The PROactive cohort study: rationale, design, and study procedures.

Children with a chronic condition face more obstacles than their healthy peers, which may impact their physical, social-emotional, and cognitive development. The PROactive cohort study identifies children with a chronic disease at high risk of debilitating fatigue, decreased daily life participation and psychosocial problems, as well as children who are resilient and thrive despite the challenges of growing up with a chronic condition. Both groups will teach us how we can best support children, adolescents and parents to adapt to and manage a disease, as well as tailor interventions to their specific needs.This cohort follows a continuous longitudinal design. It is based at the Wilhelmina Children's Hospital (WKZ) in the Netherlands and has been running since December 2016. Children with a chronic condition (e.g. cystic fibrosis, juvenile idiopathic arthritis, chronic kidney disease, or congenital heart disease) as well children with medically unexplained fatigue or pain in a broad age range (2-18 years) are included, as well as their parent(s). Data are collected from parents (of children between 2 and 18 years) and children (8-18 years), as well as data from their electronic health record (EHR). Primary outcome measures are fatigue, daily life participation, and psychosocial well-being, all assessed via patient- and proxy-reported outcome measures. Generic biological/lifestyle, psychological, and social factors were assessed using clinical assessment tools and questionnaires. In the PROactive cohort study the research assessment is an integrated part of clinical care. Children are included when they visit the outpatient clinic and are followed up annually.

Psychosocial functioning in adolescents growing up with chronic disease: The Dutch HBSC study.

Many adolescents worldwide (indirectly) grow up with a chronic disease, which may impact their functioning and wellbeing. The objective of this study is to assess whether adolescents with a (family member with a) chronic disease differ from their healthy counterparts in terms of psychosocial functioning. Data from the Dutch 2013 HBSC-survey were used, including 7168 adolescents (Meanage = 13.7, SD = 1.57, 50.5% female). Participants indicated whether they or one of their family members had a long-term (> 3 months) disease or disability (mental/physical) and were categorized into four groups based on disease presence (none, other, self, both). Psychosocial functioning was assessed in terms of life satisfaction, self-rated health, psychosomatic health, mental health problems, support, substance use, physical exercise, screen time, and school liking. Chronically diseased adolescents (n = 162) reported lower life satisfaction, self-rated and psychosomatic health, more mental health problems, lower peer support, more substance use, and less physical exercise compared to healthy peers. Chronically diseased adolescents who also had a family member with a chronic disease (n = 74) showed comparable outcomes on these life domains, although they did not differ from their healthy peers regarding peer support, substance use, and physical activity. Healthy adolescents with a chronically diseased family member (n = 737) reported significantly lower life satisfaction, self-rated and psychosomatic health, more mental health problems, and less family support compared to healthy peers who grew up in healthy families; however, they reported more positive outcomes than adolescents who had a chronic disease themselves.Conclusion: Having a (family member with a) chronic disease is associated with impaired psychosocial functioning on various life domains. Our findings aid in understanding the psychosocial associates of chronic disease and imply that caregivers should be observant of psychosocial problems among vulnerable adolescents to provide appropriate guidance. What is Known: • Adolescents who grow up with a (family member with a) chronic disease encounter numerous challenges that may be related to poorer developmental outcomes on the long term. What is New: • This study adds a comprehensive overview of the psychosocial functioning of adolescents with a (family member with a) chronic disease, as compared to healthy counterparts that grow up in a healthy family.

Long-chain polyunsaturated fatty acids in infant formula and cardiovascular markers in childhood.

To investigate whether children who consumed infant formula supplemented with long-chain polyunsaturated fatty acids (LCPUFAs) had a more favourable cardiovascular profile than children who consumed formula without these fatty acids, we used the Wheezing Illnesses Study Leidsche Rijn, a birth cohort that included 2,468 newborns between 2001 and 2014. Data on infant feeding were obtained by questionnaires. At age 5, blood pressure, carotid intima-media thickness (CIMT), and carotid distension were measured. We used multivariable linear regression analysis to compare levels of cardiovascular markers in formula-fed children born before and after the LCPUFA supplementation. To account for secular trends, we compared levels of cardiovascular markers in a control group of breastfed children from the same cohort born before and after the supplementation. Formula-fed children born after the LCPUFA supplementation (n = 48) had no different systolic blood pressure (-2.58 mmHg, 95% confidence interval, CI [-5.5, 0.30]), diastolic blood pressure (-0.13 mmHg, 95% CI [-2.3, 2.1]), or carotid distension (24.8 MPa-1 , 95% CI [-47.1, 96.6]) and had a higher CIMT (18.6 µm, 95% CI [3.7, 33.5]) than formula-fed children born before the supplementation (n = 163). In the control group, children born after the LCPUFA supplementation (n = 98) had no different systolic- or diastolic-blood pressure, or CIMT, and a higher carotid distension than children born before the supplementation (n = 142). In conclusion, children who consumed infant formula supplemented with LCPUFAs did not have a more favourable cardiovascular profile in early childhood than children who consumed formula without LCPUFAs.

Fatty acid composition in breastfeeding and school performance in children aged 12 years.

PURPOSE: Breastfeeding has been associated with improved cognition. It remains unclear whether long-chain polyunsaturated fatty acids (LC-PUFAs) play a role in this association. We assessed the association between LC-PUFA concentrations in infant feeding and school performance at age 12. METHODS: Within a population-based birth cohort, we compared school performance of 277 non-breastfed children and 157 children who had fatty acid composition of their mothers' breast milk measured. Two indicators of school performance were: (1) the score on a standardized achievement test and (2) the teacher's advice regarding a child's potential performance level in secondary education. Linear regression and multinomial logistic regression analyses were performed to assess the independent association between LC-PUFA content of breast milk and school performance. RESULTS: Girls, who received breast milk with a relative high content (above the median) of docosahexaenoic acid (DHA), had a higher Cito-test score (ß = 2.96 points, 95 % CI 0.24; 5.69) than non-breastfed girls. Among the breastfed girls, each percentage point of higher content of total n-3 LC-PUFA (ß = 4.55, 95 % CI 0.43; 8.66) and DHA (ß = 7.09, 95 % CI 0.9; 13.3) was associated with a higher Cito-test score. The association between LC-PUFA content and teacher school advice showed a similar pattern. There was no association between LC-PUFA content and school performance in boys. CONCLUSION: Although a large part of the association between infant milk feeding and cognition seems to be explained by sociodemographic and lifestyle-related factors, a relative high content of n-3 PUFAs, especially DHA, in breast milk is associated with better school performance in 12-year-old girls but not in boys.

Phylloquinone concentrations and the risk of vascular calcification in healthy women.

OBJECTIVE: To investigate the association of plasma phylloquinone concentrations with coronary artery calcification (CAC) and vascular calcification. APPROACH AND RESULTS: In a prospective cohort of 508 postmenopausal women, plasma phylloquinone concentrations were measured by high-pressure liquid chromatography. Calcification was measured in the coronary arteries, aortic valve, mitral valve, and thoracic aorta by multidetector computed tomography. To combine these calcification scores, we dichotomized each of the 4 areas into present or absent. Because of the continuous measurement of CAC, we categorized this as calcification present if Agatston score was >0, and calcification score was calculated as the sum of the calcified areas. Multivariate-adjusted prevalence ratios and odds ratios were estimated using Poisson regression and multinomial logistic regression. After 8.5 years of follow-up, 22% of the women had no calcification, whereas 5% had calcification in all measured areas. Detectable phylloquinone concentrations were associated with increased CAC compared with nondetectable phylloquinone concentrations with a prevalence ratio of 1.34 (95% confidence interval, 1.01-1.77). When dividing women with detectable phylloquinone concentrations into low detectable (>0-0.70 nmol/L) and moderate to high detectable (>0.70 nmol/L) phylloquinone concentrations versus nondetectable phylloquinone concentrations, both were associated with increased CAC with a prevalence ratio of 1.32 (95% confidence interval, 0.99-1.76) and 1.36 (95% confidence interval, 1.02-1.81), respectively. Detectable phylloquinone concentrations were not associated with the number of calcified areas with an odds ratio(no versus ≥ 3 areas calcifications) of 1.60 (95% confidence interval, 0.65-3.99; P=0.31). CONCLUSIONS: Detectable phylloquinone concentrations are not associated with reduced vascular calcification but seemed to be associated with an increased prevalence of CAC.

The relationship between fermented food intake and mortality risk in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort.

The objective of the present study was to investigate the relationship between total and subtypes of bacterial fermented food intake (dairy products, cheese, vegetables and meat) and mortality due to all causes, total cancer and CVD. From the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort, 34 409 Dutch men and women, aged 20-70 years who were free from CVD or cancer at baseline, were included. Baseline intakes of total and subtypes of fermented foods were measured with a validated FFQ. Data on the incidence and causes of death were obtained from the national mortality register. Cox proportional hazards models were used to analyse mortality in relation to the quartiles of fermented food intake. After a mean follow-up of 15 (sd 2·5) years, 2436 deaths occurred (1216 from cancer and 727 from CVD). After adjustment for age, sex, total energy intake, physical activity, education level, hypertension, smoking habit, BMI, and intakes of fruit, vegetables and alcohol, total fermented food intake was not found to be associated with mortality due to all causes (hazard ratio upper v. lowest quartile (HR(Q4 v. Q1)) 1·00, 95% CI 0·88, 1·13), cancer (HR(Q4 v. Q1) 1·02, 95% CI 0·86, 1·21) or CVD (HR(Q4 v. Q1) 1·04, 95 % CI 0·83, 1·30). Bacterial fermented foods mainly consisted of fermented dairy foods (78 %) and cheese (16%). None of the subtypes of fermented foods was consistently related to mortality, except for cheese which was moderately inversely associated with CVD mortality, and particularly stroke mortality (HR(Q4 v. Q1) 0·59, 95% CI 0·38, 0·92, P trend= 0·046). In conclusion, the present study provides no strong evidence that intake of fermented foods, particularly fermented dairy foods, is associated with mortality.

Childhood infection burden, recent antibiotic exposure and vascular phenotypes in preschool children.

BACKGROUND: Severe childhood infection has a dose-dependent association with adult cardiovascular events and with adverse cardiometabolic phenotypes. The relationship between cardiovascular outcomes and less severe childhood infections is unclear. AIM: To investigate the relationship between common, non-hospitalised infections, antibiotic exposure, and preclinical vascular phenotypes in young children. DESIGN: A Dutch prospective population-derived birth cohort study. METHODS: Participants were from the Wheezing-Illnesses-Study-Leidsche-Rijn (WHISTLER) birth cohort. We collected data from birth to 5 years on antibiotic prescriptions, general practitioner (GP)-diagnosed infections, and monthly parent-reported febrile illnesses (0-1 years). At 5 years, carotid intima-media thickness (CIMT), carotid artery distensibility, and blood pressure (BP) were measured. General linear regression models were adjusted for age, sex, smoke exposure, birth weight z-score, body mass index, and socioeconomic status. RESULTS: Recent antibiotic exposure was associated with adverse cardiovascular phenotypes; each antibiotic prescription in the 3 and 6 months prior to vascular assessment was associated with an 18.1 µm (95% confidence interval, 4.5-31.6, p = 0.01) and 10.7 µm (0.8-20.5, p = 0.03) increase in CIMT, respectively. Each additional antibiotic prescription in the preceding 6 months was associated with an 8.3 mPa-1 decrease in carotid distensibility (-15.6- -1.1, p = 0.02). Any parent-reported febrile episode (compared to none) showed weak evidence of association with diastolic BP (1.6 mmHg increase, 0.04-3.1, p = 0.04). GP-diagnosed infections were not associated with vascular phenotypes. CONCLUSIONS: Recent antibiotics are associated with adverse vascular phenotypes in early childhood. Mechanistic studies may differentiate antibiotic-related from infection-related effects and inform preventative strategies.

The Impact of the COVID-19 Outbreak on Mental Wellbeing in Children with a Chronic Condition Compared to Healthy Peers.

The aim of this study was to assess the impact of the COVID-19 pandemic on the mental wellbeing of children 8-18 years old with chronic conditions, by comparing pandemic data with pre-pandemic data and with healthy peers. Data were obtained from two ongoing longitudinal cohorts: the PROactive cohort study following children with a chronic condition, and the WHISTLER population cohort. Mental wellbeing was assessed by three indicators: life satisfaction, internalising symptoms, and psychosomatic health. The stringency of the COVID-19-related lockdown was considered a moderating factor. Data on chronic patients were recorded before (n = 934, 65% girls) and during (n = 503, 61% girls) the pandemic, and compared to healthy peers during the pandemic (n = 166, 61% girls). Children with a chronic condition reported lower life satisfaction, but no clinically relevant changes in internalising symptoms or psychosomatic health, during the pandemic compared to before. In comparison to healthy peers, children with a chronic condition experienced decreased life satisfaction and psychosomatic health, but internalising symptoms did not differ between groups during the COVID-19 pandemic. The lockdown stringency was negatively associated with all indicators of mental wellbeing-worse life satisfaction, more internalising symptoms, and more psychosomatic symptoms.

Role of parents in fatigue of children with a chronic disease: a cross-sectional study.

Objective: As parents majorly impact their child's well-being, and as fatigue is a highly prevalent threat to the well-being of children with a chronic disease, we aimed to explore the association between parental factors and fatigue in children with a chronic disease. Design: Cross-sectional study. Setting: Two Dutch children's hospitals. Population: Children 2-18 years of age with either an autoimmune disease, cystic fibrosis or post-cancer treatment, and one of their parents. Main outcome measures: Paediatric fatigue was measured using the PedsQL Multidimensional Fatigue Scale. Parental factors included parental pain, fatigue and physical symptoms, parental distress, catastrophising thoughts about their child's pain and family empowerment. Multiple linear regressions were used to study associations with paediatric fatigue. A multivariable regression model was used to assess the effect of the different parental factors on paediatric fatigue. All analyses were adjusted for the age and sex of the child. Results: 204 families participated (mean age 11.0±4.3 and 43.5±6.3 years for children and parents, respectively; 69% participation rate). More parental pain, fatigue and physical symptoms, and more parental distress and pain catastrophising were associated with more paediatric fatigue. More parental empowerment was associated with less paediatric fatigue on both subscales. In the multivariable model, only paediatric age remained significantly associated with fatigue. In a separate multivariable model for children 8-18 years old, more parental distress (ß=-1.9, 95% CI -3.7 to -0.1) was also significantly associated with more paediatric fatigue. Conclusions: In a population of children with a chronic disease, parental factors, both physical and psychosocial, were associated with paediatric fatigue. Our study provides evidence that more family empowerment is associated with less paediatric fatigue. This exploratory study adds to our knowledge of associated factors with fatigue in paediatric chronic disease, providing starting points for targeted interventions.

Fatigue among children with a chronic disease: a cross-sectional study.

Objective: To determine: (1) which biological/lifestyle, psychological and/or social factors are associated with fatigue among children with a chronic disease and (2) how much each of these factors contributes to explaining variance in fatigue. Design and setting: This was a cross-sectional study across two children's hospitals. Patients: We included children aged 8-18 years who visited the outpatient clinic with cystic fibrosis, an autoimmune disease or postcancer treatment. Main outcome measures: Fatigue was assessed using the PedsQL Multidimensional Fatigue Scale. Generic biological/lifestyle, psychological and social factors were assessed using clinical assessment tools and questionnaires. Multiple linear regression analyses were used to test the associations between these factors and fatigue. Finally, a multivariable regression model was used to determine which factor(s) have the strongest effect on fatigue. Results: A total of 434 out of 902 children were included (48% participation rate), with a median age of 14.5 years; 42% were male. Among these 434 children, 21.8% were severely fatigued. Together, all biopsychosocial factors explained 74.6% of the variance in fatigue. More fatigue was uniquely associated with poorer physical functioning, more depressive symptoms, more pressure at school, poorer social functioning and older age. Conclusions: Fatigue among children with a chronic disease is multidimensional. Multiple generic biological/lifestyle, psychological and social factors were strongly associated with fatigue, explaining 58.4%; 65.8% and 50.0% of the variance in fatigue, respectively. Altogether, almost three-quarters of the variance in fatigue was explained by this biopsychosocial model. Thus, when assessing and treating fatigue, a transdiagnostic approach is preferred, taking into account biological, psychological and social factors.

Parent-Child Dyadic Coping and Quality of Life in Chronically Diseased Children.

Different forms of dyadic coping are associated with positive outcomes in partner relationships, yet little is known about dyadic coping in parent-child relationships. The current research explored the association between parent-child dyadic coping and children's quality of life in 12-18-year old children with a chronic disease (i.e., cystic fibrosis, autoimmune diseases, and children post-cancer treatment). In a sample of 105 parent-child dyads, self-reported forms of dyadic coping (i.e., stress communication, problem-oriented, emotion-oriented, and negative dyadic coping) and children's quality of life were assessed. Children reported more stress communication and negative dyadic coping than their parents, while parents reported more problem-oriented dyadic coping and emotion-oriented dyadic coping than their children. More stress communication of the child was associated with more emotion-oriented dyadic coping and less negative dyadic coping of the parent. More negative dyadic coping of the child was associated with less stress communication, problem-oriented dyadic coping and emotion-oriented dyadic coping of the parent. Additionally, both children's and parents' negative dyadic coping were associated with lower self-reported pediatric quality of life and parents' emotion-oriented dyadic coping was associated with higher pediatric quality of life. These findings emphasize that children and their parents mutually influence each other and that dyadic coping is associated with children's quality of life. Theoretical and practical implications are discussed.

Internet and smartphone-based ecological momentary assessment and personalized advice (PROfeel) in adolescents with chronic conditions: A feasibility study.

OBJECTIVE: Growing up with a chronic disease comes with challenges, such as coping with fatigue. Many adolescents are severely fatigued, though its associated factors exhibit considerable interpersonal and longitudinal variation. We assessed whether PROfeel, a combination of a smartphone-based ecological momentary assessment (EMA) method using the internet, followed by a face-to-face dialogue and personalized advice for improvement of symptoms or tailor treatment based on a dynamic network analysis report, was feasible and useful. STUDY DESIGN: Feasibility study in fatigued outpatient adolescents 12-18 years of age with cystic fibrosis, autoimmune disease, post-cancer treatment, or with medically unexplained fatigue. Participants were assessed at baseline to personalize EMA questions. EMA was conducted via smartphone notifications five times per day for approximately six weeks. Hereby, data was collected via the internet. The EMA results were translated into a personalized report, discussed with the participant, and subsequently translated into a personalized advice. Afterwards, semi-structured interviews on feasibility and usefulness were held. RESULTS: Fifty-seven adolescents were assessed (mean age 16.2 y ± 1.6, 16% male). Adolescents deemed the smartphone-based EMA feasible, with the app being used for an average of 49 days. Forty-two percent of the notifications were answered and 85% of the participants would recommend the app to other adolescents. The personalized report was deemed useful and comprehensible and 95% recognized themselves in the personalized report, with 64% rating improved insight in their symptoms and subsequent steps towards an approach to reduce one's fatigue as good or very good. CONCLUSIONS: PROfeel was found to be highly feasible and useful for fatigued adolescents with a chronic condition. This innovative method has clinical relevance through bringing a patient's daily life into the clinical conversation.

Antenatal exposure to second hand smoke of non-smoking mothers and growth rate of their infants.

OBJECTIVES: There is limited evidence on the effect of exposure to second hand smoke (SHS) in non-smoking pregnant mothers and infant health. We assessed the effects of maternal antenatal exposure to SHS on infant growth rate, and secondarily, on birth weight, birth length and head circumference at birth. METHODS: In this prospective cohort, 305 mother-infant pairs were studied. Mothers filled out questionnaires about exposure to SHS in pregnancy at the 3rd trimester of pregnancy. Infant anthropometry was performed at birth, day 7, and months 1, 2, 4, and 6, postnatally. Linear mixed modeling and linear regression were used to calculate growth rates over the first 6 months. The association between SHS-exposure with growth rate and birth sizes was assessed using multivariate linear regression adjusted for confounders, with SHS as both number of cigarettes and as groups (no exposure, SHS < 23 cigarettes, SHS ≥ 23 cigarettes). RESULTS: Seventy-three mothers were not exposed and 232 were exposed. SHS exposure (per cigarette) was not related to gain in weight, length, head circumference, and weight for length. However, infants born to mothers exposed to ≥ 23 cigarettes/d had lower head circumference gain (-0.32 mm/m, 95% CI -0.60, -0.03) than those born to non-exposed mothers. SHS exposure (per cigarette) was not related to birth weight, length, and head circumference, but exposure to ≥ 23 cigarettes was related to lower head circumference at birth (-11.09 mm, -20.03, -2.16). CONCLUSIONS: Heavy antenatal exposure to SHS in non-smoking mothers results in reduced neonatal head circumference at birth and head circumference gain over the first 6 months of life. Our findings show no clear relations between exposure to SHS during pregnancy and other markers of neonatal growth and birth size.

Pre-pregnancy parental BMI and offspring blood pressure in infancy.

AIMS: A growing body of evidence suggests that a higher maternal pre-pregnancy body mass index results in higher offspring's blood pressure, but there is inconsistency about the impact of father's body mass index. Furthermore, evidence is limited with regard to low and middle income countries. We aimed to determine the association between parental pre-pregnancy body mass index and offspring's blood pressure during the first year of life. METHODS: In 587 infants of the BReastfeeding Attitude and Volume Optimization (BRAVO) trial systolic and diastolic blood pressure were measured twice at the right leg in a supine position, using an automatic oscillometric device at day 7, month 1, 2, 4, 6, 9 and 12. Parental pre-pregnancy body mass index was based on self-reported weight and height. Linear mixed models were performed to investigate the associations between parental pre-pregnancy body mass index and offspring blood pressure patterns. RESULTS: Each unit increase in maternal body mass index was associated with 0.24 mmHg (95% confidence interval 0.05; 0.44) and 0.13 mmHg (0.01; 0.25) higher offspring's mean systolic and diastolic blood pressure, respectively, during the first year of life. A higher offspring blood pressure with increased maternal pre-pregnancy body mass index was seen at birth and remained higher during the first year of life. The association with systolic blood pressure remained similar after including birth size and offspring's weight and height over time. The association with diastolic blood pressure attenuated slightly to a non-significant result after including these variables. Paternal body mass index was not associated with offspring's blood pressure. CONCLUSION: Higher maternal pre-pregnancy body mass index, but not paternal pre-pregnancy body mass index, is associated with higher offspring blood pressure already from birth onwards.

Hypertensive disorders of pregnancy and cardiometabolic outcomes in childhood: A systematic review.

BACKGROUND: Hypertensive disorders of pregnancy (HDPs) are among the leading causes of maternal and perinatal morbidity and mortality worldwide and have been suggested to increase long-term cardiovascular disease risk in the offspring. OBJECTIVE: The objective of this study was to investigate whether HDPs are associated with cardiometabolic markers in childhood. SEARCH STRATEGY: PubMed, The Cochrane Library and reference lists of included studies up to January 2019. SELECTION CRITERIA: Studies comparing cardiometabolic markers in 2-18-year-old children of mothers with HDP in utero, to children of mothers without HDP. DATA COLLECTION AND ANALYSIS: Sixteen studies reported in 25 publications were included in this systematic review, of which three were considered as having high risk of bias. Thus 13 studies were included in the evidence synthesis: respectively two and eight reported pregnancy induced hypertension and preeclampsia, and three studies reported on both HDPs. MAIN RESULTS: Most studies (n = 4/5) found a higher blood pressure in children exposed to pregnancy induced hypertension. Most studies (n = 7/10) found no statistically significantly higher blood pressure in children exposed to preeclampsia. No association was found between exposure to HDP and levels of cholesterol, triglycerides or glucose (n = 5/5). No studies investigated an association with (carotid) intima-media thickness, glycated haemoglobin or diabetes mellitus type 2. CONCLUSIONS: Most studies showed that exposure to pregnancy induced hypertension is associated with a higher offspring blood pressure. There is no convincing evidence for an association between exposure to preeclampsia and blood pressure in childhood. Based on current evidence, exposure to HDP is not associated with blood levels of cholesterol, triglycerides and glucose in childhood.

Fatigue in childhood chronic disease.

BACKGROUND AND OBJECTIVES: Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL). DESIGN AND SETTING: Cross-sectional study in two children's hospitals. PATIENTS: Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic. OUTCOME MEASURES: Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method. RESULTS: 481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains. CONCLUSIONS: Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.

Cardiovascular and Metabolic Health of 74 Children From Women Previously Diagnosed With Polycystic Ovary Syndrome in Comparison With a Population-Based Reference Cohort.

Women with polycystic ovary syndrome (PCOS) have compromised cardiovascular health profiles and an increased risk of pregnancy complications. In order to evaluate potential consequences, we aim to compare the cardiovascular and metabolic health of the children from women with PCOS with a population-based reference cohort. We included children from women with PCOS between the age of 2.5 to 4 years (n = 42) and 6 to 8 years (n = 32). The reference groups consisted of 168 (3-4 years old) and 130 children (7-8 years old). In an extensive cardiovascular screening program, we measured anthropometrics and blood pressure (all children), heart function and vascular rigidity (young children), metabolic laboratory assessment and carotid intima thickness (old age-group). Results showed that young PCOS offspring have a significantly lower diastolic blood pressure (ß = 2.3 [95% confidence interval, CI: 0.5-4.0]) and higher aortic pulse pressure (ß = -1.4 [95% CI: -2.5 to -0.2]), compared to the reference population. Furthermore, a higher left ventricle internal diameter but a lower tissue Doppler imaging of the right wall in systole compared to the reference group was found. Older offspring of women with PCOS presented with a significantly lower breast and abdominal circumference, but higher triglycerides (ß = -0.1 [95% CI: -0.2 to -0.1]), LDL-cholesterol (ß = -0.4 [95% CI: -0.6 to -0.1]), and higher carotid intima-media thickness (ß = -31.7 [95% CI: -46.6 to -16.9]) compared to the reference group. In conclusion, we observe subtle but distinct cardiovascular and metabolic abnormalities already at an early age in PCOS offspring compared to a population-based reference group, despite a lower diastolic blood pressure, breast, and abdominal circumference. These preliminary findings require confirmation in independent data sets.

Antenatal coffee and tea consumption and the effect on birth outcome and hypertensive pregnancy disorders.

BACKGROUND AND OBJECTIVE: Coffee and tea are commonly consumed during pregnancy. While several of their components, like caffeine, have strong pharmacological effects, the effect on the unborn fetus remains unclear. Caffeine intake has been associated with abortion, preterm birth and fetal growth restriction, but a general consensus on caffeine restriction is still lacking. We aimed to investigate antenatal coffee, tea and caffeine consumption and the effect on birth weight and length, gestational age at birth and hypertensive disorders in pregnancy. METHODS: A total of 936 healthy pregnancies from the WHISTLER birth cohort with data on coffee and tea consumption were included. Maternal and child characteristics as well as antenatal coffee and tea consumption were obtained through postpartum questionnaires. Reported consumption was validated using available preconceptional data. Caffeine intake was calculated from coffee and tea consumption. Linear and logistic regression was used to assess the association with birth outcome and hypertensive disorders. RESULTS: After adjustment for smoking and maternal age, a daily consumption of more than 300mg of caffeine compared to less than 100mg of caffeine was significantly associated with an increased gestational age (linear regression coefficient = 2.00 days, 95%CI = 0.12-4.21, P = 0.03). Tea consumption was significantly related to a higher risk of pregnancy induced hypertension (OR = 1.13, 95%CI = 1.04-1.23, P = 0.004). No associations concerning coffee consumption or birth weight and birth length were observed. CONCLUSIONS: Daily caffeine consumption of more than 300mg is possibly associated with an increase in gestational age at birth. A possible relation between high tea consumption and increased risk for pregnancy induced hypertension warrants further research. For most outcomes, we found no significant associations with coffee or tea intake.

Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction.

BACKGROUND: Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. METHODS AND RESULTS: Participants were patients with ST-segment-elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (ß=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10-4) and ISZ (ß=-0.41 [95% CI, -0.60 to -0.21]; P=3.2×10-5). In addition, 24 hours post-MI measurements of medium HDL-TG (ß=-0.40 [95% CI, -0.60 to -0.20]; P=6.4×2×10-5), small HDL-TG (ß=-0.34 [95% CI, -0.53 to -0.14]; P=7.3×10-4), and the triglyceride content of very large HDL (ß=-0.38 [95% CI, -0.58 to -0.18]; P=2.7×10-4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P=7.5×10-5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4×10-4). CONCLUSIONS: HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01217307. Unique Identifier: NCT01217307.

Adult derived genetic blood pressure scores and blood pressure measured in different body postures in young children.

Aims Several genes are related to blood pressure (BP) levels in adults, but it is largely unknown whether these genes also determine BP early in life. Methods Systolic BP (SBP) and diastolic BP (DBP) were measured in 720 5-year-old children from the WHeezing-Illnesses-STudy-LEidsche-Rijn (WHISTLER) birth cohort in sitting and supine positions using a semi-automatic oscillometric device. Illumina chip technology was used to genotype 18, 19, 11 and 12 single nucleotide polymorphisms associated with adult SBP, DBP, mean arterial pressure (MAP) and hypertension, respectively, in the children's DNA and separate weighted genetic risk scores (GRSs) were constructed. The associations are reported as linear regression coefficients (mmHg BP in childhood/GRS score point) or odds ratios (highest childhood BP quintile/hypertension GRS score point). Results A higher GRS for SBP was related to higher supine SBP (0.37, 95% CI 0.01 to 0.7), but not to supine DBP (-0.05, 95% CI -0.4 to 0.3) or supine MAP (0.19, 95% CI -0.1 to 0.5). A higher GRS for DBP was related to a higher supine SBP (0.66, 95% CI 0.1 to 1.2), but not to supine DBP (-0.07, 95% CI -0.6 to 0.4) or supine MAP (0.28, 95% CI -0.2 to 0.7). With the sitting BP measurements, the GRSs for SBP and DBP were related to neither SBP nor DBP. No association was found between GRS for MAP and SBP, DBP or MAP. Hypertension GRS was not associated with a higher BP in children. Conclusions Higher scores for adult derived diastolic and systolic BP genes appear to be related to higher supine systolic BP at age 5 years.