[Show abstract][Hide abstract] ABSTRACT: An adverse fetal environment leads to smaller kidneys, with fewer nephrons, which might predispose an individual to the development of kidney disease and hypertension in adult life. In a prospective cohort study among 1,072 children followed from early fetal life onward, we examined whether maternal smoking during pregnancy, as a significant adverse fetal exposure, is associated with fetal (third trimester of pregnancy, n = 1,031) and infant kidney volume (2 years of age, n = 538) measured by ultrasound. Analyses were adjusted for various potential confounders. Among mothers who continued smoking, we observed dose-dependent associations between the number of cigarettes smoked during pregnancy and kidney volume in fetal life. Smoking less than five cigarettes per day was associated with larger fetal combined kidney volume, while smoking more than ten cigarettes per day tended to be associated with smaller fetal combined kidney volume (p for trend: 0.002). This pattern was not significant for kidney volume at the age of 2 years. Our results suggest that smoking during pregnancy might affect kidney development in fetal life with a dose-dependent relationship. Further studies are needed to assess the underlying mechanisms and whether these differences in fetal kidney volume have postnatal consequences for kidney function and blood pressure.
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to validate dual-energy X-ray absorptiometry (DXA) as a method to assess bone age in children.
Paired dual-energy X-ray absorptiometry (DXA) scans and X-rays of the left hand were performed in 95 children who attended the paediatric endocrinology outpatient clinic of University Hospital Rotterdam, the Netherlands. We compared bone age assessments by DXA scan with those performed by X-ray. Bone age assessment was performed by two blinded observers according to the reference method of Greulich and Pyle. Intra-observer and interobserver reproducibility were investigated using the intraclass correlation coefficient (ICC), and agreement was tested using Bland and Altman plots.
The intra-observer ICCs for both observers were 0.997 and 0.991 for X-ray and 0.993 and 0.987 for DXA assessments. The interobserver ICC was 0.993 and 0.991 for X-ray and DXA assessments, respectively. The mean difference between bone age assessed by X-ray and DXA was 0.11 years. The limits of agreement ranged from -0.82 to 1.05 years, which means that 95% of all differences between the methods were covered by this range.
Results of bone age assessment by DXA scan are similar to those obtained by X-ray. The DXA method seems to be an alternative for assessing bone age in a paediatric hospital-based population.
The British journal of radiology 05/2011; 85(1010):114-20. · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To unravel the mechanisms underlying the previously demonstrated associations between low birthweight and cardiovascular disease in adulthood, we examined whether maternal smoking during pregnancy leads to fetal arterial resistance adaptations, and subsequently to fetal growth retardation and changes in postnatal blood pressure and cardiac development. Design: Prospective cohort study from early fetal life onwards.
Analyses were based on 1120 children aged 2 years.
Maternal smoking during pregnancy [non-smoking, first trimester smoking, continued smoking (< 5 and ≥ 5 cigarettes/day)] was assessed by questionnaire.
Third trimester placental and fetal arterial resistance indices and fetal growth were assessed by ultrasound and Doppler measurements. Postnatal blood pressure and cardiac structures (aortic root diameter, left atrial diameter, left ventricular mass) were measured at 2 years of age.
First trimester smoking was not associated with third trimester placental and fetal blood flow adaptations. Continued smoking of ≥ 5 cigarettes/day was associated with an increased resistance in uterine, umbilical and middle cerebral arteries, and with a decreased flow and diameter of the ascending aorta. Among mothers who continued to smoke, the third trimester estimated fetal weights and birthweights were most affected in children with the highest umbilical artery resistance. Fetal arterial resistance indices were also associated with aortic root diameter and left atrial diameter.
Fetal arterial resistance adaptations may be involved in the pathways leading from maternal smoking during pregnancy to low birthweight and cardiovascular developmental changes in childhood in the offspring.
BJOG An International Journal of Obstetrics & Gynaecology 03/2011; 118(6):755-62. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: glucocorticoid receptor-9β polymorphism (rs6198) is associated with the susceptibility for cardiovascular disease.
to examine whether the GR-9 β variant is also associated with blood pressure and heart growth in early childhood.
this study was embedded in a population-based prospective cohort study from fetal life onwards. Analyses were based on 857 children.
Left cardiac structures (aortic root diameter, left atrial diameter and left ventricular mass), shortening fraction and heart beat were measured postnatally at the ages of 1.5, 6 and 24 months. Blood pressure was measured at 24 months of age.
the distribution of the GR-9β genotype showed 75.1% homozygous reference, 23.5% heterozygous and 1.4% homozygous variant subjects. No differences in cardiovascular outcomes were observed at the ages of 1.5 and 6 months. At the age of 24 months, homozygous variants showed an increased systolic blood pressure of 2.65 mmHg (95% CI: 0.16, 5.14), an increased heart rate of 9.10 beats per minute (95% CI: 1.28, 16.7) and an increased left ventricular mass of 4.99 g (95% CI: 1.33, 8.65) compared to homozygous references. This means an increase of 2.6%, 8.6% and 16%, respectively. GR-9 β polymorphism was significantly associated with left ventricular mass growth during the first 2 years.
our findings suggest that genetically determined differences in cortisol exposure affect cardiovascular development in early life.
Early human development 02/2011; 87(2):97-102. · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hypothesis that a developmental component plays a role in subsequent disease initially arose from epidemiological studies relating birth size to both risk factors for cardiovascular disease and actual cardiovascular disease prevalence in later life. The findings that small size at birth is associated with an increased risk of cardiovascular disease have led to concerns about the effect size and the causality of the associations. However, recent studies have overcome most methodological flaws and suggested small effect sizes for these associations for the individual, but an potential important effect size on a population level. Various mechanisms underlying these associations have been hypothesized, including fetal undernutrition, genetic susceptibility and postnatal accelerated growth. The specific adverse exposures in fetal and early postnatal life leading to cardiovascular disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life may underlie the complex associations of fetal growth retardation and low birth weight with cardiovascular disease in later life. To estimate the population effect size and to identify the underlying mechanisms, well-designed epidemiological studies are needed. This review is focused on specific adverse fetal exposures, cardiovascular adaptations and perspectives for new studies.
European Journal of Epidemiology 10/2010; 25(10):677-92. · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Offspring of women with hypertensive disorders of pregnancy are at increased risk of cardiovascular complications later in life, but the mechanisms underlying these associations are unclear. Our aim was to examine whether adjusting for birth weight and familial adiposity changed the association of hypertensive disorders of pregnancy with offspring blood pressure.
Using data from 6343 nine-year-old participants in the Avon Longitudinal Study of Parents and Children, we examined the association between hypertensive disorders of pregnancy (preeclampsia and gestational hypertension) and offspring blood pressure. Both preeclampsia and gestational hypertension were associated with systolic and diastolic blood pressures in the 9-year-old offspring; after adjustment for parental and own adiposity and for other potential confounders, the mean difference in systolic blood pressure was 2.05 mm Hg (95 confidence interval, 0.72 to 3.38) and 2.04 mm Hg (95 confidence interval, 1.42 to 2.67) for preeclampsia and gestational hypertension, respectively, compared with those with no hypertensive disorders of pregnancy. Equivalent results for diastolic blood pressure were 1.00 mm Hg (95 confidence interval, -0.01 to 2.10) and 1.07 mm Hg (95 confidence interval, 0.60 to 1.54). The association of preeclampsia with offspring systolic and diastolic blood pressures attenuated toward the null with further adjustment for birth weight and gestational age, whereas these adjustments did not attenuate the association of gestational hypertension with offspring blood pressure.
The associations of hypertensive disorders of pregnancy with higher offspring blood pressure are not explained by familial adiposity. The mechanisms linking preeclampsia and gestational hypertension with offspring blood pressure may differ, with the former mediated at least in part by the effect of preeclampsia on intrauterine growth restriction.
[Show abstract][Hide abstract] ABSTRACT: Shorter duration of breastfeeding in infancy has been suggested to be associated with an increased risk of cardiovascular disease in adulthood. Early cardiovascular adaptations due to breastfeeding may explain these associations.
To investigate whether breastfeeding affects left cardiac structures and blood pressure development in early childhood.
Prospective cohort study from fetal life until the age of two years.
Information about the duration and exclusivity of breastfeeding was collected by questionnaires at the ages of 2, 6 and 12 months in 933 children.
Left cardiac structures (left atrial diameter, aortic root diameter and left ventricular mass), fractional shortening and blood pressure at the ages of 1.5, 6 and 24 months.
No differences in cardiac structures, fractional shortening and blood pressure were observed between breastfed and non-breastfed children. Duration and exclusivity of breastfeeding were not consistently associated with any cardiac structure, fractional shortening, or blood pressure until the age of 24 months. Also, there was no association of breastfeeding with cardiac growth between 6 months and 24 months. All analyses were adjusted for child age and sex. Additional adjustment for child anthropometrics, maternal age, anthropometrics, family history, maternal cardiovascular risk factors, pregnancy or delivery complications, parity, socio-economic status, smoking status and alcohol consumption during pregnancy did not materially change the effect estimates.
Our results do not support the hypothesis that early postnatal cardiovascular adaptations underlie the previously shown associations between breastfeeding and cardiovascular disease in adulthood. Further studies are needed to investigate whether and at what age the associations appear.
Early human development 08/2010; 86(8):463-8. · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Information about growth of kidney structures in early life is limited. In a population-based prospective cohort study, from
foetal life onwards, we constructed reference curves for kidney growth from the third trimester of pregnancy until early childhood,
using data from 1,158 healthy children. Kidney size, defined as length, width, depth and volume, was measured in the third
trimester of pregnancy and at the postnatal ages of 6months and 24months. Analyses were based on more than 2,500 kidney
measurements. In the third trimester of pregnancy and at 6months of age all kidney measurements were larger in boys than
in girls. At 24months of age, these gender differences were only significant for left kidney structures and right kidney
length. Both groups showed trends towards smaller left kidney measurements than right kidney measurements at all ages. Gender-specific
reference curves based on post-conceptional and postnatal ages were constructed for left and right kidney length, width, depth
and volume. We concluded that kidney size is influenced by age and gender. Left kidney size tended to be smaller than right
kidney size, except for kidney length. The reference curves can be used for assessing kidney structures by ultrasound in foetal
life and early childhood.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
American heart journal 07/2009; 158(1):71-77. · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the investigation reported here was to assess the intraobserver and interobserver variability of renal measurements in children. The study comprised 56 paired measurements in 28 children (median age 7.5 years, range 3.0-15.0 years) without renal or ureterovesical anomalies. Intraobserver and interobserver reproducibility was assessed by repeated measurements of the left and right renal length, width, and thickness. Intraclass correlation coefficients (ICCs) with the corresponding 95% confidence interval (CI) were calculated. Bland and Altman plots were computed to assess the agreement of the measurements. Limits of agreement +/- 2 standard deviations (SD) for the mean differences in renal measurements were derived. Intraobserver ICCs ranged from 0.93 (left and right renal width and right renal thickness) to 0.99 (left renal length), and interobserver ICCs ranged from 0.64 (right renal thickness) to 0.90 (right renal length). Limits of agreement in the Bland and Altman plots ranged from -8.0 to 9.2% (intraobserver left renal width) to the widest limit from -18.0 to 19.2% (interobserver left renal length). Overall, this study demonstrated the good reproducibility and agreement of most renal dimensions in children measured by ultrasound (US). Based on these results, we conclude that US is an appropriate measure to assess renal dimensions in both clinical and epidemiological studies.
[Show abstract][Hide abstract] ABSTRACT: An adverse fetal environment may lead to smaller kidneys and subsequently kidney disease and hypertension in adulthood. The aims of this study are to examine whether kidney size tracks from fetal life to childhood and whether maternal and fetal characteristics are associated with kidney size at the age of 2 years.
Prospective cohort study from fetal life onward.
The study was conducted in a group of 688 infants in Rotterdam, The Netherlands. Entry criteria were singleton, noncomplicated pregnancies, and Dutch ethnicity.
The maternal characteristics age, height, and prepregnancy weight were measured in early pregnancy. Fetal growth, head circumference, abdominal circumference, femur length and estimated fetal weight, and placental characteristics were assessed in the second and third trimesters.
Kidney size, defined as length, width, depth, and volume, was measured in the third trimester of pregnancy and at postnatal ages 6 and 24 months.
Overall median gestational age was 40.3 weeks (95% range, 36.0 to 42.3 weeks), and mean birth weight was 3,536 +/- 524 (SD) g. Children tended to remain in the lowest and highest quartiles of kidney volume from the third trimester to the age of 2 years (odds ratio, 2.05; 95% confidence interval, 1.38 to 3.06; odds ratio, 3.29; 95% confidence interval, 2.22 to 4.87, respectively). Maternal height and prepregnancy weight were associated positively with kidney volume at the age of 2 years. Third-trimester fetal head circumference, abdominal circumference, and estimated weight and postnatal length were associated positively with kidney volume at the age of 2 years. Preferential fetal blood flow to the brain was associated with smaller kidneys.
Kidney measurements successfully performed in only 86% of children.
Small kidney size in fetal life tends to persist in early childhood. Maternal anthropometrics and fetal biometrics and blood flow patterns are associated with kidney size in childhood. Follow-up studies are needed to examine whether these variations in kidney size are related to kidney function and blood pressure in later life.
American Journal of Kidney Diseases 10/2008; 53(2):248-58. · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to examine whether variants of the IGF1 gene are associated with growth patterns from foetal life until infancy. STUDY DESIGN AND MEASUREMENTS: This study was embedded in the Generation R Study, a population-based prospective cohort study of foetal life. Foetal growth (head circumference, abdominal circumference, femur length, estimated foetal weight) was assessed by ultrasound in early, mid- and late pregnancy. Growth in infancy was assessed at birth (weight) and at the ages of 6 weeks, 6 months and 14 months (head circumference, length, weight). The IGF1 promoter region genotype was determined in 738 children.
Eight alleles of the IGF1 promoter region were identified. In total, 43% of the subjects were homozygous for the most common 192-bp allele (wild-type), 45% were heterozygous, and 12% were noncarriers of the 192-bp allele. No differences were found in birthweight between the three groups. However, noncarriers had a lower estimated foetal weight in mid-pregnancy (P = 0.040), followed by an increased growth rate until 6 months (P < 0.005) in comparison to the 192-bp homozygotes. A similar difference in growth rate was found for length (P < 0.001).
Variants of the IGF1 promoter region are not associated with birthweight. However, noncarriers of the 192-bp allele tend to have a smaller foetal size, followed by an increased growth rate from mid-pregnancy to early infancy. Studies in larger cohorts are necessary to replicate our findings and to examine whether these effects persist throughout childhood.
[Show abstract][Hide abstract] ABSTRACT: Pregnancy and early life factors may permanently affect left ventricular growth and development in the offspring. The aim of this study was to examine the associations of maternal anthropometrics during pregnancy with left ventricular mass (LVM) in infancy. This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onwards. Maternal anthropometrics were obtained in early (gestational age <18 wk), mid- (gestational age 18-25 wk), and late (gestational age >25 wk) pregnancy. Echocardiographic follow-up measurements were performed in 791 infants aged 6 wk and 6 mo. We found no associations of maternal height, weight, or body mass index (BMI) measured in early, mid-, and late pregnancy with longitudinally measured left ventricular mass (LVM) from 6 wk to 6 mo. Maternal weight gain until late pregnancy was associated with an increased growth of LVM from 6 wk to 6 mo [difference 0.46 g per week for the highest tertile of weight gain compared with the lowest tertile (p value <0.05)]. We concluded that maternal weight gain until late pregnancy is associated with larger LVM at the age of 6 mo, suggesting that maternal health status during pregnancy may have permanent consequences for LVM in their children. Further studies are needed to identify the underlying causal mechanisms and the long-term consequences.
Pediatric Research 02/2008; 63(1):62-6. · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to examine whether the insulin gene variable number of tandem repeats (INS VNTR) is associated with growth patterns in fetal life and infancy.
This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life until young adulthood. Fetal growth was assessed by ultrasounds in early, mid-, and late pregnancy. Anthropometry in infancy was assessed at birth and at the ages of 6 weeks, 6 months, and 14 months. DNA for genotyping of the INS VNTR promoter region was available in 859 children.
The genotype distribution was I/I 50.8%, I/III 40.0%, and III/III 9.2%. III/III individuals had a shorter gestational age (P<0.005 versus I/I) and a lower birth weight (P<0.05 versus I/I). There were no differences in birth weight after adjusting for gestational age. Class III homozygotes had a smaller abdominal circumference/head circumference (HC) ratio (P<0.005 versus I/I) in mid-pregnancy, but not in late pregnancy. Also, III/III subjects had a relative decrease in HC (SDS) from mid-pregnancy to the age of 14 months (P<0.05 versus I/I). No other differences in pre- and postnatal growth characteristics and patterns were found.
Class III homozygotes were born at an earlier gestational age. No association was found between INS VNTR and birth weight adjusted for gestational age. Our data suggest that the III/III genotype may be associated with asymmetrical growth in mid-pregnancy, but not in late pregnancy.
European Journal of Endocrinology 12/2007; 157(6):741-8. · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An adverse fetal environment may lead to smaller kidneys and subsequent hypertension with renal disease in adult life. The aim of our study was to examine whether maternal characteristics, fetal growth, fetal blood flow redistribution, or inadequate placental perfusion in different periods of fetal life affect kidney volume in late fetal life. We also determined if fetal kidney volume was linked to the amount of amniotic fluid. In a population-based prospective study from early fetal life, fetal growth characteristics and fetal blood flow parameters were assessed by ultrasound and Doppler examinations in 1215 women in mid- and late-pregnancy. Kidney volume was measured in late pregnancy. Maternal height and pre-pregnancy weight were associated with kidney volume. After adjustment for the same characteristics in late pregnancy, fetal growth and blood flow in mid-pregnancy were not associated with kidney volume in late pregnancy. In late pregnancy, however, all fetal growth parameters were positively linked with kidney volume. The largest effect on kidney volume was found for abdominal circumference. Signs of fetal blood flow redistribution and increased placental resistance were associated with decreased kidney volume in late pregnancy. Amniotic fluid volume was positively associated with kidney volume. Our study shows that maternal anthropometrics, fetal growth, fetal blood flow redistribution, and raised placental resistance all correlate with kidney volume.
Kidney International 10/2007; 72(6):754-61. · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular disease is common in the general population, affecting 40-60% of adults older
than 60 years of age. Many lines of evidence indicate an important role of early life events in influencing
later susceptibility to cardiovascular disease. Barker and Osmond demonstrated that
areas of Britain with the highest neonatal mortality rates early in the 20th century also tended to
have the highest rates of coronary heart disease many decades later.After this, observational
studies showed that low birth weight and weight at one year were associated with an increased
risk of later cardiovascular disease, especially in subjects who show a postnatal catch-up growth
and become obese as adults. The most commonly studied risk factors for cardiovascular disease
include blood pressure and total cholesterol levels. Several studies showed small but consistent
effects. These observations resulted in the “fetal origins of adult disease” hypothesis. More
recently, this hypothesis has been transformed to a more general “developmental plasticity hypothesis”, which suggests that an organism may develop in various ways, depending on the
particular environment or setting. In this process, adverse environmental exposures in fetal
and early postnatal life lead to adaptations that permanently program the fetus’ structure, physiology
and metabolism. These adaptations may be beneficial in the short term but have adverse
consequences at birth and in postnatal life, leading to both low birth weight and cardiovascular
disease in adulthood. Thus, cardiovascular disease may at least partly originate in early fetal