Albert J. van der Heijden

The Generation R Study Biobank: a resource for epidemiological studies in children and their parents

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health from fetal life until young adulthood. In total, 9,778 mothers were enrolled in the study. Prenatal and postnatal data collection is conducted by physical examinations, questionnaires, interviews, ultrasound examinations and biological samples. Major efforts have been conducted for collecting biological specimens including DNA, blood for phenotypes and urine samples. In this paper, the collection, processing and storage of these biological specimens are described. Together with detailed phenotype measurements, these biological specimens form a unique resource for epidemiological studies focused on environmental exposures, genetic determinants and their interactions in relation to growth, health and development from fetal life onwards.

Genome-Wide Profiling of Blood Pressure in Adults and Children

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ⩽1.2% (P=9.6*10−8) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10−10] and 1.4% [P=3.3*10−5], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.

Cardiac structures track during the first 2 years of life and are associated with fetal growth and hemodynamics. The Generation R Study

BACKGROUND The aim of this study is to examine whether cardiac size and function track in early childhood and are associated with fetal and early postnatal growth and blood flow characteristics. METHODS This study was embedded in a population-based prospective cohort study from fetal life onward. Fetal growth and fetal and placental blood flow parameters in second and third trimester of pregnancy were measured by ultrasound and Doppler. Left cardiac structures and shortening fraction were measured postnatally at the ages of 1.5, 6, and 24 months. Analyses were based on 1,001 children. RESULTS Left ventricular mass tended to remain in the lowest and highest quartiles from the age of 1.5 to 24 months (odds ratio 1.70, 95% confidence interval [CI] 1.10-2.63) and 2.15 (95% CI 1.41-3.30), respectively. Similar results were found for aortic root diameter and left atrial diameter. Birth weight was positively associated with aortic root diameter (0.08 mm, 95% CI 0.01-0.17; per SD increase) and left ventricular mass (0.65 g, 95% CI 0.09-1.21; per SD increase). Resistance indices of the umbilical and uterine arteries showed weak tendencies toward inverse associations with left cardiac structures. Fetal cardiac output was positively associated with both left atrial diameter (increase of 1.96 mm, 95% CI 1.28-2.64; per mL/min increase) and left ventricular mass (increase of 1.79 g, 95% CI 0.35-3.22; per mL/min increase). CONCLUSIONS This study suggest moderate tracking of left cardiac structures during the first 2 years and that small size and hemodynamic variations in fetal life have consequences for postnatal cardiac size and function.

Diuretics in pediatrics: Current knowledge and future prospects

This review summarizes current knowledge on the pharmacology, pharmacokinetics, pharmacodynamics, and clinical application of the most commonly used diuretics in children.Diuretics are frequently prescribed drugs in children. Their main indication is to reduce fluid overload in acute and chronic disease states such as congestive heart failure and renal failure. As with most drugs used in children, optimal dosing schedules are largely unknown and empirical. This is undesirable as it can potentially result in either under- or over-treatment with the possibility of unwanted effects.The pharmacokinetics of diuretics vary in the different pediatric age groups as well as in different disease states. To exert their action, all diuretics, except spironolactone, have to reach the tubular lumen by glomerular filtration and/or proximal tubular secretion. Therefore, renal maturation and function influence drug delivery and consequently pharmacodynamics.Currently advised doses for diuretics are largely based on adult pharmacokinetic and pharmacodynamic studies. Therefore, additional pharmacokinetic and pharmacodynamic studies for the different pediatric age groups are necessary to develop dosing regimens based on pharmacokinetic and pharmacodynamic models for all routes of administration.

Fetal and Infant Growth Patterns and Kidney Function at School Age

Low birth weight is associated with ESRD. To identify specific growth patterns in early life that may be related to kidney function in later life, we examined the associations of longitudinally measured fetal and infant growth with kidney function in school-aged children. This study was embedded in a population-based prospective cohort study among 6482 children followed from fetal life onward. Fetal and childhood growth was measured during second and third trimesters of pregnancy, at birth, and at 6, 12, 24, 36, and 48 months postnatally. At the age of 6 years, we measured kidney volume by ultrasound. GFR was estimated using blood creatinine levels. Higher gestational age-adjusted birth weight was associated with higher combined kidney volume and higher eGFR (per 1 SD score increase in birth weight; 1.27 cm(3) [95% confidence interval, 0.61 to 1.93] and 0.78 ml/min per 1.73 m2 [95% CI, 0.16 to 1.39], respectively). Fetal weight, birth weight, and weight at 6 months were positively associated with childhood kidney volume, whereas higher second trimester fetal weight was positively associated with higher GFR (all P values<0.05). Fetal and childhood lengths were not consistently associated with kidney function. In this cohort, lower fetal and early infant weight growth is associated with smaller kidney volume in childhood, whereas only lower fetal weight growth is associated with lower kidney function in childhood, independent of childhood growth. Whether these associations lead to an increased risk of kidney disease needs to be studied further.

Alarm treatment is successful in children with day- and night-time wetting.

Objective: To assess the effect of alarm treatment in children with day‐ and night‐time wetting compared to those with night‐time wetting only. Material and Methods: A total of 37 consecutive children (25 boys, 12 girls), all of whom suffered from both day‐ and night‐time wetting, were compared to a group of 21 boys and 16 girls with nocturnal enuresis only. In both groups the age range was 5–13 years. Inclusion criteria were at least two wet nights a week in the previous 4 weeks combined with day‐time wetting. The parents were asked to complete a diary during the study period. Results: Sixty‐five percent of the children with day‐ and night‐time wetting became dry at night, the average time needed being 49 days (range 22–134 days). Seventy‐six percent of the children with only night‐time wetting became dry at night, the average time needed being 52 days (range 22–121 days). No significant differences were found between the success rates for the two groups or between the different age groups in the two groups. Of the children with day‐ and night‐time wetting who became dry at night after alarm treatment, 42% also became dry during the day‐time. Two years after alarm treatment, 15/16 traced children were still dry at night and all 10 traced children were still dry during the day‐time. Conclusions: As with children with only night‐time wetting, the majority of children with day‐ and night‐time wetting become dry at night with the use of an enuresis alarm. The results are good compared to the spontaneous cure rate. By using alarm treatment at night, children often also become dry during the day.

Parental smoking during pregnancy and cardiovascular structures and function in childhood: The Generation R Study

BACKGROUND Foetal smoke exposure might lead to foetal developmental adaptations that permanently affect the cardiovascular system. We assessed the associations of both maternal and paternal smoking during pregnancy with childhood cardiovascular structures and function. METHOD In a prospective cohort study among 5565 children, we examined whether maternal and paternal smoking during pregnancy are associated with blood pressure, carotid-femoral pulse wave velocity and left cardiac structures and function in 6-year-old children. RESULTS As compared with children from non-smoking mothers, children from mothers who smoked more than 10 cigarettes per day had a higher diastolic blood pressure [difference 1.43 mmHg (95% confidence interval: 0.22, 2.63)]. Maternal smoking during pregnancy was not associated with systolic blood pressure, childhood carotid-femoral pulse wave velocity or left cardiac structures. Maternal smoking of 10 or more cigarettes per day was associated with a higher fractional shortening in childhood [difference 1.01% (95% confidence interval: 0.18, 1.84)]. Among mothers who did not smoke during pregnancy, paternal smoking was associated with aortic root diameter but not with other cardiovascular outcomes. CONCLUSIONS Maternal smoking during pregnancy is associated with higher diastolic blood pressure and fractional shortening, although the effect estimates are small. The stronger effect estimates for maternal smoking compared with paternal smoking might suggest that direct intrauterine adaptive responses are involved as underlying mechanisms.

Childhood Kidney Outcomes in Relation to Fetal Blood Flow and Kidney Size

Impaired fetal abdominal blood flow may lead to smaller kidneys and subsequent impaired kidney function in later life. In a prospective cohort study among 923 pregnant women and their children, we measured fetal growth, kidney volumes, and umbilical and cerebral artery blood flow (median gestational age of 30.3 weeks; 95% range, 28.5-32.7 weeks). We used a higher umbilical/cerebral artery pulsatility index ratio as an indicator of preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs. At a median age of 5.9 years (95% range, 5.7-6.6 years), we measured childhood kidney volumes, creatinine and cystatin C blood levels, microalbuminuria, BP, and eGFR. A preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs associated only with a smaller combined kidney volume in childhood. Fetal combined kidney volume positively associated with childhood combined kidney volume and eGFR, and inversely associated with childhood creatinine and cystatin C levels (all P values <0.05), but did not associate with childhood microalbuminuria and BP. Children within the highest tertile of fetal umbilical/cerebral ratio and the lowest tertile of fetal combined kidney volume had the lowest eGFR (difference, -6.36 ml/min per 1.73 m(2); 95% confidence interval, -11.78 to -0.94 compared with children within the middle tertiles). These data suggest that impaired fetal blood to the abdominal organs and smaller fetal kidney size are associated with subclinical changes in kidney outcomes in school-aged children.

Maternal first-trimester dietary intake and childhood blood pressure: the Generation R Study

Suboptimal maternal dietary intake during pregnancy might lead to fetal cardiovascular adaptations and higher blood pressure in the offspring. The aim of the present study was to investigate the associations of maternal first-trimester dietary intake with blood pressure in children at the age of 6 years. We assessed first-trimester maternal daily dietary intake by a FFQ and measured folate, homocysteine and vitamin B₁₂ concentrations in the blood, in a population-based prospective cohort study among 2863 mothers and children. Childhood systolic and diastolic blood pressure was measured using a validated automatic sphygmomanometer. First-trimester maternal daily intake of energy, fat, protein and carbohydrate was not associated with childhood blood pressure. Furthermore, maternal intake of micronutrients was not associated with childhood blood pressure. Also, higher maternal vitamin B₁₂ concentrations were associated with a higher diastolic blood pressure (0·31 mmHg per standard deviation increase in vitamin B₁₂ (95% CI 0·06, 0·56)). After taking into account multiple testing, none of the associations was statistically significant. Maternal first-trimester folate and homocysteine concentrations were not associated with childhood blood pressure. The results from the present study suggest that maternal Fe intake and vitamin B₁₂ concentrations during the first trimester of pregnancy might affect childhood blood pressure, although the effect estimates were small and were not significant after correction for multiple testing. Further studies are needed to replicate these findings, to elucidate the underlying mechanisms and to assess whether these differences in blood pressure persist in later life.

Parental psychological distress during pregnancy and childhood cardiovascular development. The Generation R Study.

BACKGROUND Maternal psychological distress during pregnancy might lead to higher fetal cortisol exposure, which subsequently leads to fetal cardiovascular developmental adaptations and cardiovascular dysfunction in later life. AIMS We examined whether maternal and paternal psychological distress was associated with the cardiovascular outcome measurements in school age children. STUDY DESIGN AND SUBJECTS In a population-based prospective cohort study among 4831 children, we assessed maternal and paternal psychological distress during pregnancy by questionnaire, using the Brief Symptom Inventory (see Fig. 1). OUTCOME MEASURES At the child age of six years, we performed blood pressure and carotid-femoral pulse wave velocity measurements, and M-mode measurements of left cardiac structures and fractional shortening. RESULTS We did not observe associations of high maternal and paternal psychological symptom scores with childhood blood pressure and carotid-femoral pulse wave velocity after adjustment for potential confounders. Maternal overall psychological symptoms were associated with a lower childhood left ventricular mass (difference -1.10 g (95% confidence interval -2.13 to -0.07) between mothers with high scores and normal scores), but not with other cardiac structures and fractional shortening. Paternal overall psychological symptoms showed a similar association with childhood left ventricular mass (difference -1.34 grams (95% confidence interval -3.69 to 1.02) between fathers with high scores and normal scores). CONCLUSIONS Our results do not support the hypothesis that maternal psychological distress affects cardiovascular development in early life. Similar associations of maternal and paternal psychological distress with left ventricular mass suggest that these associations could be due to unmeasured social and environmental factors, rather than direct intra-uterine effects.