period, their origins may lie early in life. Therefore childhood body mass index (BMI; kg/m2) and height may be associated with adult colorectal cancer. Using a cohort design, 257,623 children from The Copenhagen School Health Records Register born from 1930 to 1972 with measured heights and weights at ages 7 to 13 years were followed for adult colon and rectal adenocarcinomas by linkage to the Danish Cancer Registry. Hazard ratios (HRs) with 95% confidence intervals (CI) were estimated by Cox proportional hazard regressions. During follow-up, 2676 colon and 1681 rectal adenocarcinomas were diagnosed. No sex differences were observed in the associations between child BMI or height and adult colon or rectal cancers. Childhood BMI and height were positively associated with colon cancer; at age 13 years the HRs were 1.09 (95% CI 1.04-1.14) and 1.14 (95% CI 1.09-1.19) per z-score, respectively. Children who were persistently taller or heavier than average, had increased risk of colon cancer. Similarly, growing taller or gaining more weight than average was positively associated with colon cancer. No associations were observed between BMI or height and rectal cancer. Childhood BMI and height, along with above average change during childhood are significantly and positively associated with adult colon cancers, but not with rectal cancer, suggesting different etiologies.

Sex-specific associations between birth weight and adult primary liver cancer in a large cohort of Danish children.

Whether the prenatal period is critical for the development of adult primary liver cancer (PLC) is sparsely investigated. Recently, attention has been drawn to potential sex-differences in the early origins of adult disease. The association between birth weight and adult PLC, separately in men and women was investigated, using a large cohort of 217,227 children (51% boys), born from 1936 to 1980, from the Copenhagen School Health Records Register, and followed them until 2010 in national registers. Hazard ratios (95% confidence intervals) of PLC (30 years or older) were estimated by Cox regression models stratified by birth cohort. During 5.1 million person-years of follow-up, 185 men and 65 women developed PLC. Sex modified the association between birth weight and adult PLC (p values for interaction = 0.0005). Compared with a sex-specific reference group of birth weights between 3.25 and 3.75 kg, men with birth weights between 2.00 and 3.25 kg and 3.75-5.50 kg, had HRs of 1.48 (1.06-2.05) and 0.85 (0.56-1.28), respectively. Among women the corresponding HRs were 1.71 (0.90-3.29) and 3.43 (1.73-6.82). Associations were similar for hepatocellular carcinoma only, across year of birth, and after accounting for diagnoses of alcohol-related disorders, viral hepatitis and biliary cirrhosis. Prenatal exposures influenced the risk of adult PLC, and the effects at the high birth weight levels appeared to be sex-specific. These findings underscore the importance of considering sex-specific mechanisms in the early origins of adult PLC.

Childhood height, adult height, and the risk of prostate cancer.

PURPOSE: We previously showed that childhood height is positively associated with prostate cancer risk. It is, however, unknown whether childhood height exerts its effects independently of or through adult height. We investigated whether and to what extent childhood height has a direct effect on the risk of prostate cancer apart from adult height. METHODS: We included 5,871 men with height measured at ages 7 and 13 years in the Copenhagen School Health Records Register who also had adult (50-65 years) height measured in the Danish Diet, Cancer and Health study. Prostate cancer status was obtained through linkage to the Danish Cancer Registry. Direct and total effects of childhood height on prostate cancer risk were estimated from Cox regressions. RESULTS: From 1996 to 2012, 429 prostate cancers occurred. Child and adult heights were positively and significantly associated with prostate cancer risk. When adjusted for adult height, height at age 7 years was no longer significantly associated with the risk of prostate cancer. Height at 13 years was significantly and positively associated with prostate cancer risk even when adult height was adjusted for; per height z-score the hazard ratio was 1.15 [95% confidence interval (CI) 1.01-1.32]. CONCLUSIONS: The effect of height at 13 years on the risk of prostate cancer was not entirely mediated through adult height, suggesting that child height and adult height may be associated with prostate cancer through different pathways.

Comparison of sensory-specific satiety between normal weight and overweight children.

Sensory properties of some foods may be of importance to energy consumption and thus the development and maintenance of childhood obesity. This study compares selected food related qualities in overweight and normal weight children. Ninety-two participants were included; 55 were overweight with a mean age of 11.6 years (range 6-18 years) and a mean BMI z-score of 2.71 (range 1.29-4.60). The 37 normal weight children had a mean age of 13.0 years (range 6-19 years) and a mean BMI z-score of 0.16 (range -1.71 to 1.24). All children completed a half-hour long meal test consisting of alternation between consumption of foods and answering of questionnaires. Compared to the normal weight, the overweight children displayed lower self-reported intake paces (χ2(2) = 6.3, p = 0.04), higher changes in liking for mozzarella (F(1,63) = 9.55, p = 0.003) and pretzels (F(1,87) = 5.27, p = 0.024), and declines in wanting for something fat, of which the normal weight children displayed an increase (F(1,83) = 4,10, p = 0.046). No differences were found for sensory-specific satiety, wanting for the main food yoghurt, hunger, or satiety. In conclusion, overweight children did not differ from normal weight children in terms of sensory-specific satiety, hunger, or satiety. However, overweight children had lower intake paces and appeared to differ from normal weight children regarding foods with a fatty taste.

No evidence of seasonality of birth in adult type 2 diabetes in Denmark.

AIMS/HYPOTHESIS: The season of birth might influence prenatal circumstances, which may influence the risk of developing type 2 diabetes. The aim of this study was to determine whether the diagnosis of type 2 diabetes in Denmark changed with the season of birth. METHODS: This study used data from the population-based Copenhagen School Health Records Register (CSHRR) that includes schoolchildren born between 1930 and 1989. Via a personal identification number, the CSHRR was linked to the National Patient Register containing hospital discharge diagnoses since 1977. The effect of seasonal variation in birth on the risk of type 2 diabetes was assessed using Cox regression, with month or season of birth as the predictor. The underlying time variable was age, and follow-up started in 1977 or at age 30 years. RESULTS: The study population consisted of 223,099 people, of whom 12,486 developed adult type 2 diabetes. Using January as the reference month, the risk of type 2 diabetes by month of birth was not statistically different for any of the 11 comparative birth months. Grouping month of birth into seasons (spring was the reference) gave essentially similar results, showing no difference in the risk of type 2 diabetes for any season. Repeating the analysis by sex, birth cohort and birthweight categories revealed no associations. CONCLUSIONS/INTERPRETATION: The risk of adult type 2 diabetes was not associated with month of birth in a large Danish population-based study. The results suggest that the causes of seasonality in birthweight are not causes of type 2 diabetes.

Adoption of the children's obesity clinic's treatment (TCOCT) protocol into another Danish pediatric obesity treatment clinic.

BACKGROUND: Treating severe childhood obesity has proven difficult with inconsistent treatment results. This study reports the results of the implementation of a childhood obesity chronic care treatment protocol. METHODS: Patients aged 5 to 18 years with a body mass index (BMI) above the 99th percentile for sex and age were eligible for inclusion. At baseline patients' height, weight, and tanner stages were measured, as well as parents' socioeconomic status (SES) and family structure. Parental weight and height were self-reported. An individualised treatment plan including numerous advices was developed in collaboration with the patient and the family. Patients' height and weight were measured at subsequent visits. There were no exclusion criteria. RESULTS: Three-hundred-thirteen (141 boys) were seen in the clinic in the period of February 2010 to March 2013. At inclusion, the median age of patients was 11.1 years and the median BMI standard deviation score (SDS) was 3.24 in boys and 2.85 in girls. After 1 year of treatment, the mean BMI SDS difference was -0.30 (95% CI: -0.39; -0.21, p < 0.0001) in boys and -0.19 (95% CI: -0.25; -0.13, p < 0.0001) in girls. After 2 years of treatment, the mean BMI SDS difference was -0.40 (95% CI: -0.56; -0.25, p < 0.0001) in boys and -0.24 (95% CI: -0.33; -0.15, p < 0.0001) in girls. During intervention 120 patients stopped treatment. Retention rates were 0.76 (95% CI: 0.71; 0.81) after one year and 0.57 (95% CI: 0.51; 0.63) after two years of treatment. Risk of dropout was independent of baseline characteristics. Median time spent by health care professionals was 4.5 hours per year per patient and the mean visit interval time was 2.7 months. The reductions in BMI SDS were dependent on gender, parental BMI, and family structure in girls, but independent of baseline BMI SDS, age, co-morbidity, SES, pubertal stage, place of referral, hours of treatment per year, and mean visit interval time. CONCLUSIONS: The systematic use of the TCOCT protocol reduced the degree of childhood obesity with acceptable retention rates with a modest time-investment by health professionals.

A prospective study of height and body mass index in childhood, birth weight, and risk of adult glioma over 40 years of follow-up.

Greater attained height and greater body mass index (BMI; weight (kg)/height (m)(2)) in young adulthood have been associated with glioma risk, but few studies have investigated the association with body size at birth or during childhood, when the brain undergoes rapid cell growth and differentiation. The Copenhagen School Health Records Register includes data on 320,425 Danish schoolchildren born between 1930 and 1989, with height and weight measurements from ages 7-13 years and parentally recorded birth weights. We prospectively evaluated associations between childhood height and BMI, birth weight, and adult glioma risk. During follow-up (1968-2010), 355 men and 253 women aged ≥18 years were diagnosed with glioma. In boys, height at each age between 7 and 13 years was positively associated with glioma risk; hazard ratios per standard-deviation score at ages 7 (approximately 5.1 cm) and 13 (approximately 7.6 cm) years were 1.17 (95% confidence interval (CI): 1.05, 1.30) and 1.21 (95% CI: 1.09, 1.35), respectively. No associations were observed for childhood height in girls or for BMI. Birth weight was positively associated with risk (per 0.5 kg: hazard ratio = 1.13, 95% CI: 1.04, 1.24). These results suggest that exposures associated with higher birth weight and, in boys, greater height during childhood may contribute to the etiology of adult glioma.

Body mass index in childhood and adult risk of primary liver cancer.

BACKGROUND & AIMS: Childhood overweight increases the risk of early development of non-alcoholic fatty liver disease, which may predispose to carcinogenesis. We investigated if childhood body size during school ages was associated with the risk of primary liver cancer in adults. METHODS: A cohort of 285,884 boys and girls, born 1930 through 1980, who attended school in Copenhagen, were followed from 1977 to 31 December 2010. Their heights and weights were measured by school doctors or nurses at ages 7 through 13 years. Body mass index (BMI) z-scores were calculated from an internal age- and sex-specific reference. Information on liver cancer was obtained from the National Cancer Registry. Hazard ratios and 95% confidence intervals (95% CI) of liver cancer were estimated by Cox regression. RESULTS: During 6,963,105 person-years of follow-up, 438 cases of primary liver cancer were recorded. The hazard ratio (95% CI) of adult liver cancer was 1.20 (1.07-1.33) and 1.30 (1.16-1.46) per 1-unit BMI z-score at 7 years and 13 years of age, respectively. Similar associations were found in boys and girls, for hepatocellular carcinoma only, across years of birth, and after accounting for diagnoses of viral hepatitis, alcohol-related disorders, and biliary cirrhosis. CONCLUSIONS: Higher BMI in childhood increases the risk of primary liver cancer in adults. In view of the high case fatality of primary liver cancer, this result adds to the future negative health outcomes of the epidemic of childhood overweight, reinforcing the need for its prevention.

Does prenatal exposure to vitamin D-fortified margarine and milk alter birth weight? A societal experiment.

The present study examined whether exposure to vitamin D from fortified margarine and milk during prenatal life influenced mean birth weight and the risk of high or low birth weight. The study was based on the Danish vitamin D fortification programme, which was a societal intervention with mandatory fortification of margarine during 1961-1985 and voluntary fortification of low-fat milk between 1972 and 1976. The influence of prenatal vitamin D exposure on birth weight was investigated among 51 883 Danish children, by comparing birth weight among individuals born during 2 years before or after the initiation and termination of vitamin D fortification programmes. In total, four sets of analyses were performed. Information on birth weight was available in the Copenhagen School Health Record Register for all school children in Copenhagen. The mean birth weight was lower among the exposed than non-exposed children during all study periods (milk initiation - 20·3 (95 % CI - 39·2, - 1·4) g; milk termination - 25·9 (95 % CI - 46·0, - 5·7) g; margarine termination - 45·7 (95 % CI - 66·6, - 24·8) g), except during the period around the initiation of margarine fortification, where exposed children were heavier than non-exposed children (margarine initiation 27·4 (95 % CI 10·8, 44·0) g). No differences in the odds of high (>4000 g) or low ( < 2500 g) birth weight were observed between the children exposed and non-exposed to vitamin D fortification prenatally. Prenatal exposure to vitamin D from fortified margarine and milk altered birth weight, but the effect was small and inconsistent, reaching the conclusion that vitamin D fortification seems to be clinically irrelevant in relation to fetal growth.

Prenatal exposures to perfluorinated chemicals and anthropometry at 7 years of age.

Fetal exposure to the perfluoroalkyl acids, perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA), has been associated with lower birth weight and lower weight and body mass index (weight (kg)/height (m)(2)) in early infancy. It is, however, unclear if exposure to prenatal PFOS and PFOA has a lasting influence on growth. We estimated the associations between the maternal plasma level of PFOS or PFOA and the children's body mass index, waist circumference, and risk of overweight at 7 years of age. A total of 1,400 women were randomly selected from the Danish National Birth Cohort among those who provided blood samples early in pregnancy and gave birth to liveborn singletons in 1996-2002. Weight and height information at 7 years was available for 811 children. Multiple linear and logistic regression models were used for analyses. Maternal PFOS and PFOA concentrations were overall inversely but nonsignificantly associated with the children's body mass index, waist circumference, and risk of overweight at 7 years of age. In conclusion, plasma levels of PFOS and PFOA in pregnant women did not seem to have any appreciable influence on their children's anthropometry at this point in childhood.

Dynamic path analysis in life-course epidemiology.

Life-course epidemiology seeks to better understand the mechanisms that lead to the development of chronic diseases. An example is the mechanism leading from body size to coronary heart disease (CHD); one way to acquire a better understanding of this mechanism is to investigate to what extent it works through other risk factors. In this paper, the dynamic path analysis model is presented as a tool to analyze these dynamic mechanisms in life-course epidemiology. A key feature of dynamic path analysis is its ability to decompose the total effect of a risk factor into a direct effect (not mediated by other variables) and indirect effects (mediated through other variables). This is illustrated by examining the associations between repeated measurements of body mass index (BMI) and systolic blood pressure (SBP) and the risk of CHD in a sample of Danish men between 1976 and 2006. The effect of baseline BMI on the risk of CHD is decomposed into a direct effect and indirect effects going through later BMI, concurrent SBP, or later SBP. In conclusion, dynamic path analysis is a flexible tool that by the decomposition of effects can be used to increase the understanding of mechanisms that underlie the etiology of chronic disease.

Prenatal exposures to perfluorinated chemicals and anthropometric measures in infancy.

Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are persistent chemicals that may affect growth early in life. The authors estimated the associations between maternal plasma levels of PFOS and PFOA and infants' weight, length, and body mass index development during the first year of life. Fourteen hundred women were randomly selected from the Danish National Birth Cohort among those who provided blood samples early in pregnancy and gave birth to liveborn singletons between 1996 and 2002. Weight and length information at 5 and 12 months of age was available for 1,010 children. Multiple linear regression models were used for analyses, and maternal PFOS and PFOA concentrations (ng/mL) were inversely related to children's weight in the first year of life: adjusted regression coefficients: 0.8 g (95% confidence interval(CI): 4.2, 2.6) at 5 months and 5.8 g (95% CI:10.4, 1.2) at 12 months for perfluorooctanesulfonate(PFOS); 9.4 g (95% CI: 28.6, 9.9) at 5 months and 19.0 g (95% CI: 44.9, 6.8) at 12 months for perfluorooctanoate(PFOA) [corrected]. A similar pattern was observed for body mass index measurements, and no associations with length were found. After sex stratification, the inverse associations with weight and body mass index were more pronounced in boys, and no clear association was seen for girls.

Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies.

OBJECTIVES: Extra-intestinal manifestations of inflammatory bowel disease (IBD) are relatively common, whereas the risk of extra-intestinal cancer (EIC) remains uncertain. The aim of this study was to obtain a reliable estimate of the risk of EIC in Crohn's disease (CD) and ulcerative colitis (UC) by performing a meta-analysis of population-based cohort studies. METHODS: A systematic literature review was performed using MEDLINE (1966-2009) and abstracts from recent international conferences. Eight population-based cohort studies comprising a total of 17,052 patients with IBD were available. Standardized incidence ratios (SIRs) of EICs were pooled in a meta-analysis approach using STATA software. RESULTS: Overall, IBD patients were not at increased risk of EIC (SIR, 1.10; 95% confidence interval (CI) 0.96-1.27). However, site-specific analyses revealed that CD patients had an increased risk of cancer of the upper gastrointestinal tract (SIR 2.87, 95% CI 1.66-4.96), lung (SIR 1.82, 95% CI 1.18-2.81), urinary bladder (SIR 2.03, 95% CI 1.14-3.63), and skin (SIR 2.35, 95% CI 1.43-3.86). Patients with UC had a significantly increased risk of liver-biliary cancer (SIR 2.58, 95% CI 1.58-4.22) and leukemia (SIR 2.00, 95% CI 1.31-3.06) but a decreased risk of pulmonary cancer (SIR 0.39, 95% CI 0.20-0.74). CONCLUSIONS: Although the overall risk of EIC was not significantly increased among patients with IBD, the risk of individual cancer types differed from that of the background population as well as between CD and UC patients. These findings may primarily be explained by smoking habits, extra-intestinal manifestations of IBD, and involvement of the upper gastrointestinal tract in CD.

Life course path analysis of birth weight, childhood growth, and adult systolic blood pressure.

The inverse associations between birth weight and later adverse health outcomes and the positive associations between adult body size and poor health imply that increases in relative body size between birth and adulthood may be undesirable. In this paper, the authors describe life course path analysis, a method that can be used to jointly estimate associations between body sizes at different time points and associations of body sizes throughout life with health outcomes. Additionally, this method makes it possible to assess both the direct effect and the indirect effect mediated through later body size, and thereby the total effect, of size and changes in size on later outcomes. Using data on childhood body size and adult systolic blood pressure from a sample of 1,284 Danish men born between 1936 and 1970, the authors compared results from path analysis with results from 3 standard regression methods. Path analysis produced easily interpretable results, and compared with standard regression methods it produced a noteworthy gain in statistical power. The effect of change in relative body size on adult blood pressure was more pronounced after age 11 years than in earlier childhood. These results suggest that increases in body size prior to age 11 years are less harmful to adult blood pressure than increases occurring after this age.