Adolescent Hypertension Is Associated With Stroke in Young Adulthood: A Nationwide Cohort of 1.9 Million Adolescents.

BACKGROUND: Adult hypertension is a well-established risk factor for stroke in young adults (aged <55 years), and the effects are even more deleterious than at an older age. However, data are limited regarding the association between adolescent hypertension and the risk of stroke in young adulthood. METHODS: A nationwide, retrospective cohort study of adolescents (aged 16-19 years) who were medically evaluated before compulsory military service in Israel during 1985 to 2013. For each candidate for service, hypertension was designated after constructed screening, and the diagnosis was confirmed through a comprehensive workup process. The primary outcome was ischemic and hemorrhagic stroke incidence as registered at the national stroke registry. Cox proportional-hazards models were used. We conducted sensitivity analyses by excluding people with a diabetes diagnosis at adolescence or a new diabetes diagnosis during the follow-up period, analysis of adolescents with overweight, and adolescents with baseline unimpaired health status. RESULTS: The final sample included 1 900 384 adolescents (58% men; median age, 17.3 years). In total, 1474 (0.08%) incidences of stroke (1236 [84%] ischemic) were recorded, at a median age of 43 (interquartile range, 38-47) years. Of these, 18 (0.35%) occurred among the 5221 people with a history of adolescent hypertension. The latter population had a hazard ratio of 2.4 (95% CI, 1.5-3.9) for incident stroke after adjustment for body mass index and baseline sociodemographic factors. Further adjustment for diabetes status yielded a hazard ratio of 2.1 (1.3-3.5). We found similar results when the outcome was ischemic stroke with a hazard ratio of 2.0 (1.2-3.5). Sensitivity analyses for overall stroke, and ischemic stroke only, yielded consistent findings. CONCLUSIONS: Adolescent hypertension is associated with an increased risk of stroke, particularly ischemic stroke, in young adulthood.

Cardiovascular morbidity, diabetes and cancer risk among children and adolescents with severe obesity.

Severe obesity among children and adolescents is a significant global public health concern. The prevalence has markedly increased over the last decades, becoming common in many countries. Overwhelming rates of obesity among youth have prompted efforts to identify an evidence-based immediate- and long-term cardiometabolic risk factor profile in childhood-onset severe obesity, and to highlight gaps that require further investigation. The PubMed database was systematically searched in accordance with PRISMA guidelines. The search yielded 831 results, of which 60 fulfilled stringent criteria and were summarized in this review. The definition of severe obesity was variable, with only one half the publications using the definition BMI > 120% of the 95th percentile. Point estimates of the prevalence of at least one cardiometabolic risk factor in children with severe obesity reportedly range from 67 to 86%. Cross-sectional studies indicate that children and adolescents with severe obesity are at greater risk than those with mild obesity for type 2 diabetes, hypertension, fatty liver disease and dyslipidemia, already at childhood and adolescence. Robust epidemiological data on the long-term risk and actual point estimates in adulthood are lacking for these diseases as well as for other diseases (coronary heart disease, stroke, chronic kidney disease and cancer). Recent longitudinal studies indicate an increased risk for cardiomyopathy, heart failure, cardiovascular mortality and all-cause mortality in adulthood for adolescents with severe obesity compared to those with mild obesity. Given the alarming increase in the prevalence of severe obesity, the persistence of adiposity from childhood to adulthood and the precarious course of young adults with chronic comorbidities, the economic and clinical services burden on the healthcare system is expected to rise.

Cognitive function in adolescence and the risk of early-onset stroke.

BACKGROUND: Stroke is increasingly prevalent at younger ages but the risk factors are uncertain. We examined the association between adolescent cognitive function and early-onset stroke. METHODS: This was a nationwide population-based cohort study of 1 741 345 Israeli adolescents (42% women) who underwent comprehensive cognitive function tests at age 16-20 years, before mandatory military service, during 1987-2012. Cognitive function (range: 1-9) was categorised as low (1-3, corresponding to IQ score below 89), medium (4-7, IQ score range: 89-118), or high (8-9, IQ score above 118). Participant data were linked to the Israeli National Stroke Registry. Cox proportional hazard models were used to estimate risks for the first occurrence of ischaemic stroke during 2014-2018. RESULTS: During 8 689 329 person-years of follow-up, up to a maximum age of 50 years, 908 first stroke events occurred (767 ischaemic and 141 haemorrhagic). Compared with a reference group of people with high cognitive function, body mass index-adjusted and sociodemographic-adjusted HRs (95% CIs) for early-onset stroke were 1.78 (1.33-2.38) in medium and 2.68 (1.96-3.67) in low cognitive function groups. There was evidence of a dose-response relationship (P for trend <0.0001) such that one-unit of lower cognitive function z-score was associated with a 33% increased risk of stroke (1.33; 1.23-1.42). These associations were similar for ischaemic stroke but lower for haemorrhagic stroke; persisted in sensitivity analyses that accounted for diabetes status and hypertension; and were evident before age 40 years. CONCLUSIONS: Alongside adolescent obesity and hypertension, lower cognitive function may be a risk factor for early-onset stroke.

Adolescent body mass index and cognitive performance: a nationwide study of 2.48 million Israeli adolescents.

IMPORTANCE: The increased incidence of adolescent obesity over recent decades may be associated with lower cognitive performance than the expected potential. OBJECTIVE: We aimed to assess the association between adolescent body mass index (BMI) and cognitive function. DESIGN: A nationwide, cross-sectional, population-based study. SETTING: Pre-recruitment evaluation for military service during 1967-2018. PARTICIPANTS: All Israeli-born adolescents, 1 459 522 males and 1 027 953 females aged 16 to ≤20 years. EXPOSURES: Weight and height were measured to calculate BMI. MAIN OUTCOME: Cognitive performance was assessed by using a validated intelligence-quotient-equivalent test and was standardized to the year- and sex-Z-score. For 445 385 persons, parental cognitive scores could be identified. Multinomial logistic regression models were applied. RESULTS: Among male adolescents with severe obesity, 29.4% achieved a cognitive score below the 25th percentile, compared with 17.7% among their normal-weight (50th-84th percentile) counterparts. A J-shaped relation was observed between BMI and the odds ratio (OR) for a low cognitive score among male adolescents: underweight, 1.45 (1.43-1.48); overweight, 1.13 (1.12-1.15); mild obesity, 1.36 (1.33-1.39); and severe obesity, 1.58 (1.52-1.64). Similar findings were observed in females. For both sexes, point estimates were overall consistent in models adjusted for sociodemographic confounders, coexisting morbidities, and parental cognitive scores. Examinees with abnormal BMI had higher ORs for a lower-than-expected cognitive score, based on their parents' data as adolescents, in a manner that depends on obesity severity. CONCLUSION AND RELEVANCE: Obesity, is associated with increased odds for a lower cognitive performance, and the inability to fully achieve cognitive potential, regardless of sociodemographic background.

Glucose intolerance in pregnancy and risk of early-onset type 2 diabetes: a population-based cohort study.

BACKGROUND: The risk of type 2 diabetes among women with glucose intolerance during pregnancy that does not meet gestational diabetes criteria requires further investigation. We aimed to explore the associations between various degrees of gestational glucose intolerance and the risk of type 2 diabetes in young adulthood. METHODS: For this population-based cohort study, the national Israeli conscription database was linked to Maccabi Healthcare Services (MHS), the second-largest state-mandated health provider in Israel. We included 177 241 women who underwent a pre-recruitment evaluation at adolescence (age 16-20 years), 1 year before mandatory military service, and later underwent, from Jan 1, 2001, to Dec 31, 2019, two-step gestational diabetes screening with a 50 g glucose challenge test (GCT) based on a threshold of 140 mg/dL (7·8 mmol/L), followed as needed by a 100 g oral glucose tolerance test (OGTT). Abnormal OGTT values were defined according to the Carpenter-Coustan thresholds: 95 mg/dL (5·3 mmol/L) or higher in the fasting state; 180 mg/dL (10·0 mmol/L) or higher at 1 h; 155 mg/dL (8·6 mmol/L) or higher at 2 h; and 140 mg/dL (7·8 mmol/L) or higher at 3 h. The primary outcome was incident type 2 diabetes in the MHS diabetes registry. Cox proportional hazards models were applied to estimate adjusted hazard ratios (HRs) with 95% CIs for incident type 2 diabetes. FINDINGS: During a cumulative follow-up of 1 882 647 person-years, and with a median follow-up of 10·8 (IQR 5·2-16·4) years, 1262 women were diagnosed with type 2 diabetes. Crude incidence rates of type 2 diabetes were 2·6 (95% CI 2·4-2·9) per 10 000 person-years in women with gestational normoglycaemia, 8·9 (7·4-10·6) per 10 000 person-years in women with an abnormal GCT and normal OGTT, 26·1 (22·4-30·1) per 10 000 person-years in women with one abnormal OGTT value (in the fasting state or 1 h, 2 h, or 3 h post-challenge), and 71·9 (66·0-78·3) per 10 000 person-years in women with gestational diabetes. After adjustment for sociodemographic characteristics, adolescent BMI, and age at gestational screening, the risk of type 2 diabetes was higher, compared to the gestational normoglycaemia group, in women with an abnormal GCT and normal OGTT (adjusted hazard ratio [HR] 3·39 [95% CI 2·77-4·16]; p<0·0001), in women with one abnormal OGTT value (9·11 [7·64-10·86]; p<0·0001), and in women with gestational diabetes (24·84 [21·78-28·34]; p<0·0001). The risk of type 2 diabetes was modestly increased in women with isolated elevated fasting glucose (adjusted HR 11·81 [95% CI 8·58-16·25]; p<0·0001), and in women with gestational diabetes and an abnormal fasting glucose (38·02 [32·41-44·61]; p<0·0001). INTERPRETATION: Gestational glucose intolerance, including conditions not meeting gestational diabetes criteria of the two-step strategy, confers a high risk of type 2 diabetes in young adulthood. These conditions should be recognised as risk factors for type 2 diabetes, especially among women with abnormal fasting glucose concentrations during pregnancy. FUNDING: None.

The Global Spread of Severe Obesity in Toddlers, Children, and Adolescents: A Systematic Review and Meta-Analysis.

INTRODUCTION: Severe obesity among children and adolescents has emerged as a public health concern in multiple places around the world. METHODS: We searched the Medline database for articles on severe obesity rates in children published between January 1960 and January 2020. For studies with available prevalence rates for an early and a more recent time period, the relative increase in prevalence was imputed. RESULTS: In total, 874 publications were identified, of which 38 contained relevant epidemiological data. Rates of severe obesity varied significantly according to age, gender, geographic area, and the definition of severe obesity. The highest rates of class II and III obesity in the USA according to the Centers of Disease Control cut-off were 9.5% and 4.5%, respectively. Seventeen studies reported prevalence rates in at least two time periods. Data for 9,190,718 individuals showed a 1.71 (95% CI, 1.53-1.90) greater odds for severe obesity in 2006-2017 (N = 5,029,584) versus 1967-2007 (N = 4,161,134). In an analysis limited to studies from 1980s with a minimum follow-up of 20 years, a 9.16 (95% CI, 7.76-10.80) greater odds for severe obesity in recent versus earlier time was found. An analysis limited to studies from 2000, with a follow-up of 5-15 years, a 1.09 (95% CI, 0.99-1.20) greater odds was noted when comparing (2011-2017; N = 4,991,831) versus (2000-2011; N = 4,134,340). CONCLUSION: Severe pediatric obesity is escalating with a marked increase from the 1980s and a slower rate from 2000.

Glucose Intolerance in Pregnancy and Offspring Obesity in Late Adolescence.

OBJECTIVE: Gestational hyperglycemia is associated with deleterious neonatal outcomes, but long-term risks for offspring obesity are less clear. We estimated the odds for offspring adolescent overweight and obesity among mothers with gestational glucose intolerance. RESEARCH DESIGN AND METHODS: In a mother-offspring historical cohort, the Israel military conscription data set was linked to a large health maintenance organization. Included were women who were evaluated at adolescence and underwent two-step gestational diabetes screening (mean age, 31 years) with a 50-g glucose challenge test (GCT), followed by a 100-g oral glucose tolerance test (OGTT) if the result was abnormal. Glucose tolerance categories included gestational normoglycemia, abnormal GCT with normal OGTT, impaired glucose tolerance (IGT; one abnormal OGTT value), and gestational diabetes. The primary outcome was offspring overweight/obesity (BMI ≥85th percentile) at adolescence, measured prior to military conscription. Logistic regression models were applied. RESULTS: Of 33,482 mother-offspring pairs, overweight and obesity were observed in 6,516 offspring. Across increasing categories of pregnancy glycemia, the proportions of offspring with adolescent overweight/obesity increased: normoglycemia, 19%; abnormal GCT with normal OGTT, 22%; gestational IGT, 24%; and gestational diabetes, 25% (P < 0.0001). Corresponding odds ratios after adjustment for the mother's late adolescent characteristics (sociodemographic confounders and BMI) and pregnancy age were 1.2 (95% CI 1.1-1.4), 1.3 (1.2-1.5), and 1.4 (1.3-1.6), respectively. Further adjustment for offspring birth weight percentile and sociodemographic variables did not materially change results. Associations were more pronounced with increasing obesity severity. CONCLUSIONS: Gestational glucose intolerance, including categories not meeting the gestational diabetes threshold, was associated with increased odds for offspring overweight/obesity at late adolescence.

Adolescent cognitive function and incident early-onset type 2 diabetes.

BACKGROUND: Cognitive function among apparently healthy adolescents has been associated with cardiovascular morbidity and mortality. We examined the relationship between global and subdomain cognitive scores in adolescence and early-onset type 2 diabetes (T2D) in men and women. METHODS: A nationwide, population-based study of 971,677 Israeli born adolescents (56% men; mean age 17.4 years) who were medically examined and their cognitive performance was assessed before compulsory military service during 1992-2010. Data included global and subdomain cognitive Z-scores (problem-solving, verbal abstraction and categorization, verbal comprehension, and mathematical abilities). Data were linked to the Israeli National Diabetes Registry. The relations between global and subdomain scores and incident T2D was determined using Cox proportional hazard models and logistic regression models. Analyses were conducted separately for men and women. FINDINGS: During 16,095,122 person-years, 3,570 individuals developed T2D. After adjustment, those in the low compared to the high quintile of global cognitive Z-score had the highest risk for T2D; HR 2.46, (95% CI 2.10-2.88) for men and 2.33 (95% CI 1.88-2.89) for women. A one-unit lower global cognitive Z-score was associated with 1.41 (95% CI 1.34-1.48) and 1.46 (95% CI 1.36-1.56) increased risks for men and women, respectively. The relationship was noted for the cognitive subdomains scores as well as for the global cognitive score, with no heterogeneity across cognitive subdomains. INTERPRETATION: This large nationally representative cohort suggests relationship between global, as well as subdomain cognitive scores in late adolescence, and incident early onset T2D in both sexes, which was independent of socioeconomic status.

Adolescent Thyroid Disorders and Risk for Type 2 Diabetes in Young Adulthood.

CONTEXT: Thyroid hormones play a key role in systemic metabolism, yet the relationship between thyroid dysfunction and risk for type 2 diabetes is unclear. OBJECTIVE: To assess type 2 diabetes risk in adulthood among adolescents with thyroid disorders. DESIGN AND SETTING: A nationwide, population-based study of Israeli adolescents who were examined before military recruitment during 1988 to 2007 and were followed until December 31, 2016. PARTICIPANTS: 1 382 560 adolescents (mean age 17.3 years). INTERVENTIONS: The diagnosis of thyroid disorders was based on recent thyroid function tests. Data were linked to the Israeli National Diabetes Registry. Cox proportional hazard models were applied. MAIN OUTCOME MEASURES: Type 2 diabetes incidence. RESULTS: During a mean follow-up of 18.5 years, 1.12% (69 of 6,152) of adolescents with thyroid disorders were diagnosed with type 2 diabetes vs 0.77% of adolescents without thyroid disorders. The hazard ratio (HR) for type 2 diabetes was 2.3 (95% CI, 1.8-2.9) among those with thyroid disorders, after adjustment for sex, birth-year, body mass index, and sociodemographic confounders. The increased diabetes risk was observed in both men and women, with the presence or absence of obesity, and in the absence of other health conditions and was associated with different types of thyroid disorders. It was also similar when the outcome was defined as type 2 diabetes diagnosed at or before the age of 30 years (HR 2.3, 95% CI, 1.5-3.5). CONCLUSIONS: Thyroid disorders diagnosed in adolescence are a risk factor for early-onset type 2 diabetes in both men and women.

Adolescent Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Young Adulthood.

CONTEXT: The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. OBJECTIVE: To assess type 2 diabetes risk among adolescents with NAFLD. DESIGN AND SETTING: A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997-2011 and were followed until December 31, 2016. PARTICIPANTS: A total of 1 025 796 normoglycemic adolescents were included. INTERVENTIONS: Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. MAIN OUTCOME MEASURES: Type 2 diabetes incidence. RESULTS: During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47-4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). CONCLUSIONS: Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.

Adolescent Obesity and Early-Onset Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) is increasingly diagnosed at younger ages. We investigated the association of adolescent obesity with incident T2D at early adulthood. RESEARCH DESIGN AND METHODS: A nationwide, population-based study evaluated 1,462,362 adolescents (59% men, mean age 17.4 years) during 1996-2016. Data were linked to the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied. RESULTS: During 15,810,751 person-years, 2,177 people (69% men) developed T2D (mean age at diagnosis 27 years). There was an interaction among BMI, sex, and incident T2D (P interaction = 0.023). In a model adjusted for sociodemographic variables, the hazard ratios for diabetes diagnosis were 1.7 (95% CI 1.4-2.0), 2.8 (2.3-3.5), 5.8 (4.9-6.9), 13.4 (11.5-15.7), and 25.8 (21.0-31.6) among men in the 50th-74th percentile, 75th-84th percentile, overweight, mild obesity, and severe obesity groups, respectively, and 2.2 (1.6-2.9), 3.4 (2.5-4.6), 10.6 (8.3-13.6), 21.1 (16.0-27.8), and 44.7 (32.4-61.5), respectively, in women. An inverse graded relationship was observed between baseline BMI and mean age of T2D diagnosis: 27.8 and 25.9 years among men and women with severe obesity, respectively, and 29.5 and 28.5 years among low-normal BMI (5th-49th percentile; reference), respectively. The projected fractions of adult-onset T2D that were attributed to high BMI (≥85th percentile) at adolescence were 56.9% (53.8-59.9%) and 61.1% (56.8-65.2%) in men and women, respectively. CONCLUSIONS: Severe obesity significantly increases the risk for incidence of T2D in early adulthood in both sexes. The rise in adolescent severe obesity is likely to increase diabetes incidence in young adults in coming decades.

Childhood Pancreatitis and Risk for Incident Diabetes in Adulthood.

OBJECTIVE: The relationship between acute pancreatitis and incident diabetes is unclear. We assessed whether a resolved single event of acute pancreatitis in childhood was associated with incident diabetes in adulthood. RESEARCH DESIGN AND METHODS: A nationwide, population-based study of 1,802,110 Israeli adolescents (mean age 17.4 years [range 16-20]) who were examined before compulsory military service between 1979 and 2008 and whose data were linked to the Israeli National Diabetes Registry (INDR). Resolved pancreatitis was defined as a history of a single event of acute pancreatitis with normal pancreatic function at enrollment. Logistic regression analysis was applied. RESULTS: Incident diabetes developed in 4.6% of subjects with resolved pancreatitis (13 of 281; none of these cases were identified as type 1 diabetes) and 2.5% among the unexposed group (44,463 of 1,801,716). Resolved acute pancreatitis was associated with incident diabetes with an odds ratio (OR) of 2.23 (95% CI 1.25-3.98) with adjustment for age, sex, and birth year. Findings persisted after further adjustments for baseline BMI and sociodemographic confounders (OR 2.10 [95% CI 1.15-3.84]). Childhood pancreatitis was associated with a diagnosis of diabetes at a younger age, with 92% of diabetes case subjects diagnosed before 40 years of age compared with 47% in the unexposed group (P = 0.002). The association accentuated when the study sample was limited to individuals of unimpaired health or normal BMI at baseline. CONCLUSIONS: A history of acute pancreatitis in childhood with normal pancreatic function in late adolescence is a risk factor for incident type 2 diabetes, especially at young adulthood.