Annemieke M. V. Evelein

Rapid early weight gain is associated with wheeze and reduced lung function in childhood

The aim of our study was to investigate the association between rapid weight gain in the first 3 months of life and the prevalence of wheeze in the first years of life and lung function at 5 yrs of age. The infants selected were participating in an ongoing birth cohort. Information on growth and respiratory symptoms was collected during the first year of life, and on primary care consultations during total follow-up. Forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 25–75% of forced vital capacity (FEF25–75%) were measured at 5 yrs of age. Information on growth and respiratory symptoms was obtained for 1,431 infants, out of whom 235 children had already had 5 yrs of follow-up. Every one-point z-score increase in weight gain resulted in a 37% increase in days with wheeze (incidence rate ratio 1.37, 95% CI 1.27–1.47; p<0.001) and in associated consultations by 16% (incidence rate ratio 1.16, 95% CI 1.01–1.34; p=0.04). Children with rapid weight gain reported significantly more physician-diagnosed asthma. FEV1 and FEF25–75% were reduced by 34 mL (adjusted regression coefficient -0.034, 95% CI -0.056– -0.013; p=0.002) and 82 mL (adjusted regression coefficient -0.082, 95% CI -0.140– -0.024; p=0.006) per every one-point z-score increase in weight gain, respectively. These associations were independent of birthweight. Rapid early weight gain is a risk factor for clinically relevant wheezing illnesses in the first years of life and lower lung function in childhood.

Body fat distribution and early arterial changes in healthy 5-year-old children

Abstract Background. It is unknown at what age overweight starts to takes its toll on the vasculature. We studied the relation between body size measures and vascular characteristics in healthy 5-year-old children. Methods. In 306 5-year-old children from an on-going birth cohort, body size characteristics were measured, including sonographic measurement of abdominal fat. Ultrasonographic measurements of the carotid artery were performed to obtain intima-media thickness (CIMT), arterial wall distensibility, and elastic modulus (EM). Results. Increased body-weight was related to thicker CIMT (linear regression coefficient 2.25 μm/kg; P = 0.003), increased EM (2.73 kPa/kg; P = 0.01), and lower distensibility (−1.23 MPa−1/kg; P = 0.03). Similar relations were found for increased BMI with CIMT and EM. Increased intra-abdominal fat was related to thicker CIMT (9.19 μm/cm; P = 0.02), and increased waist circumference with thicker CIMT (2.17 μm/cm; P = 0.02), lower distensibility (−1.70 MPa−1/cm; P = 0.01), and higher EM (2.77 kPa/cm; P = 0.02), independent of BMI. Conclusion. For the first time it is demonstrated that increased general body mass and particularly waist circumference and intra-abdominal fat are related to thicker and stiffer arteries already early in life.

The association between breastfeeding and the cardiovascular system in early childhood

BACKGROUND Breastfeeding is suggested to have beneficial effects on childrens health and future health status. However, its cardiovascular effects in childhood and possibly later in life remain largely unclear. OBJECTIVE The aim of the present study was to determine the cardiovascular effects of exclusive breastfeeding in early childhood. DESIGN We used the ongoing WHeezing Illnesses STudy LEidsche Rijn (WHISTLER) birth cohort to obtain data on infant feeding. In the first 306 children who were 5 y of age, ultrasonographic measurements of the carotid artery were performed to obtain carotid intima-media thickness (CIMT), distensibility, and elastic modulus. RESULTS At 5 y of age, children who had been exclusively breastfed in infancy for 3 to 6 mo had a CIMT that was 21.1 μm greater than that of exclusively formula-fed children (95% CI: 5.0, 37.2 μm; P = 0.01, adjusted for confounders). CIMT was not significantly different between children exclusively breastfed for either <3 or >6 mo and formula-fed children. In addition, no significant differences in carotid stiffness were observed between groups. CONCLUSIONS The duration of exclusive breastfeeding in infancy is related to properties of the carotid arterial wall at the age of 5 y, as shown by the greater CIMT in children who were exclusively breastfed for 3 to 6 mo. This relation was independent of early growth in infancy and current cardiovascular disease risk factors. The choice of infant feeding appears to have an effect on the vascular system already in early childhood.

Excess Early Postnatal Weight Gain Leads to Thicker and Stiffer Arteries in Young Children

BACKGROUND Although early life growth pattern is associated with cardiovascular disease later in life, it is unknown whether vascular changes associated with excess early weight gain already occur in early childhood. METHODS In the Wheezing-Illnesses-Study-Leidsche-Rijn (WHISTLER) birth cohort, weight and height from birth to 3 months of age were used to calculate Z-scores of individual weight and length gain rates. In the first 333 children who turned 5 years old, intima-media thickness, distensibility, and elastic modulus of the carotid artery were measured ultrasonographically. The association between weight gain rate for length gain rate (WLG), as a measure of excess weight gain, and vascular characteristics was assessed by generalized linear modeling. Interaction between birth size and WLG was tested. RESULTS Per 1 SD increase in WLG, carotid intima-media thickness was 5.1 μm (95% confidence interval, 1.0-9.2; P value = .01) higher (adjusted for age, gender, current height, and observer). The thinner the children were at birth, the stiffer the arteries were with increasing WLG (interaction between birth size and WLG-distensibility: P = .04; elastic modulus: P = .03). CONCLUSION Excess early postnatal weight gain leads to vascular changes already in early childhood, characterized by thicker arterial walls. In children who are relatively thin at birth, excess early postnatal weight gain also leads to stiffer arteries. This supports the view that cardiovascular disease risk is associated with growth pattern early in life.

Relationship between leptin and lung function in young healthy children

To the Editor: Leptin, a product of the obese (ob) gene, was discovered as a hormone that plays a key role in regulating energy intake and expenditure. Over the past years, interest in the other functions of this pleiotropic hormone has increased. Leptin is primarily produced by adipocytes and is produced in lower amounts in other tissues. In the human lung, expression of leptin has been described in bronchial epithelial cells and alveolar macrophages [1]. Leptin receptors have a universal distribution that includes the respiratory system. The lung has mainly the Ob-Rb isoform, which is considered to be the fully functional receptor and most effective isoform [2]. Receptors have been identified in human bronchial and alveolar epithelial cells, bronchial smooth muscle cells, and bronchial submucosa [3]. The presence of these receptors together with evidence of local leptin production supports the concept that leptin may play a role in the regulation of airway diameter, lung development and the pathogenesis of respiratory diseases. The role of leptin in lung development has only been studied in animals and it is not known if these findings can be extended to the development of healthy human lungs. In this study we evaluated the relationship between plasma leptin levels and lung function in healthy young children and we assessed whether this relationship was modulated by the amount of adipose tissue deposits, the main source of leptin. Participants in this study were children from the Wheezing Illness Study Leidsche Rijn (WHISTLER), an ongoing population-based birth cohort [4]. At the age of 8 years, participants were invited for a follow-up visit. During this visit, information on the child and parents was gathered by questionnaire and weight and height were measured. Spirometry was performed conforming to the latest American Thoracic Society/European …

Effect of physical activity on vascular characteristics in young children

Background: Physical activity has long been proposed as an important modifiable cardiovascular risk factor in adults. We assessed whether physical activity already has an effect on childhood vasculature. Methods: In the Wheezing-Illnesses-Study-in-Leidsche-Rijn birth cohort, we performed vascular ultrasound to measure carotid intima–media thickness (cIMT) and functional properties (distensibility, elastic modulus) at 5 and 8 years of age. Child typical physical activities were inquired using a questionnaire completed by parents. Linear regression was used with physical activity level, expressed as a standardized value of time-weighted metabolic equivalent (MET) as the independent variable and vascular properties as dependent variables with further confounder adjustment and evaluation for possible body mass index and sex effect modifications. Results: In 595 5-year-old children and in 237 of those who had reached the age of 8 years, we did not find statistically significant associations between total time-weighted MET and each vascular parameter, neither in pooled nor stratified analysis. However, sport activities were associated with thinner cIMT (−3.20 µm/SD, 95% CI −6.34, −0.22, p = 0.04) at 5 years of age; a similar pattern was seen for organized sport. This effect was strongest in children in the highest body mass index tertile (−5.38 µm/SD, 95% CI −10.54, −0.19, p = 0.04). At the age of 8 years, higher sport level tended to be associated with higher vascular distensibility (2.64 × 103 kPa/SD, 95% CI −0.18, 5.45, p = 0.07) although this was not statistically significant. Conclusions: Sport activity may have beneficial effects on arteries of young children, particularly those with higher relative body weight.

Excess Early Postnatal Weight Gain Leads to Increased Abdominal Fat in Young Children

Background. Increased childhood weight gain has been associated with later adiposity. Whether excess early postnatal weight gain plays a role in childhood abdominal fat is unknown. Design. In the ongoing Wheezing Illnesses Study Leidsche Rijn (WHISTLER), birth cohort weight and length from birth to age 3 months were obtained. In the first 316 five-year-olds, intra-abdominal and subcutaneous fat were measured ultrasonographically. Individual weight and length gain rates were assessed in each child. Internal Z-scores of weight for length gain (WLG) were calculated. Multiple imputation was used to deal with missing covariates. Results. Per-1-unit increase in Z-score WLG from birth to 3 months, BMI, waist circumference, and subcutaneous fat were significantly higher; 0.51 kg/m2, 0.84 cm, and 0.50 mm, respectively. After multiple imputation, a trend towards significance was observed for intra-abdominal fat as well (0.51 mm/SD). In the associations with 5-year adiposity, no interaction between postnatal Z-score WLG and birth size was found. Conclusion. Excess early postnatal weight gain is associated with increased general and central adiposity, characterized by more subcutaneous and likely more intra-abdominal fat at 5 years of age.

Life-course of cardio-respiratory associations

Background Several studies have shown that raised cardiovascular risk factors are associated with an impaired lung function in adulthood. Whether this association also exists in the young is unknown. Our aim was to study the relation between blood pressure and lung function from neonatal to elderly age. Study design This was a cross-sectional study in a general population cohort. Methods Within the Utrecht Health Project (UHP) 6673 adults (aged 18–91 years) had spirometry and blood pressure measurements taken. In the WHeezing Illnesses STudy LEidsche Rijn (WHISTLER) study, a satellite birth cohort of the UHP, blood pressure and respiratory mechanics were measured using the single occlusion technique in 755 newborns and spirometry in 382 5-year-old participants. Linear regression analyses were performed with lung function as an independent variable and blood pressure as a dependent variable in different age groups. The analyses were adjusted for age, sex, weight and height. Results In infancy a more favorable lung function (higher compliance and lower resistance) was associated with higher blood pressure. In 5-year-old children and young adults higher forced expiratory volume in 1 second (FEV1) was associated with higher systolic blood pressure (p-values < 0.05). At the age of 5 the adjusted regression coefficient for systolic blood pressure was 4.8 mmHg/L (95% confidence interval (95% CI) −0.3–9.98). The association decreased with increasing age and reversed in the age groups above 40 years to −7.3 mmHg/L (95% CI −15.5–0.9) in those aged over 70 years of age. The association with pulse pressure showed a similar pattern. Conclusions A positive association between the mechanical properties of the respiratory system and blood pressure in childhood and young adulthood reverses in later adulthood.

Allergies are associated with arterial changes in young children

Background Inflammation is important in atherosclerosis development. Whether common causes of inflammation, such as allergies and infections, already exert this influence in early childhood is unknown. The objective of this study was to investigate the association between both allergies and infections with children’s vasculature. Design This was a longitudinal study in a general population cohort. Methods In 390 five-year-olds of the WHISTLER (Wheezing-Illnesses-Study-LEidsche-Rijn) birth cohort, carotid intima-media thickness (CIMT) and arterial stiffness were obtained ultrasonographically. Physician-diagnosed allergies and infections and recent prescriptions of systemic antihistamines and antibiotics were obtained, as well as parental history of allergies. General linear regression was performed with vascular characteristics as dependent variables and measures of inflammation as independent variables. Results Having both a positive parental history of allergy and an allergy diagnosis showed 15.0 µm (95% confidence interval (CI): 2.3–27.8, p = 0.02) larger CIMT than not having such history and diagnosis. Having a positive parental history of allergy only showed 11.9 µm (0.87–23.0, p = 0.04) larger CIMT. Recent use of antihistamines and antibiotics showed 18.8 µm (1.6–35.9, p = 0.03) and 16.1 µm (4.5–27.7, p = 0.01) larger CIMT, respectively. Childhood infections were not clearly related to vascular parameters. Neither allergy nor infections were associated with arterial stiffness. Conclusion An allergic predisposition is already associated with thicker arterial walls in early childhood.

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study

Objective To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. Design Cross-sectional comparison of serum biomarkers. Setting University Medical Center Utrecht. Patients Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6–8 years), and a paedriatic reference population (n = 30). Main Outcome Measure(s) Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100). Results The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing. Conclusion In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.