Jaddoe, V.W.V.

Pediatric population-based neuroimaging and the Generation R Study: The intersection of developmental neuroscience and epidemiology (Article)

2013-01-01T00:00:00Z

Neuroimaging studies of typically developing children and adolescents have provided valuable information on global and regional developmental trajectories of brain development. As these studies become larger and population-based, they are generating an intersection between the fields of developmental neuroscience and epidemiology. However, few of these studies have adequately probed the contribution of multiple environmental and genetic factors on brain development. Studies designed to optimally evaluate the role of multiple environmental and genetic factors on brain development require both large sample sizes and the prospective collection of multiple environmental factors. The Generation R Study is a large, prospective, prenatal-cohort study of nearly 10,000 children that began in 2002 in Rotterdam, the Netherlands. In September of 2009, 6-8 year old children from the Generation R Study were invited to participate in a magnetic resonance imaging component of the study. We provide an overview of the study design and experience for the first 801 children recruited for the neuroimaging component of the study. The protocol includes a 1-h neuropsychological assessment using the NEPSY-II, a mock scanning session, and a neuroimaging session that includes high-resolution structural, diffusion tensor, and resting-state functional MRI sequences. Image quality has been good to excellent in over 80 % of the children to date. The infusion of imaging into the Generation R Study will set the stage for evaluating the role of multiple environmental and genetic factors in both typical and atypical neurodevelopment.

A periconceptional energy-rich dietary pattern is associated with early fetal growth: The Generation R study (Article)

2012-12-04T00:00:00Z

Objective: To identify periconceptional maternal dietary patterns associated with crown-rump length (CRL), estimated fetal weight (EFW) and birthweight. Design: Population-based prospective birth cohort study. Setting: Rotterdam, the Netherlands. Participants: For this study, 847 pregnant Dutch women were eligible. Women were included between 2001 and 2005. Methods: Information on nutritional intake was collected by a semiquantitative food frequency questionnaire. For extracting dietary patterns, principal component factor analysis was used. Fetal growth was assessed using ultrasound measurements. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used. Main outcome measures: Crown-to-rump length, estimated fetal weight in second and third trimester and birthweight. Results: An 'energy-rich dietary pattern' was identified, characterised by high intakes of bread, margarine and nuts. A significant association was shown between a high adherence to this dietary pattern (difference, mm: 2.15, 95% confidence interval 0.79-3.50) and CRL (linear trend analyses P = 0.015). No association was revealed between increasing adherence to this dietary pattern and EFW in second or third trimester, or birthweight. Conclusion: This study suggests that increasing adherence to an energy-rich dietary pattern is associated with increased CRL in the first trimester.

The generation R study: A review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward (Article)

2012-11-01T00:00:00Z

Objective: First, we give an overview of child psychiatric research in the Generation R Study, a population-based cohort from fetal life forward. Second, we examine within Generation R whether the functional polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene interacts with prenatal maternal chronic difficulties, prenatal maternal anxiety or postnatal maternal anxiety to influence child emotional development. Method: A total of 2,136 northern European children were genotyped for 5-HTTLPR and rs25531. Mothers reported chronic difficulties and anxiety symptoms at 20 weeks' pregnancy and when the child was 3 years old. Child emotion recognition was observed at 3 years, and child emotional problems were assessed with the CBCL/1-5 at 5 years. Results: There were consistent main effects of maternal difficulties and anxiety on child emotional problems, but no main effect of 5-HTTLPR. Moreover, children with the s allele were at increased risk for emotional problems if their mothers reported prenatal anxiety symptoms (β = 2.02, p <.001) or postnatal anxiety symptoms (β = 1.64, p < 0.001). Also, in children of mothers with prenatal anxiety symptoms, the s allele was associated with less accurate emotion-matching (β = -0.11, p =.004). Conclusions: This population-based study shows that vulnerability due to 5-HTTLPR is not specific for certain adverse exposures or severe events, but suggests that the small effects of gene-environment interaction on emotional development become manifest early in life.

Febrile seizures and behavioural and cognitive outcomes in preschool children: The Generation R Study (Article)

2012-11-01T00:00:00Z

Aim General developmental outcome is known to be good in school-aged children who experienced febrile seizures. We examined cognitive and behavioural outcomes in preschool children with febrile seizures, including language and executive functioning outcomes. Method This work was performed in the Generation R Study, a population-based cohort study in Rotterdam from early fetal life onwards. Information about the occurrence of febrile seizures was collected by questionnaires at the ages of 1, 2, and 3years. At the age of 3years, behaviour and emotion were assessed using the Child Behavior Checklist. Information on expressive language development was obtained by the Language Development Survey at the age of 2 years 6 months. To assess executive functioning, parents completed the Behaviour Rating Inventory of Executive Function - Preschool Version when their children were 4years old. Final analyses were based on 3157 children. Results No associations were found between febrile seizures and the risk of behavioural problems or executive functioning. In contrast to single febrile seizures, recurrent febrile seizures were significantly associated with an increased risk of delayed vocabulary development (odds ratio 3.22, [95% confidence interval 1.30-7.94]). Interpretation Febrile seizures are not associated with problem behaviour or executive functioning in preschool children, but the results suggest that children with recurrent febrile seizures might be at risk for delayed language development. © The Authors. Developmental Medicine & Child Neurology

Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior (Article)

2012-10-01T00:00:00Z

Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic-pituitary-adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta 2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene-environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.

Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior (Article)

2012-10-01T00:00:00Z

Assessing expressed emotion during pregnancy (Article)

2012-09-26T00:00:00Z

We assessed Expressed Emotion (EE) with an adapted version of the Five Minute Speech Sample in 847 pregnant women. The prevalence of high EE was 6%. High EE was significantly associated with having a first child, low income, maternal childhood trauma and lack of parental emotional warmth during childhood.

A brief observational instrument for the assessment of infant home environment: Development and psychometric testing (Article)

2012-09-01T00:00:00Z

The present paper reports on the development and the psychometric properties of a brief observational assessment of home environments for use in large-scale investigations with young infants. We generated observational items conceptually relevant for child development by two methods. First, we adapted the Infant Toddler Home Observation for Measurement of the Environment (IT-HOME) inventory for use in an exclusively observational context. Second, we added new observational items following a review of relevant literature and consulting professionals. The quality of the instrument was first evaluated in a pilot study (n = 926). In our study sample of 3406 families and their children (median age = 3.1 months, range = 1.6-6.0), exploratory factor analysis was used to identify latent constructs, Cronbach's alpha was used as a measure of internal consistency, and convergent validity was evaluated against family socio-demographic characteristics. Inter-observer agreement was investigated in a sub-sample of the respondents (n = 124). The results supported good psychometric properties of the instrument based on: (a) exploratory factor analysis yielding three meaningful latent constructs, (b) Cronbach's alphas ranging from α = 0.66 to α = 0.90, (c) inter-observer agreement ranging from r = 0.75 to r = 0.91, and (d) associations between the instrument and socio-demographic characteristics in the expected direction [e.g. Odds Ratio for low income = 15.24, 95% confidence interval (11.60, 20.01)]

Differences in Quality of Antenatal Care Provided by Midwives to Low-Risk Pregnant Dutch Women in Different Ethnic Groups (Article)

2012-09-01T00:00:00Z

Introduction: The objective of this study was to evaluate whether differences existed in the adherence to the Dutch national guidelines regarding basic antenatal care by Dutch midwives for low-risk women of different ethnic groups. Methods: This was an observational study using data from electronic antenatal charts of 7 midwife practices (23 midwives), participating in the Generation R Study. The Generation R Study is a multiethnic, population-based, prospective, cohort study that is investigating the growth, development, and health of urban children from fetal life until young adulthood. The study is conducted in Rotterdam, The Netherlands. The antenatal charts of 2093 low-risk pregnant women with an expected birthing date in 2002 through 2004 were used to determine the mean quality of antenatal care scores for 7 ethnic groups. These scores reflected the degree of adherence to the guidelines regarding 10 tests and examinations. Results: Few differences between ethnic groups were found in adherence to the guidelines that addressed the obstetric-technical quality of antenatal care. This finding applied more to nulliparous than to multiparous women. Adherence to guidelines was not always better in the antenatal care provided to native Dutch multiparous women when compared to other ethnic groups. Midwives adhered well to the guidelines regarding most tests. For all women, irrespective of ethnic background, hemoglobin was not measured as often as recommended, and this was especially the case for Moroccan, Surinamese-Creole, and Dutch-Antillean multiparous women. Discussion: The poorer adherence regarding screening for hemoglobin needs further investigation, as women with African or Mediterranean heritage are more at risk for hemoglobinopathies. However, in general, midwives adhered well to the clinical guidelines regarding most tests irrespective of the ethnic background of the pregnant women. When differences were present, these were not systematically less favorable for non-Dutch pregnant women.

Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: The generation r study (Article)

2012-02-01T00:00:00Z

Background: Maternal thyroid status and autoimmunity during pregnancy have been associated with impaired development of the offspring in animal and human studies. Our objective was to examine whether elevated titers of maternal thyroid peroxidase antibodies (TPOAbs) in early pregnancy increased the risk of cognitive impairment and problem behavior in preschool children. Second, we aimed at exploring to what extent any effect on child behavior was mediated by maternal thyroid parameters during pregnancy. Methods: In the Generation R Study, a population-based cohort of 3139 children and their mothers, we measured maternal thyroid parameters (thyrotropin [TSH], free Thyroxine, and TPOAbs) at 13.5±1.8 weeks of gestation. Children's verbal and nonverbal cognitive functioning was measured at 2.5 years using the Language Development Survey and the Parent Report of Children Abilities. At 3 years, children's behavior was assessed using the Child Behavior Checklist. Results: Elevated titers of TPOAbs during pregnancy did not predict the verbal and nonverbal cognitive functioning of the children. However, elevated titers of TPOAbs in mothers were associated with externalizing problems in children (odds ratio [OR]=1.64, 95% confidence interval [CI]: 1.17-2.29, p=0.004). In particular, children of TPOAb-positive mothers were at a higher risk of attention deficit/hyperactivity problems (OR=1.77, 95% CI: 1.15-2.72, p=0.01). To explore whether the effect of maternal TPOAbs on child problem behavior was mediated by maternal thyroid parameters, we added maternal TSH to the model. After correcting for TSH, the effect of TPOAbs on externalizing problems was attenuated slightly but remained significant (OR=1.56, 95% CI: 1.14, 2.14, p=0.005). Conclusions: Our findings imply that the elevated titers of TPOAbs during pregnancy impact children's risk of problem behavior, in particular, attention deficit/hyperactivity. The observed effect is only partially explained by maternal TSH levels. These findings may point to a specific mechanism of Attention Deficit/Hyperactivity Disorder in children. Nevertheless, we can only speculate about public health implication of the study, as there is no specific treatment for TPOAb-positive pregnant women with normal thyroid function. Further investigation is needed to explore whether TPOAb-positive pregnant women and their children can benefit from close monitoring and early detection of developmental delay in populations at risk.

The role of prenatal, perinatal and postnatal factors in the explanation of socioeconomic inequalities in preschool asthma symptoms: The Generation R Study (Article)

2012-01-19T00:00:00Z

Background: The authors assessed whether socioeconomic inequalities in asthma symptoms were already present in preschool children and to what extent prenatal, perinatal and postnatal risk factors for asthma symptoms mediate the effect of socioeconomic status (SES). Methods: The study included 3136 Dutch children participating in the Generation R Study, a prospective cohort study. Adjusted ORs of asthma symptoms for low and middle SES (household income and maternal education) compared to high SES were calculated after adjustment for potential confounders and also adjusted for prenatal, perinatal and postnatal mediators at preschool age. Results: At age 1 year, low-SES children had a 40% lower risk of asthma symptoms compared to high-SES children (p<0.01). However, the risk of asthma symptoms in 3- and 4-year-old low-SES children was 1.5 times higher compared to their high-SES age mates (p<0.05). The positive associations at age 1 year were particularly modified by postnatal factors (up to 38%). In toddlers, prenatal factors explained up to 58% of the negative associations between SES and asthma symptoms. Conclusions: SES indirectly affects asthma symptoms at preschool age. The inverse association between SES and asthma symptoms emerges at age 3 years. This is particularly due to a high level of adverse prenatal circumstances in low-SES toddlers. Future research should evaluate public health programs (during pregnancy) to reduce socioeconomic inequalities in childhood asthma. Copyright Article author (or their employer) 2012.

An observational study on socio-economic and ethnic differences in indicators of sedentary behavior and physical activity in preschool children (Article)

2012-01-01T00:00:00Z

Objective: We studied associations between social disadvantage and indicators of sedentary behavior and physical activity at preschool age. Methods: Data from 4688 children enrolled in a birth cohort in Rotterdam, the Netherlands, between 2002 and 2006 were analyzed. Indicators of sedentary behavior (watching television ≥ 2 h/day and sitting in a buggy ≥ 0.5 h/day) and physical inactivity (playing outside < 3 h/day) were measured by a parent-reported questionnaire at age 3. Adjustments were made for social circumstances and indicators of health behaviors. Logistic regression was used to obtain odds ratios (OR) and 95% confidence intervals (CI). Results: Children with low-educated mothers (OR: 3.27, 95% CI 2.12-5.05) and non-Dutch children (ORnonWestern: 2.67, 95% CI 2.04-3.49, ORWestern: 2.09, 95% CI 1.42-3.0) were more likely to watch television for at least 2h/day. Similar results were seen for sitting in a buggy for at least 0.5h/day. Non western children were more likely to play outside for less than 3h/day (OR: 1.95, 95% CI: 1.39-2.73) than native Dutch children, while no differences were seen for other western children or children from mothers with a low educational level. Conclusions: Socio-economic status and ethnicity are already associated with indicators of sedentary lifestyles at preschool age.

Duration and exclusiveness of breastfeeding and childhood asthma-related symptoms (Article)

2012-01-01T00:00:00Z

The aim of our study was to examine the associations of breastfeeding duration and exclusiveness with the risks of asthma-related symptoms in preschool children, and to explore whether these associations are explained by atopic or infectious mechanisms. This study was embedded in a population-based prospective cohort study of 5,368 children. Information on breastfeeding duration, exclusiveness and asthma-related symptoms, including wheezing, shortness of breath, dry cough and persistent phlegm, was obtained by questionnaires. Compared with children who were breastfed for 6 months, those who were never breastfed had overall increased risks of wheezing, shortness of breath, dry cough and persistent phlegm during the first 4 yrs (OR 1.44 (95% CI 1.24-1.66), 1.26 (1.07-1.48), 1.25 (1.08-1.44) and 1.57 (1.29-1.91), respectively). Similar associations were observed for exclusive breastfeeding. The strongest associations per symptom per year were observed for wheezing at 1 and 2 yrs. Additionally adjusted analyses showed that the associations of breastfeeding with asthma-related symptoms were not explained by eczema but partly by lower respiratory tract infections. Shorter duration and nonexclusivity of breastfeeding were associated with increased risks of asthma-related symptoms in preschool children. These associations seemed, at least partly, to be explained by infectious, but not by atopic, mechanisms. Copyright

Frequent fever episodes and the risk of febrile seizures: The Generation R Study (Article)

2012-01-01T00:00:00Z

Aim: To examine the association between the number of fever episodes and the risk of febrile seizures. Methods: This study was embedded in a population-based prospective cohort study from early foetal life onwards. Information about the occurrence of febrile seizures and fever episodes was collected by questionnaires at the ages of 12, 24 and 36 months. Analyses were based on 3033 subjects. The risk of febrile seizures was compared between children with frequent fever episodes (>2 per year), and children with only 1 or 2 fever episodes per year. Results: The frequency of fever episodes was not associated with the risk of febrile seizures in the age range of 6-12 months. In the second and third year of life, having more than 2 fever episodes was associated with an increased risk of febrile seizures (odds ratios 2.02 [95% confidence interval 1.13-3.62] and 2.29 [95% confidence interval 1.00-5.24], respectively). In the age range between 6 and 36 months, we observed a significant trend between the frequency of fever episodes (<2, 3-4 or >4 per year) and the risk of febrile seizures (p-value for trend < 0.001). The association between the number of fever episodes and the occurrence of febrile seizures was stronger for children with recurrent febrile seizures. Conclusion: Frequent fever episodes are associated with an increased risk of febrile seizures in the second and third years of life. Further studies are needed to identify the mechanisms underlying this association.

Folic acid supplements modify the adverse effects of maternal smoking on fetal growth and neonatal complications (Article)

2011-12-01T00:00:00Z

Maternal smoking during pregnancy leads to increased risks of neonatal complications. The use of folic acid supplements might reduce the adverse effects of smoking. We examined whether folic acid supplement use modifies the associations of maternal smoking with first trimester plasma homocysteine concentrations, fetal growth characteristics, and risks of neonatal complications. The associations were studied in 6294 mothers participating in a prospective population-based cohort study in The Netherlands. Main outcomes measurements were first trimester plasma homocysteine concentrations, fetal growth characteristics, and neonatal complications, including preterm birth, low birth weight, and small-sizefor-gestational-age. Continued maternal smoking was associated with higher first trimester plasma homocysteine concentrations [difference 0.52 μmol/L (95% range = 0.20, 2.14)], lower third trimester fetal weight (difference -44 g (95% CI = -57, -31)], and birth weight [difference -148 g (95% CI = -179, -118)]. There were significant interactions between maternal smoking and folic acid supplements on all outcome measures (all P-interaction <0.040). Among mothers who continued smoking during pregnancy, those who did not use folic acid supplements had the highest risk of delivering a child with low birth weight [OR = 3.45 (95% CI = 1.25, 9.54)] compared to those who did use periconceptional folic acid supplements. No significant effects were observed for the risks of preterm birth and small-size-for-gestationalage at birth. Our results suggest that some adverse effects of maternal smoking on fetal growth and neonatal outcomes might be reduced by the use of folic acid supplements. The observed interaction seems to be mainly driven by smoking in the first trimester only.

Recognition of scared faces and the serotonin transporter gene in young children: The Generation R Study (Article)

2011-12-01T00:00:00Z

Background: Previous research highlights the significance of a functional polymorphism located in the promoter region (5-HTTLPR) of the serotonin transporter gene in emotional behaviour. This study examined the effect of the 5-HTTLPR polymorphism on emotion processing in a large number of healthy preschoolers. Methods: The 5-HTTLPR genotype was classified in 605 children as homozygous for the short allele (SS), homozygous for the long allele (LL), or heterozygous (LS). Emotion-processing was assessed using age-appropriate computer tasks where children matched happy, sad, angry, and fearful facial expressions preceded by a shape-matching task to assess basic matching ability. Results: We found that young children could differentiate between emotion categories (F = 12.1, p <.001). The effect of 5-HTTLPR genotype depended on the emotion category presented (F = 2.3, p =.031). This effect was explained by the finding that SS children were less accurate at recognising fearful faces than LL or LS children (F = 5.3, p =.005). We did not find any significant differences as a result of 5-HTTLPR genotype for happy, sad or angry expressions (p >.05). Conclusions: Results indicate that 5-HTTLPR allele status selectively impacts the processing of fearful but not other facial expressions. This pattern is already apparent in very young typically developing children. Results may signal an early vulnerability for affective problems before disorders emerge.

Dopaminergic, serotonergic, and oxytonergic candidate genes associated with infant attachment security and disorganization? in search of main and interaction effects (Article)

2011-12-01T00:00:00Z

Background and methods: In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems (DRD4, DRD2, COMT, 5-HTT, OXTR) on attachment security and disorganization. Parenting was assessed using observational rating scales for parental sensitivity (Ainsworth, Bell, & Stayton, 1974), and infant attachment was assessed with the Strange Situation Procedure. Results: We found no consistent additive genetic associations for attachment security and attachment disorganization. However, specific tests revealed evidence for a codominant risk model for COMT Val158Met, consistent across both samples. Children with the Val/Met genotype showed higher disorganization scores (combined effect size d =.22, CI =.10-.34, p <.001). Gene-by-environment interaction effects were not replicable across the two samples. Conclusions: This unexpected finding might be explained by a broader range of plasticity in heterozygotes, which may increase susceptibility to environmental influences or to dysregulation of emotional arousal. This study is unique in combining the two largest attachment cohorts with molecular genetic and observed rearing environment data to date.

Individually customised fetal weight charts derived from ultrasound measurements: the Generation R Study (Article)

2011-11-24T00:00:00Z

Maternal and fetal characteristics are important determinants of fetal growth potential, and should ideally be taken into consideration when evaluating fetal growth variation. We developed a model for individually customised growth charts for estimated fetal weight, which takes into account physiological maternal and fetal characteristics known at the start of pregnancy. We used fetal ultrasound data of 8,162 pregnant women participating in the Generation R Study, a prospective, population-based cohort study from early pregnancy onwards. A repeated measurements regression model was constructed, using backward selection procedures for identifying relevant maternal and fetal characteristics. The final model for estimating expected fetal weight included gestational age, fetal sex, parity, ethnicity, maternal age, height and weight. Using this model, we developed individually customised growth charts, and their corresponding standard deviations, for fetal weight from 18 weeks onwards. Of the total of 495 fetuses who were classified as small size for gestational age (<10th percentile) when fetal weight was evaluated using the normal population growth chart, 80 (16%) were in the normal range when individually customised growth charts were used. 550 fetuses were classified as small size for gestational age using individually customised growth charts, and 135 of them (25%) were classified as normal if the unadjusted reference chart was used. In conclusion, this is the first study using ultrasound measurements in a large population-based study to fit a model to construct individually customised growth charts, taking into account physiological maternal and fetal characteristics. These charts might be useful for use in epidemiological studies and in clinical practice.

The health impact of social disadvantage in early childhood; the Generation R study (Article)

2011-11-01T00:00:00Z

Inequalities in child health are of major concern to policymakers, public health specialists and clinicians. This review of studies within the context of the Generation R study illustrates that inequalities in population health, at least partly, originate in pregnancy and early childhood. The review shows inequalities with regard to the health of the pregnant mother, with regard to the growth of the fetus, with regard to birth outcomes, and with regard to health indicators in early childhood. These results are shown with regard to both biological/somatic outcomes, as well as with regard to psychosocial outcomes and healthy lifestyles. Both socioeconomic inequalities and ethnic inequalities in health are present. Although some inequalities can be explained by known determinants, research needs to be done to reach a full understanding of the pathways between social disadvantage and ill health in early childhood.

Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls (Article)

2011-11-01T00:00:00Z

Background: The development of the fetal endocannabinoid receptor system may be vulnerable to maternal cannabis use during pregnancy and may produce long-term consequences in children. In this study, we aimed to determine the relationship between gestational cannabis use and childhood attention problems and aggressive behavior. Methods: Using a large general population birth cohort, we examined the associations between parental prenatal cannabis and tobacco use and childhood behavior problems at 18 months measured using the Child Behavior Checklist in N= 4077 children. Substance use was measured in early pregnancy. Results: Linear regression analyses demonstrated that gestational exposure to cannabis is associated with behavioral problems in early childhood but only in girls and only in the area of increased aggressive behavior (B= 2.02; 95% CI: 0.30-3.73; p= 0.02) and attention problems (B= 1.04; 95% CI: 0.46-1.62; p< 0.001). Furthermore, this study showed that long-term (but not short term) tobacco exposure was associated with behavioral problems in girls (B= 1.16; 95% CI: 0.20-2.12; p= 0.02). There was no association between cannabis use of the father and child behavior problems. Conclusions: Our results suggest that intrauterine exposure to cannabis is associated with an increased risk for aggressive behavior and attention problems as early as 18 months of age in girls, but not boys. Further research is needed to explore the association between prenatal cannabis exposure and child behavior at later ages. Our data support educating future mothers about the risk to their babies should they smoke cannabis during pregnancy.

Dose-response relationship between alcohol consumption before and during pregnancy and the risks of low birthweight, preterm birth and small for gestational age (SGA)-a systematic review and meta-analyses (Article)

2011-11-01T00:00:00Z

Background Descriptions of the effects of moderate alcohol consumption during pregnancy on adverse pregnancy outcomes have been inconsistent. Objective To review systematically and perform meta-analyses on the effect of maternal alcohol exposure on the risk of low birthweight, preterm birth and small for gestational age (SGA). Search strategy Using Medical Subject Headings, a literature search of MEDLINE, EMBASE, CINAHL, CABS, WHOlist, SIGLE, ETOH, and Web of Science between 1 January 1980 and 1 August 2009 was performed followed by manual searches. Selection criteria Case-control or cohort studies were assessed for quality (STROBE), 36 available studies were included. Data collection and analysis Two reviewers independently extracted the information on low birthweight, preterm birth and SGA using a standardised protocol. Meta-analyses on dose-response relationships were performed using linear as well as first-order and second-order fractional polynomial regressions to estimate best fitting curves to the data. Main results Compared with abstainers, the overall dose-response relationships for low birthweight and SGA showed no effect up to 10 g pure alcohol/day (an average of about 1 drink/day) and preterm birth showed no effect up to 18 g pure alcohol/day (an average of 1.5 drinks/day); thereafter, the relationship showed a monotonically increasing risk for increasing maternal alcohol consumption. Moderate consumption during pre-pregnancy was associated with reduced risks for all outcomes. Conclusions Dose-response relationship indicates that heavy alcohol consumption during pregnancy increases the risks of all three outcomes whereas light to moderate alcohol consumption shows no effect. Preventive measures during antenatal consultations should be initiated. © 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology

Is there an association between wheezing and constipation in preschool children? Explanations from a longitudinal birth cohort (Article)

2011-10-11T00:00:00Z

Objective: To assess whether wheezing and atopic dermatitis were associated with constipation in preschool children and to what extent shared risk factors contribute to this relationship. Methods: A population-based sample of 4651 preschool children was used. At the age of 24, 36 and 48 months, a parental report of functional constipation was available according to the Rome II criteria, and data on atopic dermatitis and wheezing were available using age-adapted questionnaires from the International Study of Asthma and Allergies in Childhood. Stepwise multivariate analyses were performed to assess whether body mass index, infection exposure, food allergy and infant nutrition, and parental stress explained the association between wheezing, atopic dermatitis and constipation. Results: Out of 4651 children, 12-17% had functional constipation between 24 and 48 months. Symptoms of wheezing decreased from 20% to 12% and atopic dermatitis decreased from 30% to 18% at the age of 24 and 48 months respectively. Between the age of 24 and 48 months, wheezing symptoms were significantly associated with functional constipation (OR 1.17; 1.02 to 1.34) but these results were mainly explained by the child's exposure to infections and use of antibiotics (adjusted odds ratio 1.08; 95% CI 0.95 to 1.24). No significant association was found between symptoms of atopic dermatitis and functional constipation (OR 1.08; 95% CI 0.94 to 1.23). Conclusions: These findings suggest that functional constipation coexists with wheezing in childhood but is mainly explained by the child's infection exposure and use of antibiotics. Therefore, an independent association between respiratory symptoms and functional bowel disorders as suggested in previous studies is questionable.

Frequent fever episodes and the risk of febrile seizures: The Generation R Study (Article)

2011-10-05T00:00:00Z

The introduction of allergenic foods and the development of reported wheezing and eczema in childhood: The generation R study (Article)

2011-10-01T00:00:00Z

Objective: To examine whether the timing of introduction of the allergenic foods cow's milk, hen's egg, peanuts, tree nuts, soy, and gluten is associated with eczema and wheezing in children 4 years of age or younger. Design: Population-based prospective cohort study from fetal life until young adulthood. Setting: Rotterdam, the Netherlands, from April 2002 through January 2006. Participants: A total of 6905 preschool children participating in the Generation R study. Main Exposure: Timing of introduction of cow's milk, hen's egg, peanuts, tree nuts, soy, and gluten collected by questionnaires at 6 and 12 months of age. Main Outcome Measures: Information on the outcomes eczema and wheezing were obtained by questions from the age-adapted version of the "International Study of Asthma and Allergies in Childhood" core questionnaire and questionnaire data on parentally reported physician diagnosis for eczema. Results: Of 6905 children, wheezing was reported in 31% at age 2 years and in 14% at ages 3 and 4 years. Eczema was reported in 38%, 20%, and 18% of children at the ages of 2, 3, and 4 years, respectively. The introduction of cow's milk, hen's egg, peanuts, tree nuts, soy, and gluten before the age of 6 months was not significantly associated with eczema or wheezing at any age after adjustment for potential confounders (P>.10 for all comparisons). The results did not alter after stratification according to the child's history of cow's milk allergy and parental history of atopy. Conclusion: This study does not support the recommendation for delayed introduction of allergenic foods after age 6 months for the prevention of eczema and wheezing.

Spot the red herring: Breastfeeding, fruitpurée, and infant autonomic functioning-the generation R study (Article)

2011-10-01T00:00:00Z

Several studies have suggested that breastfeeding is related to infant autonomic functioning. The authors investigated whether this is a causal relation. In all, 444 mothers reported breastfeeding practices 2 mo postpartum. Infant autonomic functioning was assessed by heart rate variability at age 14 mo, after discontinuation of breastfeeding. The dose-dependent association between breastfeeding and infant autonomic functioning was tested with linear regression models adjusted for multiple confounders. The authors investigated the relation of fruitpurée consumption with infant autonomic functioning. Fruitpurée consumption has similar socioeconomic epiphenomena but is not related via the same causal mechanism to autonomic regulation as breastfeeding. Nonbreastfed infants had high sympathetic modulation [7.87 log (ms)/SD, 95% CI: 7.71-8.02], partially breastfed infants had intermediate sympathetic modulation [7.75 log (ms)/SD, 95% CI: 7.51-7.82], sympathetic modulation of exclusively breastfed infants was low [7.63 log (ms)/SD, 95% CI: 7.50-7.77]. However, this association could be explained by socioeconomic confounders. Furthermore, fruitpurée consumption was similarly associated with reduced infant sympathetic modulation. The association between breastfeeding practices and infant sympathetic modulation was accounted for by socioeconomic and environmental factors. We found a similar association between fruitpurée consumption and autonomic functioning, further suggesting that the association between breastfeeding and infant autonomic functioning is noncausal. Copyright

Blood pressure in different gestational trimesters, fetal growth, and the risk of adverse birth outcomes (Article)

2011-10-01T00:00:00Z

Researchers have suggested that maternal hypertensive disorders during pregnancy affect fetal growth. The authors examined the associations between systolic and diastolic blood pressures in different trimesters of pregnancy and both repeatedly measured fetal growth characteristics and the risks of adverse birth outcomes. The present study (2001-2005) was performed in 8,623 women who were participating in a population-based prospective cohort study from fetal life onwards. Blood pressure and fetal growth characteristics were assessed in each trimester of pregnancy. Information on hypertensive complications and adverse birth outcomes was obtained from medical records. The results suggested that higher blood pressure was associated with smaller fetal head circumference and femur length, as well as lower fetal weight from the third trimester onward. An increase in blood pressure from the second trimester to the third trimester was associated with an increased risk of adverse birth outcomes. Compared with women who did not experience hypertension during pregnancy, women with preeclampsia had increased risks of having children who were preterm (odds ratio = 5.89, 95% confidence interval: 2.63, 13.14), had a low birth weight (odds ratio = 8.94, 95% confidence interval: 6.19, 12.90), or were small for their gestational age (odds ratio = 5.03, 95% confidence interval: 3.31, 7.62). The present results suggest that higher maternal blood pressure is associated with impaired fetal growth during the third trimester of pregnancy and increased risks of adverse birth outcomes.

The association between parenting and attachment security is moderated by a polymorphism in the mineralocorticoid receptor gene: Evidence for differential susceptibility (Article)

2011-09-01T00:00:00Z

Maternal sensitive responsiveness and extreme insensitivity only partly explain the variance in attachment security. Differences in attachment security may well be rooted in the interplay of genetic variations and environmental factors. The association between parenting (observed sensitive responsiveness and extreme insensitivity) and attachment security (assessed with the Strange Situation Procedure) was hypothesized to be moderated by genes involved in the regulation of the stress response: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) genes. A significant G. × E interaction was found: infants carrying the minor MR allele (G) were significantly more securely attached if their mothers showed more sensitive responsiveness and significantly less securely attached if their mothers showed more extremely insensitive behaviors. These associations were not significant for carriers of the AA genotype of MR. Findings are discussed from a differential susceptibility perspective.

Maternal age during pregnancy is associated with third trimester blood pressure level: The generation R study (Article)

2011-09-01T00:00:00Z

BACKGROUND: We hypothesized that hemodynamic adaptations related to pregnancy and ageing might be associated with differences in blood pressure levels during pregnancy between younger and older women. This might partly explain the increased risk of gestational hypertensive disorders with advanced maternal age. We examined the associations of maternal age with systolic and diastolic blood pressure in each trimester of pregnancy and the risks of gestational hypertensive disorders. METHODS: The study was conducted among 8,623 women participating in a population-based prospective cohort study from early pregnancy onwards. Age was assessed at enrolment. Blood pressure was measured in each trimester. Information about gestational hypertensive disorders was available from medical records. RESULTS: In second and third trimester, older maternal age was associated with lower systolic blood pressure (-0.9mmHg (95% confidence interval: -1.4, -0.3) and -0.6mmHg (95% confidence interval: -1.1, -0.02) per additional 10 maternal years, respectively). Older maternal age was associated with higher third trimester diastolic blood pressure (0.5mmHg (95% confidence interval: 0.04, 0.9) per additional 10 maternal years). Maternal age was associated with pregnancy-induced hypertension among overweight and obese women. CONCLUSION: Older maternal age is associated with lower second and third trimester systolic blood pressure, but higher third trimester diastolic blood pressure. These blood pressure differences seem to be small and within the physiological range. Maternal age is not consistently associated with the risks of gestational hypertensive disorders. Maternal body mass index might influence the association between maternal age and the risk of pregnancy-induced hypertension.

Major dietary patterns and blood pressure patterns during pregnancy: the Generation R Study (Article)

2011-08-18T00:00:00Z

Objective: We sought to evaluate associations between dietary patterns and systolic blood pressure (SBP) and diastolic blood pressure during pregnancy. Study design: This was a prospective study of 3187 pregnant women. Participants completed a food-frequency questionnaire in early pregnancy. The Mediterranean dietary pattern, comprising high intake of vegetables, vegetable oils, pasta, fish, and legumes, and the Traditional dietary pattern, comprising high intake of meat and potatoes, were identified using factor analysis. Results: A higher SBP was observed among mothers with high Traditional pattern adherence. Low adherence to the Mediterranean pattern was also associated with higher SBP but only in early and mid pregnancy. A higher diastolic blood pressure throughout pregnancy was observed in mothers with high adherence to the Traditional pattern and low adherence to the Mediterranean pattern. These effect estimates were most pronounced in mid pregnancy. Conclusion: Low adherence to a Mediterranean and high adherence to a Traditional dietary pattern is associated with a higher blood pressure in pregnancy.

Temporal development of the humoral immune response to surface antigens of Moraxella catarrhalis in young infants (Article)

2011-08-05T00:00:00Z

The primary Moraxella catarrhalis-specific humoral immune response, and its association with nasopharyngeal colonization, was studied in a cohort of infants from birth to 2 years of age.Results indicated that the levels of antigen-specific IgG, IgA and IgM showed extensive inter-individual variability over time, with IgM and IgA levels to all 9 recombinant domains, from 7 different OMPs, being relatively low throughout the study period. In contrast, the level of antigen-specific IgG was significantly higher for the recombinant domains Hag385-863, MID764-913, MID962-1200, UspA1557-704and UspA2165-318in cord blood compared to 6 months of age (P≤0.001). This was a most likely a consequence of maternal transmission of antigen-specific IgG to newborn babies, possibly indicating a future role for these 3 surface antigens in the development of an effective humoral immune response to M. catarrhalis. Finally, at 2 years of age, the levels of antigen-specific IgG still remained far below that obtained from cord blood samples, indicating that the immune response to M. catarrhalis has not matured at 2 years of age.We provide evidence that a humoral antibody response to OMPs UspA1, UspA2 and Hag/MID may play a role in the immune response to community acquired M. catarrhalis colonization events.

Maternal smoking during pregnancy and kidney volume in the offspring: the Generation R Study (Article)

2011-08-01T00:00:00Z

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.

Subcortical structures and the neurobiology of infant attachment disorganization: A longitudinal ultrasound imaging study (Article)

2011-08-01T00:00:00Z

Attachment disorganization in infancy is a risk factor for behavior problems and other psychopathology. Traditionally the role of parental behavior for qualitative differences in early attachment relationships has been emphasized. However, disrupted infant-parent interactions only partly explain attachment disorganization. A complementary focus on child factors such as early differences in the underlying neurobiological systems is needed. We examined whether early structural differences in the gangliothalamic ovoid, comprising the basal ganglia and the thalamus, are involved in the etiology of infant attachment disorganization. Gangliothalamic ovoid diameter was measured by ultrasound in 6-week-old participants of a prospective population-based cohort study. Attachment classification of 629 of these infants was assessed with the strange situation at 14 months of age. Neurobiological differences within the normal range were prospectively associated with attachment disorganization. Infants with a larger gangliothalamic ovoid at 6 weeks had a lower risk of attachment disorganization at 14 months (OR = 0.73 per SD increase in diameter, 95% CI 0.57-0.93, p <.05). Volume of the lateral ventricles as an index of general brain development was not associated with attachment disorganization. These findings provide new insight into the etiology of infant attachment disorganization that may in part be neurodevelopmentally determined.

C-reactive protein levels in early pregnancy, fetal growth patterns, and the risk for neonatal complications: The Generation R Study (Article)

2011-08-01T00:00:00Z

Objective: We sought to examine the associations of maternal C-reactive protein (CRP) levels with fetal growth and the risks of neonatal complications. Study Design: CRP levels were measured in early pregnancy in 6016 women. Main outcome measures were fetal growth in each trimester and neonatal complications. Results: As compared to the reference group (CRP levels <5 mg/L), elevated maternal CRP levels (<25 mg/L) were associated with lower estimated fetal weight in third trimester and lower weight at birth (differences: -29 g, 95% confidence interval [CI], -58 to 0 and -128 g, 95% CI, -195 to -60, respectively). Elevated maternal CRP levels were also associated with an increased risk of a small size for gestational age in the offspring (adjusted odds ratio, 2.94; 95% CI, 1.615.36). Conclusion: Maternal CRP levels in early pregnancy are associated with fetal growth restriction and increased risks of neonatal complications.

Maternal milk consumption, fetal growth, and the risks of neonatal complications: The Generation R Study (Article)

2011-08-01T00:00:00Z

Background: Maternal cow-milk consumption may increase birth weight. Previous studies did not assess the association of maternal milk consumption with trimester-specific fetal growth. Objective: The objective was to assess associations of first-trimester maternal milk consumption with fetal growth characteristics in different trimesters and the risk of neonatal complications. Design: In total, 3405 mothers participating in a prospective cohort study completed a 293-item semiquantitative food-frequency questionnaire to obtain information about dairy consumption during the first trimester of pregnancy. Fetal head circumference, femur length, and weight were estimated in the second and third trimesters by ultrasonography. Results: Maternal milk consumption of >3 glasses/d was associated with greater fetal weight gain in the third trimester of pregnancy, which led to an 88-g (95% CI: 39, 135 g) higher birth weight than that with milk consumption of 0 to 1 glass/d. In addition, head circumference tended to be 2.3 cm (95% CI: -0.0, 4.6 cm) larger when mothers consumed >3 glasses/d. Maternal milk consumption was not associated with length growth. Maternal protein intake (P for trend = 0.01), but not fat or carbohydrate intake, from dairy products was associated with higher birth weight. This association appeared to be limited to milk (P for trend < 0.01), whereas protein intake from nondairy food or cheese was not associated with birth weight. Conclusions: Maternal milk consumption is associated with greater fetal weight gain. The association seems to be due to milk protein, or milk components closely associated with protein, rather than to the fat or carbohydrate fraction of milk.

Exposure to the Chinese famine in early life and the risk of metabolic syndrome in adulthood (Article)

2011-08-01T00:00:00Z

Authors' reply (Article)

2011-08-01T00:00:00Z

Asthma-like symptoms in the first year of life and health-related quality of life at age 12 months: the Generation R study (Article)

2011-07-27T00:00:00Z

Purpose: This study compares HRQOL among subgroups of infants with asthma-like symptoms to a subgroup without such symptoms and examines independent associations between asthma-like symptoms during the first year of life and HRQOL at age 12 months. Methods: Our study sample included 5,000 infants participating in the Generation R study. Their parents completed structured questionnaires to obtain information on asthma-like symptoms, HRQOL, infants', and maternal characteristics. Asthma-like symptoms were defined according to the number of positive answers to 12 items on lower respiratory symptoms. HRQOL was measured using the ITQOL. Higher scores indicated better HRQOL. Results: Infants with asthma-like symptoms had significantly lower HRQOL scores for all ITQOL scales. Among the subgroup with severe symptoms (4% of the infants), relevant deficits in HRQOL were observed for most ITQOL scales, particularly for General Health, Bodily Pain, and Family Activities (effect sizes ≥ 0.8). In multivariate linear models, asthma-like symptoms were independently associated with 6 ITQOL scales. The population attributable risks were especially high for Family Activities, General Health, Parental Emotional, and Parental Time. Conclusions: Asthma-like symptoms during the first year of life are associated with impaired quality of life at age 12 months. At population level, asthma-like symptoms were associated with lower HRQOL, regardless of symptom severity.

Prenatal and postnatal psychological symptoms of parents and family functioning: The impact on child emotional and behavioural problems (Article)

2011-07-01T00:00:00Z

Although relations of various parental psychological problems and family functioning with child development are well documented, it remains unclear whether specific prenatal or specific postnatal risk factors are independently associated with child emotional and behavioural problems, or whether observed associations can be explained by general parental psychopathology. Using a stepwise approach, we examined the effects of prenatal and postnatal parental depressive symptoms, prenatal and postnatal hostility of the parents, as well as prenatal family functioning on the risk of child emotional and behavioural problems. This study was embedded in Generation R: a population-based cohort from foetal life onwards. Mothers and fathers of 2,698 children provided information about depressive symptoms, symptoms of hostility and family functioning during pregnancy and 3 years after birth. Mother and father each reported on child behaviour when the child was 3 years old. Parental depressive symptoms increased the risk of child emotional and behavioural problems, but this increase was explained by postnatal parental hostile behaviour. Postnatal symptoms of hostility of mothers (OR = 1.34, p value <0.001) and postnatal symptoms of hostility of fathers (OR = 1.30, p value <0.001) each contributed independently to the risk of child emotional and behavioural problems. Postnatal parental hostility is associated with an increased risk of child emotional and behavioural problems, independent of parental depressive symptoms. These findings suggest that prevention and intervention strategies should focus on psychological symptoms of both mothers and fathers, in particular on hostile behaviour, in families with young children.

Breast-feeding and growth in children until the age of 3 years: The Generation R Study (Article)

2011-06-14T00:00:00Z

Breast-feeding has been suggested to be associated with lower risks of obesity in older children and adults. We assessed whether the duration and exclusiveness of breast-feeding are associated with early postnatal growth rates and the risks of overweight and obesity in preschool children. The present study was embedded in a population-based prospective cohort study from early fetal life onwards, among 5047 children and their mothers in The Netherlands. Compared with children who were breast-fed, those who were never breast-fed had a lower weight at birth (difference 134 (95 % CI ' 190,' 77) g). No associations between breast-feeding duration and exclusivity with growth rates before the age of 3 months were observed. Shorter breast-feeding duration was associated with an increased gain in age- and sex-adjusted standard deviation scores for length, weight and BMI (P for trend < 0•05) between 3 and 6 months of age. Similar tendencies were observed for the associations of breast-feeding exclusivity with change in length, weight and BMI. Breast-feeding duration and exclusivity were not consistently associated with the risks of overweight and obesity at the ages of 1, 2 and 3 years. In conclusion, shorter breast-feeding duration and exclusivity during the first 6 months tended to be associated with increased growth rates for length, weight and BMI between the age of 3 and 6 months but not with the risks of overweight and obesity until the age of 3 years.

Chlamydia trachomatis infection during pregnancy associated with preterm delivery: A population-based prospective cohort study (Article)

2011-06-01T00:00:00Z

Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and may influence pregnancy outcome. This study was conducted to assess the effect of chlamydial infection during pregnancy on premature delivery and birthweight. Pregnant women attending a participating midwifery practice or antenatal clinic between February 2003 and January 2005 were eligible for the study. From 4,055 women self-administered questionnaires and urine samples, tested by PCR, were analysed for C. trachomatis infection. Pregnancy outcomes were obtained from midwives and hospital registries. Gestational ages and birthweights were analysed for 3,913 newborns. The C. trachomatis prevalence was 3.9%, but varied by age and socio-economic background. Chlamydial infection was, after adjustment for potential confounders, associated with preterm delivery before 32 weeks (OR 4.35 [95% CI 1.3, 15.2]) and 35 weeks gestation (OR 2.66 [95% CI 1.1, 6.5]), but not with low birthweight. Of all deliveries before 32 weeks and 35 weeks gestation 14.9% [95% CI 4.5, 39.5] and 7.4% [95% CI 2.5, 20.1] was attributable to C. trachomatis infection. Chlamydia trachomatis infection contributes significantly to early premature delivery and should be considered a public health problem, especially in young women and others at increased risk of C. trachomatis infection.

Exposure to the Chinese famine in early life and the risk of hypertension in adulthood (Article)

2011-06-01T00:00:00Z

Objectives: Maternal famine exposure has been associated with higher blood pressure in the offspring. The aim of the present study was to examine the associations of early life exposure to the 1959-1961 Chinese famine with the risk of hypertension in later life, and to examine whether a nutritional 'rich' environment in later life modifies this association. Methods: We used data of 7874 adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey. Excess death rate was used to determine the severity of the famine. Results: In severely affected famine areas, as compared to adults who were not exposed to famine, those exposed during fetal life had a significantly higher SBP [SBP difference 2.2 mmHg, 95% confidence interval (CI) 1.3-3.0, P < 0.0001], DBP (DBP difference 0.9 mmHg, 95% CI 0.3-1.5, P = 0.003) and a marginally higher risk of hypertension (odds ratio 1.88, 95% CI 1.00-3.53, P = 0.05), after adjustment of age, sex, socioeconomic status, lifestyle, dietary factors and family history of hypertension, which was not observed in less severely affected famine areas (P for interaction was 0.08 for SBP, 0.03 for DBP and 0.03 for hypertension). These associations were more pronounced in participants who had a western dietary pattern or who were overweight as adult. Conclusion: Our results suggest that fetal famine exposure is associated with higher blood pressure and an increased risk of hypertension in adulthood. These associations are stronger in participants who have a western dietary pattern or who are overweight as adults.

Examining continuity of early expressive vocabulary development: The generation R study (Article)

2011-06-01T00:00:00Z

The authors investigated continuity and discontinuity of vocabulary skills in a population-based cohort in the Netherlands. Mothers of 3,759 children completed the Dutch version of the MacArthur Short Form Vocabulary Checklist (Zink & Lejaegere, 2003) at 18 months and a Dutch translation of the Language Development Survey (Rescorla, 1989) at 30 months. At both ages, expressive vocabulary delay was defined as vocabulary scores <10th age- and gender-specific percentile. Results: Of the children, 85.2% had normal vocabulary development at both ages, 6.2% were "late bloomers," 6.0% had late onset expressive vocabulary delay, and 2.6% had persistent expressive vocabulary delay. Word production and comprehension at 18 months explained 11.5% of the variance in 30-month vocabulary scores, with low birth weight, child age, gender and ethnicity, maternal age and education, and parenting stress explaining an additional 6.2%. Multinomial logistic regression was used to identify biological, demographic, and psychological factors associated with each of the vocabulary delay outcome groups relative to the typically developing group. Although multiple perinatal, demographic, and maternal psychosocial factors significantly predicted vocabulary skills at 30 months, positive predictive value and sensitivity were low. Future studies should address to what extent additional factors, such as brain maturation and genetic influences, can improve the prediction and understanding of continuity and discontinuity of language delay.

Parental family stress during pregnancy and cognitive functioning in early childhood: The Generation R Study (Article)

2011-05-09T00:00:00Z

We investigated whether parental family stress during pregnancy is associated with cognitive functioning in early childhood in a population-based cohort (n= 3139). Family stress was assessed using the Family Assessment Device at the 20th week of pregnancy and was reported by mothers and fathers. Mothers completed the MacArthur Communicative Development Inventory, measuring children's verbal cognitive functioning, when children were 18 months and they completed the Parent Report of Children's Abilities, measuring nonverbal cognitive functioning, when children were 2 years old. Maternal prenatal family stress was related to children's low word comprehension and poorer nonverbal cognitive development independent of paternal reports. In a subset of 639 children, maternal prenatal family stress was also associated with observational assessments of poor effortful control at age 37 months. Paternal prenatal family stress was only related to poorer nonverbal cognitive development, independent of the mother. When both parents had high levels of prenatal family stress, children displayed particularly poor nonverbal cognitive development. These findings emphasize the significance of parental prenatal family stress for child developmental outcomes.

Maternal thyroid function during pregnancy and behavioral problems in the offspring: The generation R study (Article)

2011-05-01T00:00:00Z

Maternal thyroid function during pregnancy is implicated in the neurodevelopment of the offspring, yet little is known about the effect of maternal thyroid parameters on the behavior of children. We investigated the association of maternal thyroid function during the first half of pregnancy with parent-reported problem behavior of the offspring up to age of 3 y. In the Generation R study, a population-based cohort of 3736 children and their mothers, data on maternal thyroid function and child's behavior were examined. The degree of internalizing and externalizing problems in the children were assessed with the Child Behavior Checklist at ages 11/2 and 3 y. Higher levels of maternal TSH during pregnancy predicted a higher externalizing scores in children at 11/2 and 3 y (B = 0.22 per SD of TSH; 95% CI: 0.04, 0.40; B = 0.10 per SD for internalizing scores; 95% CI:-0.01, 0.21). Maternal free thyroxine (T4) and total T4 were not associated with internalizing or externalizing scores of children. The linear relationship with more externalizing scores was across the range of TSH; this implies that subtle impairments of maternal thyroid function may affect the child. The results suggest that thyroid function is crucial for fetal brain development, which determines problem behavior later in life. Copyright

Occupational exposure to endocrine disruptors and time to pregnancy among couples in a large birth cohort study: The Generation R Study (Article)

2011-05-01T00:00:00Z

Objective: To study the influence of occupational exposure to endocrine disruptors (EDs) on time to pregnancy (TTP). Design: Cross-sectional analysis within a prospective, population-based cohort study. Setting: Medical center. Patient(s): Mothers and fathers who filled out a questionnaire during mid-pregnancy (response 77% and 82% of enrollment, respectively) were selected if the pregnancy was planned and either parent performed paid employment. In total, 2,774 mothers and 2,728 partners were included in the statistical analyses. Interventions(s): None. Main Outcome Measure(s): Self-reported TTP (months). Result(s): There was no correlation between maternal and paternal exposure, because κ values for agreement for all exposure categories ranged from 0.03 to 0.13. Paternal occupational exposure to heavy metals (hazard ratio of pregnancy 0.83; 95% confidence interval 0.71-0.97) and overall exposure to EDs (hazard ratio 0.85; 95% confidence interval 0.75-0.96) was statistically significantly associated with an increased TTP. Maternal occupational exposure to all categories of EDs showed prolonged TTP, but the decreased hazard ratios were not statistically significant. Conclusion(s): This birth cohort study provides indications for adverse effects of parental occupational exposure to EDs on TTP.

Variants near CCNL1/LEKR1 and in ADCY5 and fetal growth characteristics in different trimesters (Article)

2011-05-01T00:00:00Z

Context: A recent genome-wide association study identified variants near CCNL1/LEKR1 (rs900400) and in ADCY5 (rs9883204) to be associated with birth weight. We examined the associations of these variants with fetal growth characteristics in different trimesters, with a main interest in the timing of the associations and the affected body proportions. Methods: We used data from two prospective cohort studies from fetal life onward in The Netherlands and Australia. Repeated fetal ultrasound examinations were performed to measure head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW). Analyses were based on a total group of 3909 subjects. Results: The C-allele of rs900400 was associated in second trimester with smaller fetal HC and FL, and in third trimester with smaller HC, AC, FL, and EFW. For each C-allele, the combined effect estimate for EFW in third trimester was - 18.6 g (95% confidence interval, -27.5, -9.7 g; P = 4.2 x 10-5). The C-allele of rs9883204 was not associated with fetal growth characteristics in second trimester but was associated with restriction of all growth characteristics, except HC, in third trimesterandat birth. For each C-allele, thecombinedeffect estimatewas-16.9g(95%confidence interval, -26.8, -7.0 g; P = 8.4 x 10-4) for EFW in third trimester. Both genetic variants were associated with lower birth and placenta weight. Conclusions: Our results suggest that a genetic variant of rs900400 leads to symmetric growth restriction from early pregnancy onward, whereas a genetic variant of rs9883204 leads to asymmetric growth restriction, characterized by a relatively larger HC, from third trimester. Copyright

Growth, obesity, and cardiac structures in early childhood: The generation r study (Article)

2011-05-01T00:00:00Z

Cardiac structural adaptations in response to physical growth and obesity in older children have been identified and might have long-term consequences. We examined the associations of growth and obesity with cardiac structures during the first 2 years of life. In a population-based prospective cohort study among 974 children, left atrial diameter, left ventricular diastolic diameter, left ventricular mass, aortic root diameter, and fractional shortening were repeatedly measured by ultrasound at the ages of 1.5, 6, and 24 months. Height, weight, and subcutaneous fat mass were measured at the same visits, and blood pressure was measured at the age of 24 months. Height, weight, body mass index, and body surface area were positively associated with all of the cardiac structures during the first 2 years of life. At the age of 24 months, as compared with normal weight children, obese children had a greater left ventricular mass (1.04 SD score [95% CI: 0.20 to 1.89]) and a higher fractional shortening (0.91 SD score [95% CI: 0.02 to 1.80]). Nonsignificant tendencies were found for left atrial diameter, left ventricular diastolic diameter, and aortic root diameter. Our results suggest that normal variation in growth affects cardiac structures in early life. Overweight and obese children show cardiac adaptations already at the age of 2 years. Further studies are needed to assess whether these structural adaptations influence the risk of cardiovascular disease in later life.

Associations of maternal obesity with blood pressure and the risks of gestational hypertensive disorders. the Generation R Study (Article)

2011-05-01T00:00:00Z

Objective: We examined the associations of maternal prepregnancy BMI and gestational weight gain with SBP and DBP in different trimesters of pregnancy and the risks of pregnancy-induced hypertension and preeclampsia in a population-based prospective cohort study among 6902 mothers. Methods: Information about maternal weight just before pregnancy was obtained by questionnaires. Maternal anthropometrics and blood pressure were measured in each trimester. Information about gestational hypertensive disorders was available from medical records. Results: As compared to mothers with a normal weight, maternal obesity (BMI 30-34.9 kg/m) and morbid obesity (BMI â‰1 35 kg/m) were associated with higher first trimester SBP [differences for obese women and morbidly obese women: 10.80 mmHg (95% confidence interval: 9.44-12.17) and 13.07 mmHg (95% confidence interval: 10.91-15.23), respectively] and DBP [differences for obese women and morbidly obese women: 8.69 mmHg (95% confidence interval: 7.63-9.74) and 13.12 mmHg (95% confidence interval: 11.44-14.79), respectively]. Similar differences were observed during second and third trimester. The risks of pregnancy-induced hypertension and preeclampsia were increased among obese mothers [odds ratio 4.67 (95% confidence interval: 3.07-7.09) and odds ratio 2.49 (95% confidence interval: 1.29-4.78), respectively] and morbidly obese mothers [odds ratio 11.34 (95% confidence interval: 6.80-18.86) and odds ratio 3.40 (95% confidence interval: 1.39-8.28), respectively]. Maternal weight gain was associated with the risk of pregnancy-induced hypertension. Conclusion: Maternal obesity and morbid obesity are strongly associated with blood pressure in each trimester, and increased risks of gestational hypertensive disorders.

Maternal smoking during pregnancy, fetal arterial resistance adaptations and cardiovascular function in childhood (Article)

2011-05-01T00:00:00Z

Objective 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. Setting Academic hospital. Population Analyses were based on 1120 children aged 2 years. Methods Maternal smoking during pregnancy [non-smoking, first trimester smoking, continued smoking (<5 and ≥5 cigarettes/day)] was assessed by questionnaire. Main outcome measures 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. Results 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. Conclusions 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.

Cortisol diurnal rhythm and stress reactivity in constipation and abdominal pain: The generation R study (Article)

2011-04-16T00:00:00Z

OBJECTIVES: The aim of this study was to assess whether diurnal cortisol rhythm and cortisol stress reactivity were associated with functional constipation and abdominal pain in infancy. METHODS: This study was embedded in a subset of the Generation R Study, a prospective cohort study from fetal life onwards in Rotterdam, The Netherlands. Data of infants between 14 and 24 months of age (N = 483) were used. Salivary cortisol diurnal rhythm and salivary cortisol stress reactivity after a Strange Situation Procedure were assessed at the age of 14 months. Data on functional constipation was available according to the ROME II criteria and data on abdominal pain on the basis of the Abdominal Pain Index were available from questionnaire data at 24 months. RESULTS: In the second year of life, 13% of the infants had functional constipation and 17% had abdominal pain. Only 4% had symptoms of both functional constipation and abdominal pain. Diurnal cortisol rhythm did not differ significantly between children with and those without functional constipation and abdominal pain. Cortisol stress reactivity was slightly higher in infants with abdominal pain than those without it but this was not statistically significant (OR: 1.41; 95%CI: 0.46-4.31). No association was found between the cortisol stress reactivity and functional constipation. CONCLUSIONS: Our results suggest that cortisol as a marker for stress does not play a major role in functional constipation or abdominal pain in infancy.

The influence of attachment and temperament on venipuncture distress in 14-month-old infants: The Generation R Study (Article)

2011-04-01T00:00:00Z

Objective: This study examined the effects of attachment and temperament on infant distress during venipuncture. Method: The study was embedded in the Generation R Study, a prospective population-based study. Two different research procedures (i.e., blood sampling and the Ainsworth Strange Situation Procedure) yielded measures of venipuncture distress and attachment security and disorganization in 246 infants aged 14 months. Four temperament traits (distress to limitations, fear, recovery from distress, and sadness) were assessed using the maternally reported Infant Behavior Questionnaire - Revised, at the age of 6 months. Results: There were no differences between mean levels of distress during venipuncture in infants classified as having insecure attachment, but there was a trend for disorganized attachment. The temperament traits were not related to distress. However, children with a disorganized attachment and higher temperamental fear had more venipuncture distress. Conclusion: When different risk factors are present simultaneously, infant distress is heightened.

Maternal smoking during pregnancy and subcutaneous fat mass in early childhood. The Generation R Study (Article)

2011-04-01T00:00:00Z

Maternal smoking during pregnancy increases the risk of obesity in the offspring. Not much is known about the associations with other measures of body composition. We assessed the associations of maternal smoking during pregnancy with the development of subcutaneous fat mass measured as peripheral and central skinfold thickness measurements in early childhood, in a population-based prospective cohort study from early fetal life onward in the city of Rotterdam, The Netherlands. The study was performed in 907 mothers and their children at the ages of 1.5, 6 and 24 months. As compared to non-smoking mothers, mothers who continued smoking during pregnancy were more likely to have a younger age and a lower educational level. Their children had a lower birth weight, higher risk of small size for gestational age and were breastfed for a shorter duration (P-values <0.01). We did not observe differences in peripheral, central and total subcutaneous fat mass between the offspring of non-smoking mothers, mothers who smoked in first trimester only and mothers who continued smoking during pregnancy (P > 0.05). Also, the reported number of cigarettes smoked by mothers in both first and third trimester of pregnancy were not associated with peripheral, central and total subcutaneous fat mass in the offspring at the ages of 1.5, 6 and 24 months. Our findings suggest that fetal exposure to cigarette smoke during pregnancy does not influence subcutaneous fat mass in early childhood. Follow-up studies are needed in children at older ages and to identify associations of maternal smoking during pregnancy with other measures of body composition.

Recognition of facial expressions of emotions by 3-year-olds (Article)

2011-04-01T00:00:00Z

Very few large-scale studies have focused on emotional facial expression recognition (FER) in 3-year-olds, an age of rapid social and language development. We studied FER in 808 healthy 3-year-olds using verbal and nonverbal computerized tasks for four basic emotions (happiness, sadness, anger, and fear). Three-year-olds showed differential performance on the verbal and nonverbal FER tasks, especially with respect to fear. That is to say, fear was one of the most accurately recognized facial expressions as matched nonverbally and the least accurately recognized facial expression as labeled verbally. Sex did not influence emotion-matching nor emotion-labeling performance after adjusting for basic matching or labeling ability. Three-year-olds made systematic errors in emotion-labeling. Namely, happy expressions were often confused with fearful expressions, whereas negative expressions were often confused with other negative expressions. Together, these findings suggest that 3-year-olds' FER skills strongly depend on task specifications. Importantly, fear was the most sensitive facial expression in this regard. Finally, in line with previous studies, we found that recognized emotion categories are initially broad, including emotions of the same valence, as reflected in the nonrandom errors of 3-year-olds.

Does disturbed sleeping precede symptoms of anxiety or depression in toddlers? the Generation R study (Article)

2011-04-01T00:00:00Z

OBJECTIVE: To examine whether sleep problems in infancy and early toddlerhood precede symptoms of anxiety or depression at 3 years. METHODS: Data on specific sleep problems at 2 months and 24 months were available for 4,782 children participating in a population-based cohort in The Netherlands. The Child Behavior Checklist for toddlers containing the Anxious/Depressed syndrome scale was assessed at 36 months. We adjusted the logistic regression analyses for several confounding factors; the analyses with sleep problems at 24 months were additionally adjusted for preexisting anxiety or depressive symptoms (at 18 months). RESULTS: Dyssomnia and parental presence during sleep onset at 2 months and 24 months were associated with anxiety or depressive symptoms at 3 years (e.g., parental presence: odds ratio2 months, 1.22; 95% confidence interval, 1.04-1.44; odds ratio24months, 1.58; 95% confidence interval, 1.30-1.92). Parasomnia, short sleep duration, and absence of set bedtime at 24 months, but not at 2 months, also preceded anxiety or depressive symptoms. These significant associations were not due to children's anxiety or depressive symptoms at 18 months. Rhythmicity and co-sleeping were not associated with later anxiety or depressive symptoms. Additional analyses provided little evidence for a bidirectional association with anxiety or depressive symptoms preceding later sleep problems. CONCLUSIONS: Our findings highlight the importance of sleep problems early in life, because different sleep problems are associated with the frequency of anxiety or depressive symptoms. Therefore, healthcare practitioners must be particularly attentive to these problems in young children. Future research should address possible mechanisms underlying the association between disturbed sleeping and anxiety or depressive symptoms. Copyright

Natural antibodies against several pneumococcal virulence proteins in children during the pre-pneumococcal-vaccine era: The generation R study (Article)

2011-04-01T00:00:00Z

The currently available pneumococcal vaccines do not protect against all serotypes of Streptococcus pneumoniae. A shift toward nonvaccine serotypes causing colonization and invasive disease has occurred, and studies on protein-based vaccines have been undertaken. We assessed the association between specific antibodies against pneumococcal virulence proteins and colonization and respiratory tract infections (RTIs). Additionally, we assessed the extent to which colonization induces a humoral immune response. Nasopharyngeal swabs collected from children at 1.5, 6, 14, and 24 months of age were cultured for pneumococcus. Serum samples were obtained at birth and at 6, 14, and 24 months (n = 57 children providing 177 serum samples). Data were collected prior to the pneumococcal vaccine era. IgG, IgA, and IgM levels against 17 pneumococcal protein vaccine candidates were measured using a bead-based flow cytometry technique (xMAP; Luminex Corporation). Information regarding RTIs was questionnaire derived. Levels of IgG against all proteins were high in cord blood, decreased in the first 6 months and increased again thereafter, in contrast to the course of IgA and IgM levels. Specific antibodies were induced upon colonization. Increased levels of IgG against BVH-3, NanA, and SP1003 at 6 months, NanA, PpmA, PsaA, SlrA, SP0189, and SP1003 at 14 months, and SlrA at 24 months were associated with a decreased number of RTIs in the third year of life but not with colonization. Maternal antipneumococcal antibodies did not protect against pneumococcal colonization and infection. Certain antibodies against pneumococcal virulence proteins, some of which are induced by colonization, are associated with a decreased number of RTIs in children. This should be taken into account in future pneumococcal vaccine studies.

Exposure to the Chinese famine in early life and the risk of metabolic syndrome in adulthood (Article)

2011-04-01T00:00:00Z

OBJECTIVE - To examine whether exposure to the Chinese famine during fetal life and early childhood is associated with the risks of metabolic syndrome and whether this association is modified by later life environment. RESEARCH DESIGN AND METHODS - We used data of 7,874 adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey. Famine exposure groups were defined as nonexposed; fetal exposed; and early childhood, midchildhood, or late childhood exposed. Excess death rate was used to determine the severity of the famine. The ATP III criteria were used for the definition of metabolic syndrome (three or more of the following variables: elevated fasting triglyceride levels, lower HDL cholesterol levels, elevated fasting glucose levels, higher waist circumference, high blood pressure). RESULTS - In severely affected famine areas, adults who were exposed to the famine during fetal life had a higher risk of metabolic syndrome, as compared with nonexposed subjects (odds ratio 3.13 [95%CI 1.24-7.89, P = 0.016]). Similar associations were observed among adults who were exposed to the famine during early childhood, but not for adults exposed to the famine during mid- or late childhood. Participants who were born in severely affected famine areas and had Western dietary habits in adulthood or were overweight in adulthood had a particularly high risk of metabolic syndrome in later life. CONCLUSIONS - Exposure to the Chinese famine during fetal life or infancy is associated with an increased risk of metabolic syndrome in adulthood. These associations are stronger among subjects with a Western dietary pattern or who were overweight in adulthood.

Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality (Article)

2011-03-15T00:00:00Z

Background: Consistent with the fetal programming hypothesis, effects of maternal prenatal anxiety have been found to predict various measures of infant temperament in the early postnatal period. In recent years, a polymorphism in the serotonin transporter gene (5-HTTLPR) emerged as a moderator of diverse environmental influences on different outcomes, with individuals carrying the short allele being generally more vulnerable to adversity. Methods: We tested whether the association between self-reported maternal anxiety at 20 weeks gestation (Brief Symptom Inventory) and mother-rated infant negative emotionality at 6 months after birth (Infant Behavior Questionnaire-Revised) would be moderated by the 5-HTTLPR in a large Dutch cohort sample (n = 1513). We hypothesized that infants carrying the 5-HTTLPR short allele would be more susceptible and therefore more affected by both low and high prenatal maternal anxiety vis-à-vis negative emotionality than other genotypes. Results: Findings of a significant gene X environment interaction (B = .65, p = .01) were supportive of a vulnerability model, with infants carrying the short allele being more negatively emotional when mothers reported anxiety during pregnancy, whereas there was no difference between genotypes on negative emotionality when maternal anxiety was low. Conclusions: The association between maternal anxiety during pregnancy and negative emotionality in early infancy was significant in infants carrying one or more copies of the short allele but not in those homozygous for the long allele. The 5-HTTLPR short allele might increase vulnerability to adverse environmental influences as early as the fetal period.

Explaining differences in birth outcomes in relation to maternal age: The generation R study (Article)

2011-03-01T00:00:00Z

Please cite this paper as: Bakker R, Steegers E, Biharie A, Mackenbach J, Hofman A, Jaddoe V. Explaining differences in birth outcomes in relation to maternal age: the Generation R Study. BJOG 2011;118:500-509. Objective To examine the association between maternal age and birth outcomes, and to investigate the role of sociodemographic and lifestyle-related determinants. Design Population-based prospective cohort study from early pregnancy onwards. Setting Rotterdam, the Netherlands. Population A cohort of 8568 mothers and their children. Methods Maternal age was assessed at enrolment. Information about sociodemographic (height, weight, educational level, ethnicity, parity) and lifestyle-related determinants (alcohol consumption, smoking habits, folic acid supplement use, caffeine intake, daily energy intake) and birth outcomes was obtained from questionnaires and hospital records. Multivariate linear and logistic regression analyses were used. Main outcomes measures Birthweight, preterm delivery, small-for-gestational-age, and large-for-gestational-age. Results As compared with mothers aged 30-34.9 years, no differences in risk of preterm delivery were found. Mothers younger than 20 years had the highest risk of delivering small-for-gestational-age babies(OR 1.6, 95% CI: 1.1-2.5); however, this increased risk disappeared after adjustment for sociodemographic and lifestyle-related determinants. Mothers older than 40 years had the highest risk of delivering large-for-gestational-age babies (OR 1.3, 95% CI: 0.8-2.4). The associations of maternal age with the risks of delivering large-for-gestational-age babies could not be explained by sociodemographic and lifestyle-related determinants. Conclusions As compared with mothers aged 30-34.9 years, younger mothers have an increased risk of small-for-gestational- age babies, whereas older mothers have an increased risk of large-for- gestational-age babies. Sociodemographic and lifestyle-related determinants cannot fully explain these differences.

The effects of work-related maternal risk factors on time to pregnancy, preterm birth and birth weight: The seneration R study (Article)

2011-03-01T00:00:00Z

Objective: To investigate the influence of maternal working conditions on fertility and pregnancy outcomes. Methods: 8880 women were enrolled in a large prospective birth cohort during early (76%), mid (21%) or late pregnancy (3%) (61% participation). Complete questionnaire information was available for 6302 women (71% response). Outcomes were prolonged time to pregnancy (TTP) (>6 months), preterm birth (<37 weeks) and decreased birth weight (<3000 g). Self-reported exposure to chemical agents was based on a limited list of chemicals. Physical load questions concerned manual materials handling, prolonged sitting and long periods of standing. A job-exposure matrix (JEM) linked reported job title to workplace chemical exposure within jobs according to expert judgement. Associations between maternal occupational exposure and fertility and pregnancy outcomes, adjusted for age, education, minority, parity, smoking and alcohol use, were studied using logistic regression analysis. Results: Women in jobs with regular handling of loads ≥5 kg had better fertility and pregnancy outcomes. No self-reported exposure to chemicals was associated with any outcomes and self-assessments had very low reliability compared with JEM-based assessments. JEM-based maternal occupational exposure to phthalates was associated with prolonged TTP (OR 2.16, 95% CI 1.02 to 4.57) and exposure to pesticides was associated with decreased birth weight (OR 2.42, 95% CI 1.10 to 5.34). The population attributable fractions were small at 0.7% for phthalates and 0.7% for pesticides. Conclusion: This birth cohort study presents evidence of health-based selection into the workforce and adverse effects of maternal occupational exposure to phthalates and pesticides on fertility and pregnancy outcomes.

Air pollution, blood pressure, and the risk of hypertensive complications during pregnancy: The generation r study (Article)

2011-03-01T00:00:00Z

Exposure to air pollution is associated with elevated blood pressure and cardiovascular disease. We assessed the associations of exposure to particulate matter (PM10) and nitrogen dioxide (NO2) levels with blood pressure measured in each trimester of pregnancy and the risks of pregnancy-induced hypertension and preeclampsia in 7006 women participating in a prospective cohort study in the Netherlands. Information on gestational hypertensive disorders was obtained from medical records. PM10 exposure was not associated with first trimester systolic and diastolic blood pressure, but a 10-μg/m increase in PM10 levels was associated with a 1.11-mm Hg (95% confidence interval [CI] 0.43 to 1.79) and 2.11-mm Hg (95% CI 1.34 to 2.89) increase in systolic blood pressure in the second and third trimester, respectively. Longitudinal analyses showed that elevated PM10 exposure levels were associated with a steeper increase in systolic blood pressure throughout pregnancy (P<0.01), but not with diastolic blood pressure patterns. Elevated NO2exposure was associated with higher systolic blood pressure levels in the first, second, and third trimester (P<0.05), and with a more gradual increase when analyzed longitudinally (P<0.01). PM10 exposure, but not NO2exposure, was associated with an increased risk of pregnancy-induced hypertension (odds ratio 1.72 [95% CI 1.12 to 2.63] per 10-μg/m increase). In conclusion, our results suggest that air pollution may affect maternal cardiovascular health during pregnancy. The effects might be small but relevant on a population level.

Glucocorticoid receptor-9beta polymorphism is associated with systolic blood pressure and heart growth during early childhood. The Generation R Study (Article)

2011-02-01T00:00:00Z

Background: Glucocorticoid receptor-9β polymorphism (rs6198) is associated with the susceptibility for cardiovascular disease. Aim: To examine whether the GR-9β variant is also associated with blood pressure and heart growth in early childhood. Study design: This study was embedded in a population-based prospective cohort study from fetal life onwards. Analyses were based on 857 children. Outcome measures: 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. Results: 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 mm. Hg (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-9β polymorphism was significantly associated with left ventricular mass growth during the first 2 years. Conclusion: Our findings suggest that genetically determined differences in cortisol exposure affect cardiovascular development in early life.

Ethnic differences in antenatal care use in a large multi-ethnic urban population in the Netherlands (Article)

2011-02-01T00:00:00Z

Objective: to determine differences in antenatal care use between the native population and different ethnic minority groups in the Netherlands. Design: the Generation R Study is a multi-ethnic population-based prospective cohort study. Setting: seven midwife practices participating in the Generation R Study conducted in the city of Rotterdam. Participants: in total 2093 pregnant women with a Dutch, Moroccan, Turkish, Cape Verdean, Antillean, Surinamese-Creole and Surinamese-Hindustani background were included in this study. Measurements: to assess adequate antenatal care use, we constructed an index, including two indicators; gestational age at first visit and total number of antenatal care visits.Logistic regression analysis was used to assess differences in adequate antenatal care use between different ethnic groups and a Dutch reference group, taking into account differences in maternal age, gravidity and parity. Findings: overall, the percentages of women making adequate use are higher in nulliparae than in multiparae, except in Dutch women where no differences are present.Except for the Surinamese-Hindustani, all women from ethnic minority groups make less adequate use as compared to the native Dutch women, especially because of late entry in antenatal care. When taking into account potential explanatory factors such as maternal age, gravidity and parity, differences remain significant, except for Cape-Verdian women. Dutch-Antillean, Moroccan and Surinamese-Creole women exhibit most inadequate use of antenatal care. Key conclusions: this study shows that there are ethnic differences in the frequency of adequate use of antenatal care, which cannot be attributed to differences in maternal age, gravidity and parity. Future research is necessary to investigate whether these differences can be explained by socio-economic and cultural factors. Implications for practise: clinicians should inform primiparous women, and especially those from ethnic minority groups, on the importance of timely antenatal care entry.

Individual accumulation of heterogeneous risks explains perinatal inequalities within deprived neighbourhoods (Article)

2011-02-01T00:00:00Z

Dutch' figures on perinatal mortality and morbidity are poor compared to EU-standards. Considerable within-country differences have been reported too, with decreased perinatal health in deprived urban areas. We investigated associations between perinatal risk factors and adverse perinatal outcomes in 7,359 pregnant women participating in population-based prospective cohort study, to establish the independent role, if any, for living within a deprived urban neighbourhood. Main outcome measures included perinatal death, intrauterine growth restriction (IUGR), prematurity, congenital malformations, Apgar at 5 min < 7, and pre-eclampsia. Information regarding individual risk factors was obtained from questionnaires, physical examinations, ultrasounds, biological samples, and medical records. The dichotomous Dutch deprivation indicator was additionally used to test for unexplained deprived urban area effects. Pregnancies from a deprived neighbourhood had an increased risk for perinatal death (RR 1.8, 95% CI [1.1; 3.1]). IUGR, prematurity, Apgar at 5 min < 7, and pre-eclampsia also showed higher prevalences (P < 0.05). Residing within a deprived neighbourhood was associated with increased prevalence of all measured risk factors. Regression analysis showed that the observed neighbourhood related differences in perinatal outcomes could be attributed to the increased risk factor prevalence only, without a separated role for living within a deprived neighbourhood. Women from a deprived neighbourhood had significantly more 'possibly avoidable' risk factors. To conclude, women from a socioeconomically deprived neighbourhood are at an increased risk for adverse pregnancy outcomes. Differences regarding possibly avoidable risk factors imply that preventive strategies may prove effective.

Foetal and postnatal growth and bone mass at 6 months: The Generation R Study (Article)

2011-02-01T00:00:00Z

Objective To examine whether parental, foetal and postnatal characteristics and growth patterns in foetal life and infancy are associated with bone mass at 6 months, as bone acquisition seems to be associated with genetic and environmental factors. Design This study was embedded in the Generation R Study, a prospective cohort from early foetal life onwards. Patients and measurements Bone mineral density (BMD) and bone mineral content (BMC) total body (TB) and BMD lumbar spine (LS) were measured by dual-energy X-ray absorptiometry in 252 infants at 6 months. Parental, foetal and postnatal data were collected by physical and foetal ultrasound examinations and questionnaires. Results Maternal, foetal and postnatal anthropometrics were positively associated with BMDTBand BMCTBat 6 months, but only postnatal anthropometrics were associated with BMDLS. A gain in weight-SD-score during foetal life and prenatal catch-up in weight were positively associated with BMDTB. After birth, a gain in weight-SD-score was positively associated with BMDLSand bone mineral apparent density (BMADLS). The effect was strongest between 6 weeks and 6 months. Catch-up in weight was associated with a lower probability of low (lowest quartile of) BMDTBand BMDLS. Children remaining in the first tertile of weight from birth to 6 months had a much higher risk of low BMDTBat 6 months [OR (95% CI): 15 (2, 88)]. Conclusions Our findings suggest that growth patterns in foetal and postnatal life are associated with bone mass in infancy and may have consequences for bone mass in later life. Follow-up studies are needed to assess whether and to what extent maternal anthropometrics, foetal and postnatal growth patterns have an effect on bone status in adulthood.

Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: The complex nature of genetic association through growth and development (Article)

2011-02-01T00:00:00Z

An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10-20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10-23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (-0.40% (95% CI: -0.74, -0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (-4.72% (-5.81, -3.63), p = 10-17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

Low autonomic arousal as vulnerability to externalising behaviour in infants with hostile mothers (Article)

2011-01-30T00:00:00Z

Maternal psychopathology and the child's autonomic nervous system functioning are risk factors for aggressive behaviour later in life. While research has shown that maternal psychopathology already affects young children, less is known about the association between autonomic functioning and aggressive behaviour in young children. In addition, maternal psychopathology and autonomic nervous system functioning may interact to determine the risk of aggressive behaviour.In a sample of 375 infants and their mothers, maternal psychiatric symptoms were assessed with the Brief Symptom Inventory and toddler aggressive behaviour with the Child Behaviour Checklist. Infant heart rate was recorded at 14. months.Maternal psychiatric problems, including hostility and depression, were associated with toddler aggressive behaviour. Maternal psychiatric problems interacted with mean heart rate (P= 0.01) and HF variability (P= 0.03) in their effect on toddler aggressive behaviour.Mothers with high psychiatric problems, in particular, high hostility, were more likely to have toddlers with high aggressive behaviour. Moreover, in the presence of maternal risk factors, low autonomic arousal renders children particularly susceptible to aggressive behaviour.

Risk factors for otitis media in children with special emphasis on the role of colonization with bacterial airway pathogens: The Generation R study (Article)

2011-01-01T00:00:00Z

Acute otitis media is the most frequent diagnosis in children visiting physicians' offices. Risk factors for otitis media have been widely studied. Yet, the correlation between bacterial carriage and the development of otitis media is not entirely clear. Our aim was to study in a population-based prospective cohort the risk factors for otitis media in the second year of life with special emphasis on the role of colonization with Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. The study was embedded in the Generation R Study. Data on risk factors and doctor-diagnosed otitis media were obtained by midwives, hospital registries and postal questionnaires in the whole cohort (n = 7,295). Nasopharyngeal swabs were obtained at the age of 1.5, 6 and 14 months in the focus cohort (n = 1,079). Of these children, 2,515 (47.2%) suffered at least one period of otitis media in their second year of life. The occurrence of otitis media during the follow-up period in the first 6 months of life and between 6 and 12 months of age was associated with the risk of otitis media in the second year of life (aOR, 1.83 95% CI 1.24-2.71 and aOR 2.72, 95% CI 2.18-3.38, respectively). Having siblings was associated with an increased risk for otitis media in the second year of life (aOR 1.42, 95% CI 1.13-1.79). No associations were found between bacterial carriage in the first year of life and otitis media in the second year of life. In our study, otitis media in the first year of life is an independent risk factor for otitis media in the second year of life. Surprisingly, bacterial carriage in the first year of life did not add to this risk. Moreover, no association was observed between bacterial carriage in the first year of life and otitis in the second year of life.

Intrauterine effects of maternal prepregnancy overweight on child cognition and behavior in 2 cohorts (Article)

2011-01-01T00:00:00Z

OBJECTIVE: Greater maternal prepregnancy adiposity has been associated with behavioral problems, such as attention-deficit/hyperactivity disorder, and lower intellectual function in offspring. However, few studies of humans have explored this, and it is unclear if intrauterine mechanisms or confounding factors drive these associations. PATIENTS AND METHODS: Parental adiposity and offspring verbal skills, nonverbal skills, and behavioral problems were assessed in the British Avon Longitudinal Study of Parents and Children (N = ∼5000) and Dutch Generation R (N = ∼2500) cohorts. We aimed to determine the plausibility of intrauterine effects by (1) adjusting for multiple confounders, (2) comparing associations between maternal and paternal overweight with offspring cognition/behaviors, and (3) searching for cross-cohort consistency. RESULTS: Maternal prepregnancy overweight was associated with reduced child verbal skills (unadjusted). However, after adjusting for confounders, this result was not consistently observed in both cohorts. Maternal overweight was also associated with child total behavior problems and externalizing problems even after adjusting for confounders. However, this was observed in Generation R only and was not replicated in the British Avon Longitudinal Study of Parents and Children. No associations of maternal overweight with child attention problems, emotional/internalizing problems, or nonverbal skills were observed in either cohort. Paternal overweight was not associated with any of the child outcomes but was also less strongly related to potential confounding factors than was maternal overweight. CONCLUSIONS: Overall, we found little consistent evidence of intrauterine effects of maternal prepregnancy overweight on child cognition and behavior. Some associations initially observed were not consistently replicated across cohorts or robust to adjustment for confounding factors and, thus, are likely to reflect confounding by socioeconomic or postnatal factors. Copyright

Colonization of healthy children by Moraxella catarrhalis is characterized by genotype heterogeneity, virulence gene diversity and co-colonization with Haemophilus influenzae (Article)

2011-01-01T00:00:00Z

The colonization dynamics of Moraxella catarrhalis were studied in a population comprising 1079 healthy children living in Rotterdam, The Netherlands (the Generation R Focus cohort). A total of 2751 nasal swabs were obtained during four clinic visits timed to take place at 1.5, 6, 14 and 24 months of age, yielding a total of 709 M. catarrhalis and 621 Haemophilus influenzae isolates. Between January 2004 and December 2006, approximate but regular 6-monthly cycles of colonization were observed, with peak colonization incidences occurring in the autumn/winter for M. catarrhalis, and winter/spring for H. influenzae. Co-colonization was significantly more likely than single-species colonization with either M. catarrhalis or H. influenzae, with genotypic analysis revealing no clonality for co-colonizing or single colonizers of either bacterial species. This finding is especially relevant considering the recent discovery of the importance of H. influenzae-M. catarrhalis quorum sensing in biofilm formation and host clearance. Bacterial genotype heterogeneity was maintained over the 3-year period of the study, even within this relatively localized geographical region, and there was no association of genotypes with either season or year of isolation. Furthermore, chronological and genotypic diversity in three immunologically important M. catarrhalis virulence genes (uspA1, uspA2 and hag/mid) was also observed. This study indicates that genotypic variation is a key factor contributing to the success of M. catarrhalis colonization of healthy children in the first years of life. Furthermore, variation in immunologically relevant virulence genes within colonizing populations, and even within genotypically identical M. catarrhalis isolates, may be a result of immune evasion by this pathogen. Finally, the factors facilitating M. catarrhalis and H. influenzae co-colonization need to be further investigated.

The inverse correlation between Staphylococcus aureus and Streptococcus pneumoniae colonization in infants is not explained by differences in serum antibody levels in the generation R study (Article)

2011-01-01T00:00:00Z

Colonization rates of Streptococcus pneumoniae and Staphylococcus aureus are inversely correlated in infants. Several studies have searched for determinants of this negative association. We studied the association between antipneumococcal antibodies with Staphylococcus aureus colonization and the association between antistaphylococcal antibodies with pneumococcal colonization in healthy children in the pneumococcal vaccine era. In the first year of life, no association between maternal IgG levels and colonization was seen. In addition, no association between the IgG and IgA levels in the child versus colonization status was seen. Copyright

Socioeconomic Status is not Inversely Associated with Overweight in Preschool Children (Article)

2010-12-01T00:00:00Z

Objective: To assess whether socioeconomic inequalities were already present in preschool children. Study design: We used data from 2954 Dutch children participating in a longitudinal birth cohort study. Indicators of socioeconomic status were mother's educational level and household income. Body mass index (BMI)-for-age standard deviation scores were derived from a national reference. Overweight was defined at 24 and 36 months according to age- and sex-specific cut-off points for BMI. Multivariable regression analyses were performed. Results: Relative to children from mothers with the highest educational level, mean BMI standard deviation scores was lower at age 24 months in children from mothers with the low, mid-low, and mid-high educational level, and in the mid-low group at 36 months (P < .001). Prevalence of overweight was lower in children from mothers with the mid-low educational level at age 24 and 36 months (adjusted odds ratio at 24 months: 0.61; 95% confidence interval: 0.43-0.87 and at 36 months: 0.65; 95% confidence interval: 0.44-0.96) but was not significantly different for the other educational levels. There were no significant differences in childhood overweight by income level. Conclusions: The inverse association between socioeconomic status and childhood overweight presumably emerges after age 3 years. Before this age, the gradient may be the reverse.

Breastfeeding patterns among ethnic minorities: The Generation R Study (Article)

2010-12-01T00:00:00Z

Background Because breastfeeding is the best method of infant feeding, groups at risk of low breastfeeding rates should be identified. Therefore, this study compared breastfeeding patterns of ethnic minority groups in The Netherlands with those of native mothers and established how they were influenced by generational status and socio-demographic determinants of breastfeeding. Methods We used data on 2914 Dutch, 366 Mediterranean first-generation, 143 Mediterranean second-generation, 285 Caribbean first-generation and 140 Caribbean second-generation mothers. Information on starting breastfeeding and breastfeeding at 2 and 6 months after birth were obtained from questionnaires during the first year after birth. Results Overall, 90.6% of women started breastfeeding after delivery. This percentage was lowest among the native Dutch (89.1%) and highest among the Mediterranean second-generation women (98.6%; p≤0.001). At 6 months postpartum, 30.6% of mothers were still breastfeeding, ranging from 19.3% in the Caribbean second-generation mothers to 42.6% in first-generation Mediterranean mothers. After adjustment for covariates, more non-native mothers started breastfeeding than native Dutch mothers. While Mediterranean first-generation mothers had higher breastfeeding rates at 6 months (OR: 2.71, 95% CI: 2.09 to 3.51), there were no differences in Mediterranean second-generation and Caribbean mothers compared to native Dutch mothers. Conclusion More non-native mothers started breastfeeding than native mothers, but relative fewer continued. Although both native Dutch and non-native mothers had low continuation rates, ethnic minorities may face other difficulties in continuing breastfeeding than native women.

Agreement between maternal cannabis use during pregnancy according to self-report and urinalysis in a population-based cohort: The generation R study (Article)

2010-12-01T00:00:00Z

Aim: To verify self-reported information on prenatal drug use in urine because reporting in pregnancy is sensitive to stigma and might lead to misclassification. Methods: Using semiquantitative immunochemical analysis, the presence of the urinary metabolite (11-nor-Δ9-tetrahydrocannabinol- 9-carboxylic acid) was compared to self-reported prenatal cannabis use. Sensitivity and specificity for self-report and urinalysis outcomes were calculated and Yule's Y was used as an agreement measure. Results: Urine samples were available for 3,997 pregnant women. Of these women, 92 reported having used cannabis during pregnancy (2.3%) and 71 had positive urine screens (1.8%). In total 35% of the 92 women with self-reported cannabis use also had a positive urine screen. Positive urines were relatively frequent in women reporting cannabis use before pregnancy only (7.6%) and in women with missing information (2.6%). Sensitivity and specificity of urinalysis compared to self-report were 0.46 and 0.98. Sensitivity and specificity of self-report compared to urinalysis were 0.36 and 0.99. Yule's Y amounted to 0.77, indicating substantial agreement between the measures. Conclusions: Our findings illustrate the difficulties in obtaining valid information on prenatal cannabis use. To improve the quality of cannabis use data, we suggest a 2-step approach starting with self-report. Copyright

Paroxysmal disorders in infancy and their risk factors in a population-based cohort: The Generation R Study (Article)

2010-11-01T00:00:00Z

Aim To examine the incidence of paroxysmal epileptic and non-epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population-based cohort.Method This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth.Results Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% (n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non-epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth (p<0.001) and low Apgar score at 1 minute (p<0.05) were significantly associated with paroxysmal disorders in the first year of life. Continued maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life (p<0.05).Interpretation Paroxysmal disorders are frequent in infancy. They are associated with preterm birth and a low Apgar score. Epileptic seizures only form a minority of the paroxysmal events in infancy. In this study, children whose mothers continued smoking during pregnancy had a higher reported incidence of febrile seizures in the first year of life. These findings may generate various hypotheses for further investigations.

National origin and behavioural problems of toddlers: The role of family risk factors and maternal immigration characteristics (Article)

2010-11-01T00:00:00Z

In many societies the prevalence of behavioural problems in school-aged children varies by national origin. We examined the association between national origin and behavioural problems in 11/2-year-old children. Data on maternal national origin and the Child Behavior Checklist for toddlers (n = 4943) from a population-based cohort in the Netherlands were used. Children from various non-Dutch backgrounds all had a significantly higher mean behavioural problem score. After adjustment for family risk factors, like family income and maternal psychopathology, the differences attenuated, but remained statistically significant. Non-Dutch mothers with immigration risk factors, such as older age at immigration or no good Dutch language skills, reported significantly more behavioural problems in their offspring. In conclusion, the present study indicated more behavioural problems in immigrant toddlers from various backgrounds. Researchers and policymakers aiming to tackle disparities in behavioural problems should take into account that risks associated with national origin are intertwined with unfavourable family and immigration characteristics.

Maternal smoking and blood pressure in different trimesters of pregnancy: The Generation R Study (Article)

2010-11-01T00:00:00Z

Objective: Smoking during pregnancy is a risk factor for various adverse birth outcomes but lowers the risk of preeclampsia. Cardiovascular adaptations might underlie these associations. We examined the associations of smoking in different trimesters of pregnancy with repeatedly measured blood pressure and the risks of preeclampsia and pregnancy-induced hypertension in a low-risk population-based cohort of 7106 pregnant women. Methods: This study was embedded in a population-based prospective cohort study from early pregnancy onwards. Smoking and systolic and diastolic blood pressures were assessed by questionnaires and physical examinations in each trimester of pregnancy. Information about preeclampsia and pregnancy-induced hypertension was obtained from medical records. Results: Compared to nonsmoking women, both first-trimester-only and continued smoking were associated with a steeper increase for systolic blood pressure and a lowest mid-pregnancy level and steeper increase thereafter for diastolic blood pressure throughout pregnancy. We did not find any significant associations in risk of preeclampsia for first-trimester-only smoking (odds ratio of 1.28, 95% confidence interval 0.74, 2.21) and continued smoking (odds ratio of 0.83, 95% confidence interval 0.50, 1.36), respectively. Conclusions: Our results suggest that both first-trimester-only and continued smoking are associated with persistent maternal cardiovascular adaptations during pregnancy. Strategies for prevention of smoking during pregnancy should be focused on the preconception period. The effects of early and late-pregnancy smoking on the risk of preeclampsia should be further explored. Our results should be carefully interpreted to the general population of pregnant women.

FKBP5 and resistant attachment predict cortisol reactivity in infants: Gene-environment interaction (Article)

2010-11-01T00:00:00Z

Quality of the parent-infant attachment relationship influences physiological stress regulation. Genetic factors also contribute to the stress regulatory HPA-axis. Quality of attachment as an index of the rearing environment (measured with the Strange Situation Procedure, SSP), and HPA-axis related SNPs (BclI, rs41423247; TthIIII, rs10052957; GR-9β, rs6198; N363S, rs6195; ER22/23EK, rs6189 and 6190; and FKBP5, rs1360780) were hypothesized to be related to cortisol reactivity in the stressful SSP. In this large population based sample, FKBP5 rs1360780, but not GR haplotype, was related to cortisol reactivity. Moreover, we found a significant interaction effect for insecure-resistant attachment and FKBP5 rs1360780, indicating a double-risk for heightened cortisol reactivity levels in infants with one or two T-alleles of the FKBP5 SNP and an insecure-resistant attachment relationship with their mother. Findings are discussed from the perspective of gene-environment interaction.

The Generation R Study: Design and cohort update 2010 (Article)

2010-11-01T00:00:00Z

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 during fetal life, childhood and adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. General follow-up rates until the age of 4 years exceed 75%. Data collection in mothers, fathers and preschool children included questionnaires, detailed physical and ultrasound examinations, behavioural observations, and biological samples. A genome wide association screen is available in the participating children. Regular detailed hands on assessment are performed from the age of 5 years onwards. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

Fetal growth retardation and risk of febrile seizures (Article)

2010-10-01T00:00:00Z

OBJECTIVE: The goal was to examine the associations between fetal growth characteristics in different trimesters of pregnancy and the occurrence of febrile seizures in early childhood. METHODS: This study was embedded in a population-based, prospective, cohort study from early fetal life onward. Fetal growth characteristics (femur length, abdominal circumference, estimated fetal weight, head circumference, biparietal diameter, and transverse cerebellar diameter [TCD]) were measured with ultrasonography in the second and third trimesters of pregnancy. Information on the occurrence of febrile seizures was collected with questionnaires at the ages of 12 and 24 months. Analyses were based on data for 3372 subjects. RESULTS: In the second trimester, children in the lowest tertile of TCDs were at increased risk of developing febrile seizures, compared with children in the highest tertile (odds ratio 2.87 [95% confidence interval: 1.31-6.28]). In the third trimester, children in the lowest tertile of all general growth characteristics (femur length, abdominal circumference, and estimated fetal weight) were at increased risk of developing febrile seizures. This association was strongest for children in the lowest tertile of estimated fetal weight (odds ratio: 2.57 [95% confidence interval: 1.34-4.96]). Children in the lowest tertile of biparietal diameter in the third trimester also were at increased risk of febrile seizures. Similar but not statistically significant tendencies were observed for head circumference and TCD. CONCLUSIONS: Fetal growth retardation is associated with increased risk of febrile seizures in the first 2 years of life. Adverse environmental and genetic factors during pregnancy may be important in the development of febrile seizures.

The Generation R study: A candidate gene study and genome-wide association study (GWAS) on health-related quality of life (HRQOL) of mothers and young children (Article)

2010-10-01T00:00:00Z

Aim: The aim of this paper is to describe the Generation R study as a template that enables candidate gene study and genome-wide association study regarding health-related quality of life (HRQOL) of mothers and their young children. Methods: Generation R is a population-based prospective cohort study from fetal life onwards in Rotterdam, The Netherlands. Children were born in 2002-2006. Blood from mothers and placenta cord blood were sampled. Mothers' HRQOL was measured 5 times during pregnancy and after birth using SF-12 and EQ-5D. Children's HRQOL was measured 5 times between age 1 and 5/6 years using Infant-Toddler Quality Of Life questionnaire (ITQOL), Health Status Classification System PreSchool (HSCS-PS) and Child Health Questionnaire Parent Form 28 items (CHQ-PF28), respectively. Results: DNA is available for 8,055 mothers and 5,908 children. Genotyping of various candidate genes and a genome-wide association (GWA) scan (Illumina 610K) of child DNA were done. A template for gene-HRQOL analyses is provided. We start with candidate gene study on HRQOL of mothers and children. Gene-environment interaction and interaction with medical indicators of health status will be explored. Next, GWA study on HRQOL will be performed. Conclusions: Gaining insight into the determinants of HRQOL is essential to assisting efforts in health policy and clinical application to improve well-being and health. In the future, it might be possible to complement HRQOL assessments by examinations of genetic markers. Strengths and weaknesses of the Generation R study are discussed.

Mother's educational level and fetal growth: The genesis of health inequalities (Article)

2010-10-01T00:00:00Z

Background: Women of low socio-economic status (SES) give birth to lighter babies. It is unknown from which moment during pregnancy socio-economic differences in fetal weight can be observed, whether low SES equally affects different fetal-growth components, or what the effect of low SES is after taking into account mediating factors. Methods: In 3545 pregnant women participating in the Generation R Study, we studied the association of maternal educational level (high, mid-high, mid-low and low) as a measure of SES with fetal weight, head circumference, abdominal circumference and femur length. We did this before and after adjusting for potential mediators, including maternal height, pre-pregnancy body mass index and smoking. Results: In fetuses of low-educated women relative to those of high-educated women, fetal growth was slower, leading to a lower fetal weight that was observable from late pregnancy onwards. In these fetuses, growth of the head [-0.16 mm/week; 95% confidence interval (CI): -0.25 to -0.07; P = 0.0004], abdomen (-0.10 mm/week; 95% CI: -0.21 to 0.01; P = 0.08) and femur (-0.03 mm/week; 95% CI: -0.05 to -0.006; P = 0.01) were all slower; from mid-pregnancy onwards, head circumference was smaller, and from late pregnancy onwards, femur length was also smaller. The negative effect of low education was greatest for head circumference (difference in standard deviation score in late pregnancy: -0.26; 95% CI: -0.36 to -0.15; P < 0.0001). This effect persevered even after adjustment for the potential mediators (adjusted difference: -0.14; 95% CI: -0.25 to -0.03; P = 0.01). Conclusions: Low maternal education is associated with a slower fetal growth and this effect appears stronger for growth of the head than for other body parts. Published by Oxford University Press on behalf of the International Epidemiological Association

Early influences on cardiovascular and renal development (Article)

2010-10-01T00:00:00Z

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. Copyright

Infant brain development and vulnerability to later internalizing difficulties: The generation R study (Article)

2010-10-01T00:00:00Z

Objective Although clinical studies have demonstrated smaller subcortical volumes in structures such as the amygdala, hippocampus, caudate nucleus, and thalamus in adults and adolescents with depressive disorders and anxiety, no study has assessed such structures in babies, long before the development of the disorders. This study examined whether the size of the "gangliothalamic ovoid" (encompassing the basal ganglia and thalamus) assessed during infancy is associated with increased internalizing problems in early childhood. Method Cranial ultrasounds were used to assess gangliothalamic ovoid diameter and ventricular volume at 6 weeks of postnatal age; moreover, head circumference was measured. Outcome data included ratings of internalizing and externalizing problems using the Child Behavior Checklist (reported by mothers and fathers) at 18 and/or 36 months. Analyses were based on a total of 651 children. Results Smaller gangliothalamic diameter was associated with higher Child Behavior Checklist Internalizing scores at ages 18 and 36 months. Results remained significant after correcting for head circumference and were evident for the DSM-oriented subscales of anxiety problems and affective problems. Total ventricular volume was not consistently associated with Internalizing scores. Conclusions Findings associating infant brain measurements with Child Behavior Checklist mother and father reports at two time points are consistent with previous cross-sectional reports of smaller subcortical volumes in depression. Results were not simply reflective of overall brain development, because the pattern held after adjustment for head circumference. This is the first study to point toward a biological vulnerability evident in infancy, involved in the development of internalizing problems in childhood.

Perinatal complications increase the risk of postpartum depression. The Generation R Study (Article)

2010-10-01T00:00:00Z

Objective: To examine whether specific pregnancy and delivery complications are risk factors for postpartum depression. Design: A prospective longitudinal study. Setting: Rotterdam, the Netherlands. Population A cohort of 4941 pregnant women who enrolled in the Generation R Study. Methods: Information on perinatal complications was obtained from the midwife and hospital registries or by questionnaire. Logistic regression analyses were used to calculate the risk of postpartum depression for the separate perinatal complications. Main outcome measures: Postpartum psychiatric symptoms were assessed 2 months after delivery using the Edinburgh postnatal depression scale. Results: Several perinatal complications were significantly associated with postpartum depression, namely: pre-eclampsia (adjusted OR, aOR 2.58, 95% CI 1.30-5.14), hospitalization during pregnancy (aOR 2.25, 95% CI 1.19-4.26), emergency caesarean section (aOR 1.53, 95% CI 1.02-2.31), suspicion of fetal distress (aOR 1.56, 95% CI 1.08-2.27), a medically indicated delivery provided by an obstetrician (aOR 2.43, 95% CI 1.56-3.78), and hospital admission of the baby (aOR 1.45, 95% CI 1.10-1.92). Unplanned pregnancy, thrombosis, meconium-stained amniotic fluid, and Apgar score were not associated with postpartum depression after adjustment for confounding factors, such as pre-existing psychopathological symptoms and sociodemographic characteristics. The risk of postpartum depression increased with the number of perinatal complications women experienced (P < 0.001). Conclusions: We showed that several pregnancy and delivery complications present a risk for women's mental health in the postpartum period. Obstetricians, midwives, general practitioners, and staff at baby well clinics should be aware that women who experienced perinatal complications-especially those with a number of perinatal complications-are at risk for developing postpartum depression.

Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood (Article)

2010-10-01T00:00:00Z

OBJECTIVE - Early developmental adaptations in response to undernutrition may play an essential role in susceptibility to type 2 diabetes, particularly for those experiencing a "mismatched rich nutritional environment" in later life. We examined the associations of exposure to the Chinese famine (1959-1961) during fetal life and childhood with the risk of hyperglycemia and type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS - We used the data for 7,874 rural adults born between 1954 and 1964 in selected communities from the cross-sectional 2002 China National Nutrition and Health Survey. Hyperglycemia was defined as fasting plasma glucose ≥6.1 mmol/l and/or 2-h plasma glucose ≥7.8 mmol/l and/or a previous clinical diagnosis of type 2 diabetes. RESULTS - Prevalences of hyperglycemia among adults in nonexposed, fetal exposed, early-childhood, mid-childhood, and late-childhood exposed cohorts were 2.4%, 5.7%, 3.9%, 3.4%, and 5.9%, respectively. In severely affected famine areas, fetal-exposed subjects had an increased risk of hyperglycemia compared with nonexposed subjects (odds ratio = 3.92; 95% CI: 1.64 -9.39; P = 0.002); this difference was not observed in less severely affected famine areas (odds ratio = 0.57; 95% CI: 0.25-1.31; P = 0.185). The odds ratios were significantly different between groups from the severe and less severe famine areas (P for interaction = 0.001). In severely affected famine areas, fetalexposed subjects who followed an affluent/Western dietary pattern (odds ratios = 7.63; 95% CI: 2.41-24.1; P = 0.0005) or who had a higher economic status in later life experienced a substantially elevated risk of hyperglycemia (odds ratios = 6.20; 95% CI: 2.08 -18.5; P = 0.001). CONCLUSIONS - Fetal exposure to the severe Chinese famine increases the risk of hyperglycemia in adulthood. This association appears to be exacerbated by a nutritionally rich environment in later life.

Early detection and counselling intervention of asthma symptoms in preschool children: Study design of a cluster randomised controlled trial (Article)

2010-09-17T00:00:00Z

Background. Prevention of childhood asthma is an important public health objective. This study evaluates the effectiveness of early detection of preschool children with asthma symptoms, followed by a counselling intervention at preventive child health centres. Early detection and counselling is expected to reduce the prevalence of asthma symptoms and improve health-related quality of life at age 6 years. Methods/design. This cluster randomised controlled trial was embedded within the Rotterdam population-based prospective cohort study Generation R in which 7893 children (born between April 2002 and January 2006) participated in the postnatal phase. Sixteen child health centres are involved, randomised into 8 intervention and 8 control centres. Since June 2005, an early detection tool has been applied at age 14, 24, 36 and 45 months at the intervention centres. Children who met the intervention criteria received counselling intervention (personal advice to parents to prevent smoke exposure of the child, and/or referral to the general practitioner or asthma nurse). The primary outcome was asthma diagnosis at age 6 years. Secondary outcomes included frequency and severity of asthma symptoms, health-related quality of life, fractional exhaled nitric oxide and airway resistance at age 6 years. Analysis was according to the intention-to-treat principle. Data collection will be completed end 2011. Discussion. This study among preschool children provides insight into the effectiveness of early detection of asthma symptoms followed by a counselling intervention at preventive child health centres. Trial registration. Current Controlled Trials ISRCTN15790308.

Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: The generation R study (Article)

2010-09-01T00:00:00Z

Context: Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and children's cognitive development are sparse. Objective: Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T4(FT4) levels across the entire range with cognitive functioning in early childhood. Design and Setting: We conducted a population-based cohort in The Netherlands. Participants: Participants included 3659 children and their mothers. Main Measures: In pregnant women with normal TSH levels at 13 wk gestation (SD = 1.7), mild and severe maternal hypothyroxinemia were defined as FT4concentrations below the 10th and 5th percentile, respectively. Children's expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Children's Abilities measuring verbal and nonverbal cognitive functioning. Results: Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT4predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; P = 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; P = 0.007). Conclusions: Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood. Copyright

Breastfeeding is not associated with left cardiac structures and blood pressure during the first two years of life. The Generation R Study (Article)

2010-08-01T00:00:00Z

Background: 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. Aim: To investigate whether breastfeeding affects left cardiac structures and blood pressure development in early childhood. Study design: Prospective cohort study from fetal life until the age of two years. Subjects: Information about the duration and exclusivity of breastfeeding was collected by questionnaires at the ages of 2, 6 and 12 months in 933 children. Outcome measures: 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. Results: 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. Conclusions: 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.

Breastfeeding is not associated with left cardiac structures and blood pressure during the first two years of life. The Generation R Study (Article)

2010-08-01T00:00:00Z

Background: 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. Aim: To investigate whether breastfeeding affects left cardiac structures and blood pressure development in early childhood. Study design: Prospective cohort study from fetal life until the age of two years. Subjects: Information about the duration and exclusivity of breastfeeding was collected by questionnaires at the ages of 2, 6 and 12. months in 933 children. Outcome measures: 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. Results: 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. Conclusions: 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.

Fetal growth from mid- to late pregnancy is associated with infant development: The Generation R Study (Article)

2010-07-01T00:00:00Z

Aim: The aim of this study was to investigate within a population-based cohort of 4384 infants (2182 males, 2202 females) whether fetal growth from early pregnancy onwards is related to infant development and whether this potential relationship is independent of postnatal growth. Method: Ultrasound measurements were performed in early, mid-, and late pregnancy. Estimated fetal weight was calculated using head and abdominal circumference and femur length. Infant development was measured with the Minnesota Infant Development Inventory at 12 months (SD 1.1mo, range 10-17mo). Information on postnatal head size and body weight at 7 months was obtained from medical records. Results: After adjusting for potential confounders and for postnatal growth, faster fetal weight gain from mid- to late pregnancy predicted a reduced risk of delayed social development (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.71-0.95, p=0.008), self-help abilities (OR 0.84; 95% CI 0.73-0.98, p=0.023), and overall infant development (OR 0.65; 95% CI 0.49-0.87, p=0.003). Similar findings were observed for fetal head growth from mid- to late pregnancy. Interpretation: Faster fetal growth predicts a lower risk of delayed infant development independent of postnatal growth. These results suggest that reduced fetal growth between mid- and late pregnancy may determine subsequent developmental outcomes.

Determinants of Moraxella catarrhalis colonization in healthy Dutch children during the first 14 months of life (Article)

2010-07-01T00:00:00Z

Moraxella catarrhalis is an established bacterial pathogen, previously thought to be an innocent commensal of the respiratory tract of children and adults. The objective of this study was to identify significant risk factors associated with M. catarrhalis colonization in the first year of life in healthy Dutch children. This study investigated a target cohort group of 1079 children forming part of the Generation R Study, a population-based prospective cohort study following children from fetal life until young adulthood, conducted in Rotterdam, The Netherlands. Nasopharyngeal swabs for M. catarrhalis culture were obtained at 1.5, 6 and 14 months of age, with all three swabs being available for analyses from 443 children. Data on risk factors possibly associated with M. catarrhalis colonization were obtained by questionnaire at 2, 6 and 12 months. M. catarrhalis colonization increased from 11.8% at age 1.5 months to 29.9% and 29.7% at 6 and 14 months, respectively. Two significantly important colonization risk factors were found: the presence of siblings and day-care attendance, which both increased the risk of being positive for M. catarrhalis colonization on two or more occasions within the first year of life. Colonization with M. catarrhalis was not associated with gender, educational level of the mother, maternal smoking, breast-feeding, or antibiotic use. Apparently, crowding is an important risk factor for early and frequent colonization with M. catarrhalis in the first year of life.

Attachment, depression, and cortisol: Deviant patterns in insecure-resistant and disorganized infants (Article)

2010-07-01T00:00:00Z

Both attachment insecurity and maternal depression are thought to affect infants' emotional and physiological regulation. In the current study, Strange Situation Procedure (SSP) attachment classifications, and cortisol stress reactivity and diurnal rhythm were assessed at 14 months in a prospective cohort study of 369 mother-infant dyads. Maternal lifetime depression was diagnosed prenatally using the Composite International Diagnostic Interview (CIDI). Insecure-resistant infants showed the largest increase in cortisol levels from pre-to post-SSP; the effect was even stronger when they had depressive mothers. Disorganized children showed a more flattened diurnal cortisol pattern compared to nondisorganized children. Findings are discussed from the perspective of a cumulative risk model.

Prolonged and exclusive breastfeeding reduces the risk of infectious diseases in infancy (Article)

2010-07-01T00:00:00Z

OBJECTIVE: To examine the associations of duration of exclusive breastfeeding with infections in the upper respiratory (URTI), lower respiratory (LRTI), and gastrointestinal tracts (GI) in infancy. METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward in the Netherlands. Rates of breastfeeding during the first 6 months (never; partial for <4 months, not thereafter; partial for 4-6 months; exclusive for 4 months, not thereafter; exclusive for 4 months, partial thereafter; and exclusive for 6 months) and doctor-attended infections in the URTI, LRTI, and GI until the age of 12 months were assessed by questionnaires and available for 4164 subjects. RESULTS: Compared with never-breastfed infants, those who were breastfed exclusively until the age of 4 months and partially thereafter had lower risks of infections in the URTI, LRTI, and GI until the age of 6 months (adjusted odds ratio [aOR]: 0.65 [95% confidence interval (CI): 0.51-0.83]; aOR: 0.50 [CI: 0.32-0.79]; and aOR: 0.41 [CI: 0.26-0.64], respectively) and of LRTI infections between the ages of 7 and 12 months (aOR: 0.46 [CI: 0.31-0.69]). Similar tendencies were observed for infants who were exclusively breastfed for 6 months or longer. Partial breastfeeding, even for 6 months, did not result in significantly lower risks of these infections. CONCLUSIONS: Exclusive breastfeeding until the age of 4 months and partially thereafter was associated with a significant reduction of respiratory and gastrointestinal morbidity in infants. Our findings support healthpolicy strategies to promote exclusive breastfeeding for at least 4 months, but preferably 6 months, in industrialized countries.

Explaining Ethnic Differences in Late Antenatal Care Entry by Predisposing, Enabling and Need Factors in the Netherlands. The Generation R Study (Article)

2010-06-09T00:00:00Z

Despite compulsory health insurance in Europe, ethnic differences in access to health care exist. The objective of this study is to investigate how ethnic differences between Dutch and non-Dutch women with respect to late entry into antenatal care provided by community midwifes can be explained by need, predisposing and enabling factors. Data were obtained from the Generation R Study. The Generation R Study is a multi-ethnic population-based prospective cohort study conducted in the city of Rotterdam. In total, 2,093 pregnant women with a Dutch, Moroccan, Turkish, Cape Verdean, Antillean, Surinamese Creole and Surinamese Hindustani background were included in this study. We examined whether ethnic differences in late antenatal care entry could be explained by need, predisposing and enabling factors. Subsequently, logistic regression analysis was used to assess the independent role of explanatory variables in the timing of antenatal care entry. The main outcome measure was late entry into antenatal care (gestational age at first visit after 14 weeks). With the exception of Surinamese-Hindustani women, the percentage of mothers entering antenatal care late was higher in all non-Dutch compared to Dutch mothers. We could explain differences between Turkish (OR = 0.95, CI: 0.57-1.58), Cape Verdean (OR = 1.65. CI: 0.96-2.82) and Dutch women. Other differences diminished but remained significant (Moroccan: OR = 1,74, CI: 1.07-2.85; Dutch Antillean OR 1.80, CI: 1.04-3.13). We found that non-Dutch mothers were more likely to enter antenatal care later than Dutch mothers. Because we are unable to explain fully the differences regarding Moroccan, Surinamese-Creole and Antillean women, future research should focus on differences between 1st and 2nd generation migrants, as well as on language barriers that may hinder access to adequate information about the Dutch obstetric system.

Employment status and the risk of pregnancy complications: The Generation R Study (Article)

2010-06-01T00:00:00Z

Objectives: This study explored the relationships of employment status, type of unemployment and number of weekly working hours, with a wide range of pregnancy outcomes. Methods: Information on employment characteristics and pregnancy outcomes was available for 6111 pregnant women enrolled in a population-based cohort study in the Netherlands. Results: After adjustment for confounders, there were no statistically significant differences in risks of pregnancy complications between employed and unemployed women. Among unemployed women, women receiving disability benefit had an increased risk of preterm ruptured membranes (OR 3.16, 95% CI 1.49 to 6.70), elective caesarean section (OR 2.98, 95% CI 1.21 to 7.34) and preterm birth (OR 2.64, 95% CI 1.32 to 5.28) compared to housewives. Offspring of students and women receiving disability benefit had a significantly lower mean birth weight than offspring of housewives (difference: -93, 95% CI -174 to -12; and -97, 95% CI -190 to -5, respectively). In employed women, long working hours (≥40 h/week) were associated with a decrease of 45 g in offspring's mean birth weight (adjusted analysis; 95% CI -89 to -1) compared with 1-24 h/weekly working hours. Conclusions: We found no indications that paid employment during pregnancy effects the health of the mother and child. However, among unemployed and employed women, women receiving disability benefit, students and women with long working hours during pregnancy were at risk for some adverse pregnancy outcomes. More research is needed to replicate these results and explain these findings. Meanwhile, prenatal care providers should be made aware of the risks associated with specific types of unemployment and long working hours.

Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: The Generation R Study (Article)

2010-06-01T00:00:00Z

Background: Caffeine is a widely used and accepted pharmacologically active substance. The effect of caffeine intake during pregnancy on fetal growth and development is still unclear. Objective: We examined the associations of maternal caffeine intake, on the basis of coffee and tea consumption, with fetal growth characteristics measured in each trimester of pregnancy and the risks of adverse birth outcomes. Design: Associations were studied in 7346 pregnant women participating in a population-based prospective cohort study from early pregnancy onward in the Netherlands (2001-2005). Caffeine intake in the first, second, and third trimesters was on the basis of coffee and tea consumption and was assessed by questionnaires. Fetal growth characteristics were repeatedly measured by ultrasound. Information about birth outcomes was obtained from hospital records. Results: We observed no consistent associations of caffeine intake with fetal head circumference or estimated fetal weight in any trimester. Higher caffeine intake was associated with smaller first-trimester crown-rump length, second- and third-trimester femur length, and birth length (P for trend <0.05). Offspring of mothers who consumed ≥6 caffeine units/d tended to have increased risks of small-for-gestational-age infants at birth. Conclusions: Our results suggest that caffeine intake of ≥6 units/d during pregnancy is associated with impaired fetal length growth. Caffeine exposure might preferentially adversely affect fetal skeletal growth. Further studies are needed to assess these associations in non-European populations and to assess the postnatal consequences.

A comparison of parent-reported wheezing or shortness of breath among infants as assessed by questionnaire and physician-interview: The Generation R study (Article)

2010-05-01T00:00:00Z

Purpose The prevalence of asthma symptoms among preschool children is difficult to determine with accuracy because no gold standard is available for diagnosis. The aim of this study was to compare parent-reported wheezing or shortness of breath among infants as assessed by questionnaire and physician-interview. Methods We studied 1,202 children participating in the Generation R study. Their parents completed a written questionnaire at home when the infant was 12 months old, including items on wheezing or shortness of breath. During the regular free-of-charge youth healthcare visit at age 14 months, the physician interviewed the parents to assess the presence of wheezing or shortness of breath. Results The prevalence of wheezing or shortness of breath estimated from questionnaire was significantly higher than from physician-interview (36% vs. 20%; P < 0.001): observed agreement 73% (kappa 0.36). Only 41% of questionnaire-reported symptoms were assessed through the physician-interview, while 73% of physician-interviewed symptoms were reported in the questionnaire. Compared with infants in the subgroup with agreement on the presence of wheezing or shortness of breath, the infants in the subgroups without agreement significantly less often received anti-asthma medication and significantly less often had abnormal respiratory sounds or bronchiolitis or croup, and their mothers were significantly less often working. The proportion of infants receiving anti-asthma medication was higher in interview-data compared with questionnaire-data (22.7% vs. 3.9%; P < 0.001). Conclusions Questionnaire yielded higher prevalence rates for wheezing or shortness of breath than physician-interview. Physician-reported symptoms are associated with a higher proportion of infants receiving anti-asthma medication. Parent-reported asthma symptoms should be confirmed by pediatricians whenever possible. Pediatr Pulmonol. 2010; 45:500-507.

Growth in foetal life and infancy is associated with abdominal adiposity at the age of 2 years: The generation R study (Article)

2010-05-01T00:00:00Z

Objective Early weight gain is associated with an increased risk of obesity. It is not known whether rapid weight gain in foetal life and infancy is also associated with increased abdominal adiposity. We examined the associations of foetal and postnatal growth characteristics with abdominal fat mass at the age of 2 years. Design This study was performed in 481 children participating in a prospective cohort study from early foetal life onward. Measurements Foetal and postnatal growth characteristics in second and third trimester, at birth and at the age of 2 years were related to abdominal fat mass (subcutaneous distance and area, preperitoneal distance and area) measured by ultrasound at the age of 2 years. Results Foetal and birth weight were not associated with abdominal subcutaneous fat mass. Estimated foetal weight in second trimester of pregnancy was inversely associated with preperitoneal fat area [-3·73% (95% confidence interval -7·23, -0·10)] per standard deviation score increase in weight. Weight gain from birth to the age of 2 years was positively associated with preperitoneal fat mass measures. These associations remained significant after adjustment for age, sex, breastfeeding and body mass index. Positive associations were found between catch-up growth in weight and abdominal fat mass measures. Conclusions Our results suggest that rapid growth rates during foetal life and infancy are associated with increased abdominal subcutaneous and preperitoneal fat mass in healthy children. Further studies need to explore whether these associations persist in later life and are related to metabolic syndrome outcomes.

Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight (Article)

2010-05-01T00:00:00Z

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 × 10 35) and rs9883204 in ADCY5 (P = 7 × 10 15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113g (95% CI 89-137g) lighter at birth than the 24% with zero or one alleles (P trend = 7 × 10 30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Pregnancy outcome in women with repaired versus unrepaired isolated ventricular septal defect (Article)

2010-05-01T00:00:00Z

Objective To compare the risks of pregnancy complications in women with repaired and unrepaired isolated ventricular septal defect (VSD). Design A retrospective multicentre study. Setting Tertiary centres in the Netherlands and Belgium. Methods Women were identified using two congenital heart disease registries. Eighty-eight women were identified who had experienced 202 pregnancies, including 46 miscarriages and nine terminations of pregnancy. Information on each completed pregnancy (n = 147; unrepaired VSD, n = 104; repaired VSD, n = 43) was obtained using medical records and telephone interviews. Data from the Generation R database (prospective cohort study; n = 9667) were used to determine the background risk (controls). Odds ratios and 95% CI were estimated using general estimation equation analysis adjusted for multiple pregnancies per woman, maternal age and parity status. Main outcome measures Adjusted odds ratios (AORs) for developing pregnancy complications in relation to corrective status. Results Pregnancies in women with an unrepaired VSD were associated with a higher risk of pre-eclampsia (AOR 4.59, 95% CI 2.01-10.5, P < 0.001) compared with controls. No differences were observed when comparing women with repaired VSD and controls. Pregnancies in women with repaired VSD were associated with a higher risk of premature labour (AOR 4.02, 95% CI 1.12-14.4, P = 0.03) and small-for-gestational-age (SGA) births (AOR 4.09, 95% CI 1.27-13.2, P = 0.02) compared with women with unrepaired VSD. Conclusions Women with unrepaired VSD are at increased risk of pre-eclampsia, which suggests that it is not a benign condition. In addition, women with repaired VSD are at increased risk of premature labour and SGA births compared with women with unrepaired VSD.

Infant Nutritional Factors and Functional Constipation in Childhood: The Generation R Study (Article)

2010-04-01T00:00:00Z

OBJECTIVES:Food allergy and celiac disease may lead to childhood constipation. Early introduction of food allergens and gluten in the first year of life has been suggested to have a function in these food intolerances, but it is unclear whether this also holds true for development of childhood constipation. The aim of this study was to assess the association between the timing of introduction of food allergens and gluten early in life and functional constipation in childhood.METHODS:This study was embedded in the Generation R study, a population-based prospective cohort study from fetal life until young adulthood. Functional constipation at 24 months of age was defined in 4,651 children according to the Rome II criteria of defecation frequency <3 times a week or the presence of mainly hard feces for at least 2 weeks.RESULTS:At the age of 24 months, 12% of the children had functional constipation. Children with functional constipation got introduced to gluten more often before or at the age of 6 months than children without functional constipation (37% and 27%, respectively). After adjustment for birth weight, gestational age, gender, ethnicity, maternal education, and family history of atopy and chronic intestinal disorders, functional constipation was significantly associated with early gluten introduction (odds ratio (OR): 1.35; 95% confidence interval (CI): 1.10-1.65). No association was found between timing of introduction of cow's milk, hen's egg, soy, peanuts, and tree nuts with functional constipation. A history of cow's milk allergy in the first year of life was significantly associated with functional constipation in childhood (OR: 1.57; 95% CI: 1.04-2.36).CONCLUSIONS:These results suggest that early gluten introduction in the first year of life provide a trigger for functional constipation in a subset of children. In case of functional constipation, there also might be a role for cow's milk allergy initiated in the first year of life.Am J Gastroenterol advance online publication, 2 March 2010; doi:10.1038/ajg.2010.96.

Maternal psychological distress and fetal growth trajectories: the Generation R Study (Article)

2010-04-01T00:00:00Z

Abstract BACKGROUND: Previous research suggests, though not consistently, that maternal psychological distress during pregnancy leads to adverse birth outcomes. We investigated whether maternal psychological distress affects fetal growth during the period of mid-pregnancy until birth. METHOD: Pregnant women (n=6313) reported levels of psychological distress using the Brief Symptom Inventory (anxious and depressive symptoms) and the Family Assessment Device (family stress) at 20.6 weeks pregnancy and had fetal ultrasound measurements in mid- and late pregnancy. Estimated fetal weight was calculated using head circumference, abdominal circumference and femur length. RESULTS: In mid-pregnancy, maternal distress was not linked to fetal size. In late pregnancy, however, anxious symptoms were related to fetal size after controlling for potential confounders. Anxious symptoms were also associated with a 37.73 g [95% confidence interval (CI) -69.22 to -6.25, p=0.019] lower birth weight. When we related maternal distress to fetal growth curves using multilevel models, more consistent results emerged. Maternal symptoms of anxiety or depression were associated with impaired fetal weight gain and impaired fetal head and abdominal growth. For example, depressive symptoms reduced fetal weight gain by 2.86 g (95% CI -4.48 to -1.23, p<0.001) per week. CONCLUSIONS: The study suggests that, starting in mid-pregnancy, fetal growth can be affected by different aspects of maternal distress. In particular, children of prenatally anxious mothers seem to display impaired fetal growth patterns during pregnancy. Future work should address the biological mechanisms underlying the association of maternal distress with fetal development and focus on the effects of reducing psychological distress in pregnancy.

Determinants of somatic complaints in 18-month-old children: The generation R study (Article)

2010-04-01T00:00:00Z

ObjectiveTo investigate the effect of child temperament, maternal psychologic symptoms, maternal chronic pain, and parenting stress on children's somatic complaints.MethodsThe study was embedded in the Generation R Study, a population-based cohort study. Child somatic complaints were assessed via mother-report in 5,171 children of 18 months of age. Questionnaires assessed maternal somatic symptoms, symptoms of depression, anxiety during pregnancy and 2 months after delivery, maternal chronic pain during pregnancy, parenting stress 18 months after birth, and mother-reported child temperament 6 months after birth, as the determinants.ResultsFearful temperament, temperamental falling reactivity, maternal somatic symptoms, anxiety symptoms, and parenting stress each independently and prospectively increased the likelihood of children's somatic complaints at 18 months of age.ConclusionsIn toddlers, temperament, maternal stress, and maternal somatic symptoms seem particularly important for the development of somatic complaints, but long-term research is needed to establish causality and predictive value of these factors.

A prospective study on intrauterine cannabis exposure and fetal blood flow (Article)

2010-04-01T00:00:00Z

Background: Cannabis is commonly used among pregnant women. It is unclear whether cannabis exposure causes hemodynamic modifications in the fetus, like tobacco does. Aims: This study aims to ascertain fetal blood redistribution due to intrauterine cannabis exposure. Methods: This study was embedded in the Generation R Focus Study, a population-based cohort of parents and children followed from pregnancy onwards. In late pregnancy, fetal hemodynamics was assessed with ultrasound measurements in cannabis-exposed and non-exposed fetuses. Pregnant women reported about substance use during pregnancy. A distinction was made between continued cannabis use (n=9), cannabis use only in early pregnancy (n=14), continued tobacco use (n=85), tobacco use only in early pregnancy (n=92), and no tobacco or cannabis use during pregnancy (n=85). Results: Continued cannabis use was associated with an increased pulsatility and resistance index of the uterine artery, while discontinued cannabis use was associated with a decreased pulsatility, and resistance index, as compared to controls. Additionally, continued cannabis exposure resulted in a significantly higher uterine pulsatility index and uterine resistance index compared to tobacco exposure. Continued cannabis use was found to be associated with a smaller aortic diameter, as well. No association between intrauterine cannabis exposure and the fetal cerebral vascular system was found. Conclusions: Our findings suggest that intrauterine cannabis exposure was associated with changes in hemodynamic programming of the vascular system of the fetus in late pregnancy mainly due to tobacco exposure, but intrauterine cannabis exposure did demonstrate a specific effect on the uterine blood flow.

Glucocorticoid receptor gene polymorphisms do not affect growth in fetal and early postnatal life. The Generation R Study (Article)

2010-03-03T00:00:00Z

Background: Glucocorticoids have an important role in early growth and development. Glucocorticoid receptor gene polymorphisms have been identified that contribute to the variability in glucocorticoid sensitivity. We examined whether these glucocorticoid receptor gene polymorphisms are associated with growth in fetal and early postnatal life.Methods: This study was embedded in a population-based prospective cohort study from fetal life onwards. The studied glucocorticoid receptor gene polymorphisms included BclI (rs41423247), TthIIII (rs10052957), GR-9β (rs6198), N363S (rs6195) and R23K (rs6789 and6190). Fetal growth was assessed by ultrasounds in second and third trimester of pregnancy. Anthropometric measurements in early childhood were performed at birth and at the ages of 6, 14 and 24 months postnatally. Analyses focused on weight, length and head circumference. Analyses were based on 2,414 healthy, Caucasian children.Results: Glucocorticoid receptor gene polymorphisms were not associated with fetal weight, birth weight and early postnatal weight. Also, no associations were found with length and head circumference. Neither were these polymorphisms associated with the risks of low birth weight or growth acceleration from birth to 24 months of age.Conclusions: We found in a large population-based cohort no evidence for an effect of known glucocorticoid receptor gene polymorphisms on fetal and early postnatal growth characteristics. Further systematic searches for common genetic variants by means of genome-wide association studies will enable us to obtain a more complete understanding of what genes and polymorphisms are involved in growth in fetal life and infancy.

Associations of light and moderate maternal alcohol consumption with fetal growth characteristics in different periods of pregnancy: The generation R study (Article)

2010-03-01T00:00:00Z

Background: Excessive alcohol consumption during pregnancy has adverse effects on fetal growth and development. Less consistent associations have been shown for the associations of light-to-moderate maternal alcohol consumption during pregnancy with health outcomes in the offspring. Therefore, we examined the associations of light-to-moderate maternal alcohol consumption with various fetal growth characteristics measured in different periods of pregnancy. Methods: This study was based on 7333 pregnant women participating in a population-based cohort study. Alcohol consumption habits and fetal growth were assessed in early (gestational age <17.9 weeks), mid- (gestational age 18-24.9 weeks) and late pregnancy (gestational age ≥25 weeks). We assessed the effects of different categories of alcohol consumption (no; less than one drink per week; one to three drinks per week; four to six drinks per week; one drink per day and two to three drinks per day) on repeatedly measured fetal head circumference, abdominal circumference and femur length. Results: In total, 37% of all mothers continued alcohol consumption during pregnancy, of whom the majority used less than three drinks per week. We observed no differences in growth rates of fetal head circumference, abdominal circumference or femur length between mothers with and without continued alcohol consumption during pregnancy. Compared with mothers without alcohol consumption, mothers with continued alcohol consumption during pregnancy had an increased fetal weight gain [difference 0.61 g (95% confidence interval: 0.18, 1.04) per week]. Cross-sectional analyses in mid- and late pregnancy showed no consistent associations between the number of alcoholic consumptions and fetal growth characteristics. All analyses were adjusted for potential confounders. Conclusions: Light-to-moderate maternal alcohol consumption during pregnancy does not adversely affect fetal growth characteristics. Further studies are needed to assess whether moderate alcohol consumption during pregnancy influences organ growth and function in postnatal life.

Correlation of bacterial colonization status between mother and child: The generation R study (Article)

2010-03-01T00:00:00Z

Determinants of bacterial colonization in children have been described. In the Generation R Study, a population-based cohort study, we determined whether the colonization statuses of mothers and children are correlated. Such a correlation was observed for Staphylococcus aureus and Haemophilus influenzae. Direct transmission, genetic susceptibility and/or unidentified environmental factors may play a role here. Copyright

Risk factors and outcomes associated with first-trimester fetal growth restriction (Article)

2010-02-10T00:00:00Z

Context: Adverse environmental exposures lead to developmental adaptations in fetal life. The influences of maternal physical characteristics and lifestyle habits on first-trimester fetal adaptations and the postnatal consequences are not known. Objective: To determine the risk factors and outcomes associated with firsttrimester growth restriction. Design, Setting, and Participants: Prospective evaluation of the associations of maternal physical characteristics and lifestyle habits with first-trimester fetal crown to rump length in 1631 mothers with a known and reliable first day of their last menstrual period and a regular menstrual cycle. Subsequently, we assessed the associations of first-trimester fetal growth restriction with the risks of adverse birth outcomes and postnatal growth acceleration until the age of 2 years. The study was based in Rotterdam, the Netherlands. Mothers were enrolled between 2001 and 2005. Main Outcome Measures: First-trimester fetal growth was measured as fetal crown to rump length by ultrasound between the gestational age of 10 weeks 0 days and 13 weeks 6 days. Main birth outcomes were preterm birth (gestational age <37 weeks), low birth weight (<2500 g), and small size for gestational age (lowest fifth birth centile). Postnatal growth was measured until the age of 2 years. Results In the multivariate analysis, maternal age was positively associated with firsttrimester fetal crown to rump length (difference per maternal year of age, 0.79 mm; 95% confidence interval [CI], 0.41 to 1.18 per standard deviation score increase). Higher diastolic blood pressure and higher hematocrit levels were associated with a shorter crown to rump length (differences, -0.40 mm; 95% CI, -0.74 to -0.06 and -0.52 mm; 95% CI, -0.90 to -0.14 per standard deviation increase, respectively). Compared with mothers who were nonsmokers and optimal users of folic acid supplements, those who both smoked and did not use folic acid supplements had shorter fetal crown to rump lengths (difference, -3.84 mm; 95% CI, -5.71 to -1.98). Compared with normal first-trimester fetal growth, first-trimester growth restriction was associated with increased risks of preterm birth (4.0% vs 7.2%; adjusted odds ratio [OR], 2.12; 95% CI, 1.24 to 3.61), low birth weight (3.5% vs 7.5%; adjusted OR, 2.42; 95% CI, 1.41 to 4.16), and small size for gestational age at birth (4.0% vs 10.6%; adjusted OR, 2.64; 95% CI, 1.64 to 4.25). Each standard deviation decrease in firsttrimester fetal crown to rump length was associated with a postnatal growth acceleration until the age of 2 years (standard deviation score increase, 0.139 per 2 years; 95% CI, 0.097 to 0.181). Conclusions Maternal physical characteristics and lifestyle habits were independently associated with early fetal growth. First-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes and growth acceleration in early childhood.

Fetal programming of infant neuromotor development: The generation R study (Article)

2010-02-01T00:00:00Z

The objective of the study was to examine whether infant neuromotor development is determined by fetal size and body symmetry in the general population. This study was embedded within the Generation R Study, a population-based cohort in Rotterdam. In 2965 fetuses, growth parameters were measured in mid-pregnancy and late pregnancy. After birth, at age 9 to 15 wks, neuromotor development was assessed with an adapted version of Touwen's Neurodevelopmental Examination. Less optimal neuromotor development was defined as a score in the highest tertile. We found that higher fetal weight was beneficial to infant neurodevelopment. A fetus with a 1-SD score higher weight in mid-pregnancy had an 11% lower risk of less optimal neuromotor development (OR: 0.89; 95% CI: 0.82-0.97). Similarly, a fetus with a 1-SD score larger abdominal-to-head circumference (AC/HC) ratio had a 13% lower risk of less optimal neuromotor development (OR: 0.87; 95% CI: 0.79-0.96). These associations were also present in late pregnancy. Our findings show that fetal size and body symmetry in pregnancy are associated with infant neuromotor development. These results suggest that differences in infant neuromotor development, a marker of behavioral and cognitive problems, are at least partly caused by processes occurring early in fetal life.

Do social disadvantage and early family adversity affect the diurnal cortisol rhythm in infants? The Generation R Study (Article)

2010-02-01T00:00:00Z

Dysregulation of diurnal cortisol secretion patterns may explain the link between adversities early in life and later mental health problems. However, few studies have investigated the influence of social disadvantage and family adversity on the hypothalamic-pituitary-adrenal (HPA) axis early in life. In 366 infants aged 12-20 months from the Generation R Study, a population-based cohort from fetal life onwards, parents collected saliva samples from their infant at 5 moments over the course of 1 day. The area under the curve (AUC), the cortisol awakening response (CAR) and the diurnal cortisol slope were calculated as different composite measures of the diurnal cortisol rhythm. Information about social disadvantage and early adversity was collected using prenatal and postnatal questionnaires. We found that older infants showed lower AUC levels; moreover, infants with a positive CAR were significantly older. Both the AUC and the CAR were related to indicators of social disadvantage and early adversity. Infants of low income families, in comparison to high income families, showed higher AUC levels and a positive CAR. Infants of mothers who smoked during pregnancy were also significantly more likely to show a positive CAR. Furthermore, infants of mothers experiencing parenting stress showed higher AUC levels. The results of our study show that effects of social disadvantage and early adversity on the diurnal cortisol rhythm are already observable in infants. This may reflect the influence of early negative life events on early maturation of the HPA axis.

Kidney growth curves in healthy children from the third trimester of pregnancy until the age of two years. The Generation R Study (Article)

2010-02-01T00:00:00Z

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 6 months and 24 months. Analyses were based on more than 2,500 kidney measurements. In the third trimester of pregnancy and at 6 months of age all kidney measurements were larger in boys than in girls. At 24 months 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.

Insulin VNTR and IGF-1 promoter region polymorphisms are not associated with body composition in early childhood: The generation R study (Article)

2010-02-01T00:00:00Z

Objective: The objective of this study was to examine the associations between insulin gene variable number of tandem repeats (INS VNTR) and insulin-like growth factor 1 (IGF1) gene promoter region polymorphisms with body composition in early childhood. Methods: This study was embedded in an ongoing prospective cohort study. Growth in early childhood (body mass index, total subcutaneous fat mass and waist-hip ratio) was assessed at birth and at the ages of 6 weeks and 24 months. DNA for genotyping was available in 738 children. Results: The genotype distribution of the INS VNTR gene was I/I 50.4%, I/III 40.4%, and III/III 9.2%. IGF1 genotypes were categorized in the following categories based on their 192-bp allele: homozygous (wild-type) 43.1%, heterozygous 45.8%, and noncarrier 11.2%. No differences were found in body mass index, total subcutaneous fat mass and waist-hip ratio in early childhood between the three groups for both the INS VNTR and IGF1 genotypes. We also did not find interactions between these genotypes and gender or birth weight on the effects of body composition measures. Conclusions: Our results do not support previous studies showing associations between INS VNTR and IGF1 promoter region polymorphisms with body composition in early childhood. Copyright

Grandparental anxiety and depression predict young children's internalizing and externalizing problems. The generation R study (Article)

2010-01-01T00:00:00Z

Background: Family history is a major risk factor for child problem behaviour, yet few studies have examined the association between grandparental psychiatric disorder and child problem behaviour. Results are inconsistent as to whether the effect of grandparental depression on child problem behaviour is independent of parental psychopathology. Methods: Mothers and their children participated in an ethnically Dutch subcohort of a population-based prospective cohort in the Netherlands. N = 816 (66%) mothers and n = 691 fathers participated in the prenatal interviews. N = 687 (84%) mothers and children and n = 565 (82%) fathers participated three years postpartum. (Grand)parental psychopathology was assessed during pregnancy of the mothers with the Family Informant Schedule and Criteria (FISC), the Composite International Diagnostic Interview (CIDI) and the Brief Symptom Inventory (BSI). Child behaviour was assessed with the Child Behavior Checklist (CBCL) by mother and father when the child was three years old. Results: Grandparental anxiety disorder predicted maternal reports of children's internalizing problems (OR = 1.98, 95% C.I. (1.20, 3.28), p-value < 0.01) and externalizing problems (OR = 1.73, 95% C.I. (1.04, 2.87), p-value = 0.03), independent of parental psychopathology. Results were similar for grandparental depression; internalizing OR = 1.75, 95% C.I (1.11, 2.75), p-value = 0.02 and externalizing OR = 1.67, 95% C.I. (1.05, 2.64) p-value = 0.03. However, grandparental psychopathology was not associated with children's problem behaviour as reported by the father. Limitations: Information on grandparental lifetime psychiatric disorder was assessed through a parental interview which may have led to an underestimation of the prevalence rates. Conclusions: These results confirm the importance of a family history including not only the parental but also the grandparental generations.

Interactions between TCF7L2 genotype and growth hormone-induced changes in glucose homeostasis in small for gestational age children (Article)

2010-01-01T00:00:00Z

Context The Transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism has been associated with risk of developing type 2 diabetes mellitus (DM), possibly by decreasing insulin secretion. Small for gestational age (SGA) birth has been associated with type 2 DM in later life. Growth hormone (GH) treatment reduces insulin sensitivity and increases insulin secretion. Therefore, GH-treated SGA children are an ideal group to investigate whether the TCF7L2 rs7903146 genotype is associated with changes in glucose homeostasis. Objective To determine the impact of the TCF7L2 rs7903146 polymorphism on changes in insulin secretion and insulin sensitivity during 4 years of GH treatment in children born SGA. Subjects A total of 246 Caucasian short children born SGA, with a median age of 7·8 years. Outcome measures Insulin sensitivity and insulin secretion were measured by the frequently sampled intravenous glucose tolerance test (FSIGT) (n = 68) and homeostasis model assessment (HOMA) calculations (all). Results There was no association between rs7903146 genotype and insulin sensitivity or insulin secretion at baseline but after adjustment for possible confounders, insulin secretion was higher in the CT/TT group than in the CC group. During GH treatment, carriers of the rs7903146 T allele had an increase in insulin secretion similar to that of carriers of the CC genotype. The decrease in insulin sensitivity was only significant in the CT/TT group, but the difference in decrease between genotype groups did not reach significance (P = 0·06). The disposition index (insulin secretion × insulin sensitivity), which is an estimate of beta cell function, was not associated with genotype and did not change during GH treatment. Conclusion The TCF7L2 rs7903146 polymorphism is not associated with the change in insulin secretion during GH treatment in short SGA children.

Abdominal Fat in Children Measured by Ultrasound and Computed Tomography (Article)

2009-12-01T00:00:00Z

The prevalence of childhood obesity is increasing rapidly. Visceral fat plays an important role in the pathogenesis of metabolic and cardiovascular diseases. Currently, computed tomography (CT) is broadly seen as the most accurate method of determining the amount of visceral fat. The main objective was to examine whether measures of abdominal visceral fat can be determined by ultrasound in children and whether CT can be replaced by ultrasound for this purpose. To assess whether preperitoneal fat thickness and area are good approximations of visceral fat at the umbilical level, we first retrospectively examined 47 CT scans of nonobese children (body mass index <30 kg/m2; median age 7.9 y [95% range 1.2 to 16.2]). Correlation coefficients between visceral and preperitoneal fat thickness and area were 0.58 (p < 0.001) and 0.76 (p < 0.001), respectively. Then, to assess how preperitoneal and subcutaneous fat thicknesses and areas measured by ultrasound compare with these parameters in CT, we examined 34 nonobese children (median age 9.5 [95% range 0.3 to 17.0]) by ultrasound and CT. Ultrasound measurements of preperitoneal and subcutaneous fat were correlated with CT measurements, with correlation coefficients ranging from 0.75-0.97 (all p < 0.001). Systematic differences of up to 24.0 cm2for preperitoneal fat area (95% confidence interval -29.9 to 77.9 cm2) were observed when analyzing the results described by the Bland-Altman method. Our findings suggest that preperitoneal fat can be used as an approximation for visceral fat in children and that measuring abdominal fat with ultrasound in children is a valid method for epidemiological and clinical studies. However, the exact agreement between the ultrasound and CT scan was limited, which indicates that ultrasound should be used carefully for obtaining exact fat distribution measurements in individual children. (E-mail: v.jaddoe@erasmusmc.nl).

Residential traffic exposure and pregnancy-related outcomes: A prospective birth cohort study (Article)

2009-12-01T00:00:00Z

Background. The effects of ambient air pollution on pregnancy outcomes are under debate. Previous studies have used different air pollution exposure assessment methods. The considerable traffic-related intra-urban spatial variation needs to be considered in exposure assessment. Residential proximity to traffic is a proxy for traffic-related exposures that takes into account within-city contrasts. Methods. We investigated the association between residential proximity to traffic and various birth and pregnancy outcomes in 7,339 pregnant women and their children participating in a population-based cohort study. Residential proximity to traffic was defined as 1) distance-weighted traffic density in a 150 meter radius, and 2) proximity to a major road. We estimated associations of these exposures with birth weight, and with the risks of preterm birth and small size for gestational age at birth. Additionally, we examined associations with pregnancy-induced hypertension, (pre)eclampsia, and gestational diabetes. Results. There was considerable variation in distance-weighted traffic density. Almost fifteen percent of the participants lived within 50 m of a major road. Residential proximity to traffic was not associated with birth and pregnancy outcomes in the main analysis and in various sensitivity analyses. Conclusions. Mothers exposed to residential traffic had no higher risk of adverse birth outcomes or pregnancy complications in this study. Future studies may be refined by taking both temporal and spatial variation in air pollution exposure into account.

Comparison of pregnancy outcomes in women with repaired versus unrepaired atrial septal defect (Article)

2009-11-01T00:00:00Z

Objective To compare the risks of complications during pregnancy in women with repaired andunrepaired atrial septal defects (ASDs) without associated complex cardiac lesions. Design A retrospective multicentre study. Setting Tertiary centres in the Netherlands and Belgium. Population Women with ASD without associated complex cardiac lesions. Methods Women were identified using two congenital heart disease registries. One hundred women were identified who had 243 pregnancies, including 49 miscarriages and six terminations of pregnancy. Detailed information on each completed pregnancy (n = 188; unrepaired ASD, n = 133; repaired ASD, n = 55) was obtained using medical records and telephone interviews. In addition, data from the Generation R database (a prospective cohort study; n = 9667) were used to determine the background risk (control group). Main outcome measures Adjusted odds ratios (AORs) for cardiac, obstetric and neonatal events controlled for multiple pregnancies per woman using general estimating equation analysis. Results Women with an unrepaired ASD had a higher risk of neonatal events (AOR = 2.99, 95% confidence interval [CI] 1.14-7.89, P = 0.027) than women with a repaired ASD. The risk of cardiac and obstetric complications was comparable between women with unrepaired and repaired ASDs. Compared with the general population, women with an unrepaired ASD had higher risks of pre-eclampsia (AOR = 3.54, 95% CI 1.26-9.98, P = 0.017), small-for-gestational-age births (AOR = 1.95, 95% CI 1.15-3.30, P = 0.013) and fetal mortality (AOR = 5.55, 95% CI 1.77-17.4, P = 0.003). By contrast, no differences were observed when comparing women with a repaired ASD versus controls. Conclusions Women with an unrepaired ASD are at increased risk of neonatal events in comparison with women with a repaired ASD. Compared with the general population, women with an unrepaired ASD are at increased risk of pre-eclampsia, small-for-gestational-age births and fetal mortality.

Antenatal education programmes: do they work? (Article)

2009-09-11T00:00:00Z

Levels of metabolites of organophosphate pesticides, phthalates, and bisphenol A in pooled urine specimens from pregnant women participating in the Norwegian Mother and Child Cohort Study (MoBa) (Article)

2009-09-01T00:00:00Z

Concerns about reproductive and developmental health risks of exposure to organophosphate (OP) pesticides, phthalates, and bisphenol A (BPA) among the general population are increasing. Six dialkyl phosphate (DAP) metabolites, 3,5,6-trichloro-2-pyridinol (TCPy), BPA, and fourteen phthalate metabolites were measured in 10 pooled urine samples representing 110 pregnant women who participated in the Norwegian Mother and Child Birth Cohort (MoBa) study in 2004. Daily intakes were estimated from urinary data and compared with reference doses (RfDs) and daily tolerable intakes (TDIs). The MoBa women had a higher mean BPA concentration (4.50 μg/L) than the pregnant women in the Generation R Study (Generation R) in the Netherlands and the National Health and Nutrition Examination Survey (NHANES) in the United States. The mean concentration of total DAP metabolites (24.20 μg/L) in MoBa women was higher than that in NHANES women but lower than that in Generation R women. The diethyl phthalate metabolite mono-ethyl phthalate (MEP) was the dominant phthalate metabolite in all three studies, with the mean concentrations of greater than 300 μg/L. The MoBa and Generation R women had higher mean concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) than the NHANES women. The estimated average daily intakes of BPA, chlorpyrifos/chlorpyrifos-methyl and phthalates in MoBa (and the other two studies) were below the RfDs and TDIs. The higher levels of metabolites in the MoBa participants may have been from intake via pesticide residues in food (organophosphates), consumption of canned food, especially fish/seafood (BPA), and use of personal care products (selected phthalates).

Sonographic assessment of abdominal fat distribution in infancy (Article)

2009-09-01T00:00:00Z

There is growing evidence that not only the total amount of fat, but also the distribution of body fat determines risks for metabolic and cardiovascular disease. Developmental studies on factors influencing body fat distribution have been hampered by a lack of appropriate techniques for measuring intraabdominal fat in early life. Sonography, which is an established method for assessing abdominal fat distribution in adults, has not yet been evaluated in infants. To adapt the sonographic measurement of abdominal fat distribution to infants and study its reliability. The Generation R study, a population-based prospective cohort study. We included 212 one- and 227 two-year old Dutch infants in the present analysis. Sixty-two infants underwent replicate measurements to assess reproducibility. We developed a standardized protocol to measure the thickness of (1) subcutaneous and (2) preperitoneal fat in the upper abdomen of infants. To this end we defined infancy specific measurement areas to quantify fat thickness. Reproducibility of fat measurements was good to excellent with intraclass correlation coefficients of 0.93-0.97 for intra-observer agreement and of 0.89-0.95 for inter-observer agreement. We observed a pronounced increase in preperitoneal fat thickness in the second year of life while subcutaneous fat thickness increased only slightly, resulting in an altered body fat distribution. Gender did not significantly influence fat distribution in the first two years of life. Our age specific protocol for the sonographic measurement of central subcutaneous and preperitoneal fat is a reproducible method that can be instrumental for investigating fat distribution in early life.

Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: The Generation R Study (Article)

2009-09-01T00:00:00Z

Countries worldwide, including the Netherlands, recommend that women planning pregnancy use a folic acid supplement during the periconception period. Some countries even fortify staple foods with folic acid. These recommendations mainly focus on the prevention of neural tube defects, despite increasing evidence that folic acid may also influence birth weight. We examined whether periconception folic acid supplementation affects fetal growth and the risks of low birth weight, small for gestational age (SGA) and preterm birth, in the Generation R Study in Rotterdam, the Netherlands. Main outcome measures were fetal growth measured in mid- and late pregnancy by ultrasound, birth weight, SGA and preterm birth in relation to periconception folic supplementation (0.4-0.5mg). Data on 6353 pregnancies were available. Periconception folic acid supplementation was positively associated with fetal growth. Preconception folic acid supplementation was associated with 68g higher birth weight (95% CI 37.2, 99.0) and 13g higher placental weight (95% CI 1.1, 25.5), compared to no folic acid supplementation. In these analyses parity significantly modified the effect estimates. Start of folic acid supplementation after pregnancy confirmation was associated with a reduced risk of low birth weight (OR 0.61, 95% CI 0.40, 0.94). Similarly, reduced risks for low birth weight and SGA were observed for women who started supplementation preconceptionally, compared to those who did not use folic acid (OR 0.43, 95% CI 0.28, 0.69 and OR 0.40, 95% CI 0.22, 0.72). In conclusion, periconception folic acid supplementation is associated with increased fetal growth resulting in higher placental and birth weight, and decreased risks of low birth weight and SGA.

Role of Staphylococcus aureus nasal colonization in atopic dermatitis in infants: The generation R study (Article)

2009-08-01T00:00:00Z

Objective: To study the association between Staphylococcus aureus nasal colonization and atopic dermatitis (AD) in infancy. Design: Population-based prospective cohort study of pregnant women and their children. Setting: This project was embedded in the Generation R Study. Participants: A total of 1079 postnatal Dutch infants/ children participated in the focus cohort. Main Exposures: Nasal swabs for S aureus cultivation were taken at ages 1.5, 6, and 14 months. Main Outcome Measure: Questionnaires that pertain to AD and confounders (birth weight, gestational age, sex, and parental eczema) were completed prenatally and postnatally. The outcome was AD in the first and second years of life. Results: A first positive culture for S aureus at age 6 months was associated with AD prevalence in the first and second years of life (adjusted odds ratio [aOR], 2.13; 95% confidence interval [CI], 1.17-3.87; and aOR, 2.88; 95% CI, 1.60-5.19, respectively) and also with severity (aOR, 3.27; 95% CI, 1.30-8.03). Moreover, frequent colonization in the first year of life (≥2 times) held a 4.29-fold (95% CI, 1.03- to 17.88-fold) risk of moderate to severe AD in the second year of life. Conclusion: Colonization with S aureus at age 6 months and frequent colonization in the first year of life are associated with AD and its severity in young children.

Reliability of echocardiographic measurements of left cardiac structures in healthy children (Article)

2009-08-01T00:00:00Z

Background: Echocardiographic measurements are widely used as outcomes of different studies. The aim of this study was to assess intraobserver and interobserver reliability of echocardiographic measurements in healthy children. Materials and methods: We studied 28 children, with a median age of 7.5 years, and inter-quartile range from 3 to 11 years. Intraobserver and interobserver reliability were assessed by repeated measurements of the diameters of the aortic root, the left atrium, and left ventricular end-diastolic structure. We also measured the ventricular end-diastolic septal thickness and the end-diastolic thickness of the left ventricular posterior wall. We calculated intraclass correlation coefficients, with corresponding 95% confidence intervals, and computed Bland and Altman plots, permitting us to derive limits of agreement plus or minus 2 standard deviations for the mean differences in cardiac measurements. Results: We found high intraobserver and interobserver intraclass correlation coefficient, ranging from 0.91 for ventricular septal thickness, with 95% confidence intervals from 0.78 to 0.96, to 0.99 for the diameter of the aortic root, 95% confidence interval from 0.97 to 1.00. Limits of agreement in the Bland and Altman plots ranged from zero millimetres for left ventricular end-diastolic posterior wall thickness to 1.60 millimeters (6.3%) for left atrial diameter. Conclusions: Our study demonstrated good repeatability and reproducibility for ultrasonic measurements of left cardiac structures in children, showing that values obtained for measurement of these structures in both clinical and epidemiological research projects can be confidently accepted. Copyright

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies (Article)

2009-07-17T00:00:00Z

Background: An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy. Methods: This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort. Results: Minor allele frequency did not differ significantly (p = 0.47)between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort. Conclusion: We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.

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

2009-07-01T00:00:00Z

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.

Maternal symptoms of anxiety during pregnancy affect infant neuromotor development: The generation R study (Article)

2009-07-01T00:00:00Z

Several studies found that maternal symptoms of anxiety or depression are related to functioning and development of the offspring. Within a population-based study of 2,724 children, we investigated the effect of maternal anxiety or depression on infant neuromotor development. Symptoms of anxiety and depression were measured during pregnancy and after giving birth; infant neuromotor development was assessed by trained research nurses during a home visit at the age of 3 months. The current study showed that mothers who were anxious during pregnancy had an elevated risk of having an infant with non-optimal neuromotor development.

Paternal depressive symptoms during pregnancy are related to excessive infant crying (Article)

2009-07-01T00:00:00Z

OBJECTIVE: Excessive infant crying, or infantile colic, is a common and often stress-inducing problem for parents that can ultimately result in child abuse. From previous research it is known that maternal depression is related to excessive crying, but so far little is known about the influence of paternal depression. METHODS: In a prospective, population-based study, we obtained information on both maternal and paternal depressive symptoms at 20 weeks of pregnancy by using the Brief Symptom Inventory. Parental depressive symptoms were related to excessive crying in 4426 two-month-old infants. The definition of excessive crying was based on the widely used Wessel's criteria (ie, crying >3 hours for >3 days in the past week). RESULTS: After adjustment for depressive symptoms of the mother and relevant confounders, we found a 1.29 (95% confidence interval: 1.09-1.52) higher risk of excessive infant crying per SD of paternal depressive symptoms. CONCLUSIONS: Our findings indicate that paternal depressive symptoms during pregnancy might be a risk factor for excessive infant crying. This finding could be related to genetic transmission, interaction of a father with lasting depressive symptoms with the infant, or related indirectly through contextual stressors such as marital, familial, or economic distress. Copyright

Maternal smoking during pregnancy and child behaviour problems: The generation R study (Article)

2009-06-15T00:00:00Z

Background: Several studies showed that maternal smoking in pregnancy is related to behavioural and emotional disorders in the offspring. It is unclear whether this is a causal association, or can be explained by other smoking-related vulnerability factors for child behavioural problems. Methods: Within a population-based birth cohort, both mothers and fathers reported on their smoking habits at several time-points during pregnancy. Behavioural problems were measured with the Child Behavior Checklist in 4680 children at the age of 18 months. Results: With adjustment for age and gender only, children of mothers who continued smoking during pregnancy had higher risk of Total Problems [odds ratio (OR) 1.59, 95% confidence interval (CI): 1.21-2.08] and Externalizing problems (OR 1.45, 95% CI: 1.15-1.84), compared with children of mothers who never smoked. Smoking by father when mother did not smoke, was also related to a higher risk of behavioural problems. The statistical association of parental smoking with behavioural problems was strongly confounded by parental characteristics, chiefly socioeconomic status and parental psychopathology; adjustment for these factors accounted entirely for the effect of both maternal and paternal smoking on child behavioural problems. Conclusions: Maternal smoking during pregnancy, as well as paternal smoking, occurs in the context of other factors that place the child at increased developmental risk, but may not be causally related to the child's behaviour. It is essential to include sufficient information on parental psychiatric symptoms in studies exploring the association between pre-natal cigarette smoke exposure and behavioural disorders. © Published by Oxford University Press on behalf of the International Epidemiological Association

Fetal size in mid- and late pregnancy is related to infant alertness: The generation R study (Article)

2009-06-03T00:00:00Z

The vulnerability for behavioral problems is partly shaped in fetal life. Numerous studies have related indicators of intrauterine growth, for example, birth weight and body size, to behavioral development. We investigated whether fetal size in mid- and late pregnancy is related to infant irritability and alertness. In a population-based birth cohort of 4,255 singleton full-term infants ultrasound measurements of fetal head and abdominal circumference in mid- and late pregnancy were performed. Infant irritability and alertness scores were obtained by the Mother and Baby Scales at 3 months and z-standardized. Multiple linear regression analyses revealed curvilinear associations (inverted J-shape) of measures of fetal size in both mid- and late pregnancy with infant alertness. Fetal size characteristics were not associated with infant irritability. These results suggest that alterations of intrauterine growth affecting infant alertness are already detectable from mid-pregnancy onwards.

Fetal and postnatal growth and blood pressure at the age of 2 years. The Generation R Study (Article)

2009-06-01T00:00:00Z

Objectives To examine which fetal and postnatal growth characteristics are associated with blood pressure (BP) in children at the age of 2 years. Methods This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Fetal ultrasound examinations were carried out at the visits in one of the research centers in early, mid- and late pregnancy. Fetal femur length standard deviation scores (SDS) were used as a proxy for body length SDS in the prenatal data. BP measurements were performed at the age of 2 years. Analyses were performed in 566 children. Results Inverse tendencies for fetal femur length and estimated fetal weight in mid-pregnancy and late pregnancy with SBP at the age of 2 years were found. The association was only significant for femur length in late pregnancy [-1.22 (95% confidence interval (CI), -2.09, -0.34) mmHg/femur length SDS score]. Length change from late pregnancy to the age of 2 years was positively associated with SBP and DBP [0.97 (95% CI, 0.27,1.66) mmHg and 0.82 (95% CI, 0.09, 1.55) mmHg per SDS length change, respectively]. A similar association between weight change and SBP was found. Conclusion Increased skeletal and nonskeletal growth rates from late pregnancy to the age of 2 years are associated with somewhat higher SBP and DBP in early childhood. Replication of these findings and studies examining the underlying biological pathways and the long-term consequences are needed.

Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. the generation R study (Article)

2009-06-01T00:00:00Z

Objective We aimed to examine the associations of maternal anthropometrics with fetal weight measured in different periods of pregnancy and with birth outcomes. Design Population-based birth cohort study. Setting Data of pregnant women and their children in Rotterdam, the Netherlands. Population In 8541 mothers, height, prepregnancy body mass index (BMI) and gestational weight gain were available. Methods Fetal growth was measured by ultrasound in mid- and late pregnancy. Regression analyses were used to assess the impact of maternal anthropometrics on fetal weight and birth outcomes. Main outcome measures Fetal weight and birth outcomes: weight (grams) and the risks of small (<5th percentile) and large (>95th percentile) size for gestational age at birth. Results Maternal BMI in pregnancy was positively associated with estimated fetal weight during pregnancy. The effect estimates increased with advancing gestational age. All maternal anthropometrics were positively associated with fetal size (P-values for trend <0.01). Mothers with both their prepregnancy BMI and gestational weight gain quartile in the lowest and highest quartiles showed the highest risks of having a small and large size for gestational age child at birth, respectively. The effect of prepregnancy BMI was strongly modified by gestational weight gain. Conclusions Fetal growth is positively affected by maternal BMI during pregnancy. Maternal height, prepregnancy BMI and gestational weight gain are all associated with increased risks of small and large size for gestational age at birth in the offspring, with an increased effect when combined.

Fetal and postnatal growth and body composition at 6 months of age (Article)

2009-06-01T00:00:00Z

Objectives: The objectives of the study was to examine which parental, fetal, and postnatal characteristics are associated with fat and lean mass at the age of 6 months and examine the effect of growth (catch-down, catch-up) in fetal life and early infancy on fat and lean mass. Design: This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. Body composition was measured by dual-energy X-ray absorptiometry in 252 infants at 6 months. Parental, fetal, and postnatal data were collected by physical and fetal ultrasound examinations and questionnaires. Results: Children with fetal catch-up in weight (gain in weight SD score >0.67) in the second trimester tended to have a higher fat mass percentage [FM(%)] at 6 months of age, whereas children with fetal catch-down in weight had a lower FM(%) compared with nonchangers. In the third trimester, both catch-up and catch-down in weight were associated with an increase in FM(%) at 6 months. Children with catch-down in the third trimester had a greater risk for postnatal catch-up in weight greater than 0.67 SD score. Birth weight and weight at 6 wk were positively associated with fat mass at 6 months. Postnatal catch-up in weight within 6 wk after birth had the highest association with total and truncal FM(%) at 6 months. Total and truncal FM were higher in girls. Conclusion: Catch-down in weight in the third trimester was strongly associated with postnatal catch-up within 6 wk after birth, and both were associated with an increase in fat mass at the age of 6 months. Our study shows that fetal as well as postnatal growth patterns are associated with body composition in early childhood. Copyright

Are starting and continuing breastfeeding related to educational background? The generation R study (Article)

2009-06-01T00:00:00Z

OBJECTIVE. To assess the effect of a woman's educational level on starting and continuing breastfeeding and to assess the role of sociodemographic, lifestyle-related, psychosocial, and birth characteristics in this association. METHODS. We used the data of 2914 participants in a population-based prospective cohort study. Information on educational level, breastfeeding, sociodemographic (maternal age, single parenthood, parity, job status), lifestyle-related (BMI, smoking, alcohol use), psychosocial (whether the pregnancy was planned, stress), and birth (gestational age, birth weight, cesarean delivery, place and type of delivery) characteristics were obtained between pregnancy and 12 months postpartum. Odds ratios and 95% confidence intervals of starting and continuing breastfeeding for educational level were obtained by logistic regression, adjusted for each group of covariates and for all covariates simultaneously. RESULTS. Of 1031 highest-educated mothers, 985 (95.5%) started breastfeeding; the percentage was 73.1% (255 of 349) in the lowest-educated mothers. At 6 months, 39.3% (405 of 1031) of highest-educated mothers and 15.2% (53 of 349) of lowest-educated mothers were still breastfeeding. Educationally related differences were present in starting breastfeeding and the continuation of breastfeeding until 2 months but not in breastfeeding continuation between 2 and 6 months. Lifestyle-related and birth characteristics attenuated the association between educational level and breastfeeding, but the association was hardly affected by sociodemographic and psychosocial characteristics. CONCLUSIONS. Decisions to breastfeed were underlain by differences in educational background. The underlying pathways require further research. For the time being, interventions on promoting breastfeeding should start early in pregnancy and should increase their focus on low-educated women. Copyright

Explaining educational inequalities in birthweight: The Generation R Study (Article)

2009-05-01T00:00:00Z

Although low socio-economic status has consistently been associated with lower birthweight, little is known about the factors whereby socio-economic disadvantage influences birthweight. We therefore examined explanatory mechanisms that may underlie the association between the educational level of pregnant women, as an indicator of socio-economic status, and birthweight. The study was embedded within a population-based cohort study in the Netherlands. Information on maternal education, offspring's birthweight and several determinants of birthweight was available for 3546 pregnant women of Dutch origin. Infants of the lowest educated women had a statistically significantly lower birthweight than infants of the highest educated women [difference adjusted for gender and gestational age: -123 g (95% CI -167, -79)]. Parity, age of the pregnant women, hypertension, parental height and parental birthweight, marital status, pregnancy planning, financial concerns, number of people in household, weight gain and smoking habits individually explained part of the differences in birthweight, while adjustment for working hours and body mass index resulted in increases in birthweight differences between the educational levels. After full adjustment, the difference in birthweight between lowest and highest education was reduced by 66%. Our study confirmed remarkable educational inequalities in birthweight, a large part of which was explained by pregnancy characteristics, anthropometrics, the psychosocial and material situation, and lifestyle-related factors. Altering smoking habits may be an option to reduce educational differences in birthweight, as many lower-educated women tend to continue smoking during pregnancy. In order to tackle inequalities in birthweight, it is important that interventions are accessible for pregnant women in lower socio-economic strata.

Effect of birth weight and postnatal weight gain on body composition in early infancy. The Generation R Study (Article)

2009-05-01T00:00:00Z

Background: Rapid postnatal weight gain is associated with obesity and type 2 diabetes in later life. The influence of rapid weight gain on body composition in early infancy is still unknown and the critical periods of weight gain for later disease are debated. Aims: To investigate the effect of birth weight and rapid weight gain on body composition in the first 6 months of life. Study design: The Generation R Study, a population-based prospective cohort study from fetal life onwards. Subjects and outcome measures: We measured body fat and fat distribution by skinfold thickness at the age of 6 weeks and 6 months in 909 Dutch term infants. Analyses were adjusted for current body mass index, sex and maternal socioeconomic status, pre-pregnancy body mass index, height and duration of breastfeeding. Results: Upward postnatal weight percentile change was associated with increased skinfold thickness, percentage body fat at 6 weeks and 6 months and a larger truncal/peripheral fat ratio at 6 months (p < 0.01 for all). Birth weight was inversely associated with truncal/peripheral fat ratio (p < 0.01) but not with relative body fat at 6 months. Conclusion: During early postnatal rapid weight gain infants do not grow in all body tissues in equal measure. Instead, they acquire relatively large amounts of fat, which is preferentially distributed to the truncal region. Long term observational studies have to assess if such changes in body composition persist into adulthood.

Maternal Psychopathology Influences Infant Heart Rate Variability: Generation R Study (Article)

2009-04-01T00:00:00Z

Abstract OBJECTIVE: To assess the determinants of heart rate (HR) and heart rate variability (HRV) in children. The autonomic nervous system as measured by HR and HRV is considered a biological marker of psychopathology in children. METHODS: We examined the relationship of maternal psychopathology with infant HR and HRV. HR was recorded at 14 months in 528 infants. The high-frequency component of HRV was used as an indicator of cardiac vagal modulation. The presence of a lifetime maternal psychiatric diagnosis was assessed with the Composite International Diagnostic Interview. Presence of maternal psychiatric symptoms during pregnancy and 2 months after birth was assessed, using the Brief Symptom Inventory. RESULTS: A maternal history of a psychiatric disorder was associated with a 0.24-standard deviation (SD) higher mean HR in the infant (beta = 0.24, 95% Confidence Interval (CI) = 0.03, 0.4, p = .025) and a 0.14-SD lower high-frequency power (beta = -0.14, 95% CI = -0.6, -0.03, p = .003). Likewise, postnatal maternal anxiety and depression symptoms were associated with infant mean HR. A 1-point increase in the mean anxiety symptom score was associated with 0.14-SD higher mean HR in the infant (beta = 0.14, 95% CI = 0.05, 0.2, p = .004), and a 1-point increase in mean depression score with a 0.11-SD increase (beta = 0.11, 95% CI = 0.01, 0.2, p = .025). No significant associations of prenatal maternal affective symptoms with infants autonomic functioning were found. CONCLUSION: Maternal lifetime psychiatric diagnosis and postnatal psychiatric symptoms are associated with infant autonomic functioning, namely, higher mean HR and lower vagal modulation.

Breast-feeding modifies the association of PPARγ2 polymorphism pro12Ala with growth in early life: The generation R study (Article)

2009-04-01T00:00:00Z

OBJECTIVE-We examined whether the PPARyγ2 Ala12 allele influences growth in early life and whether this association is modified by breast-feeding. RESEARCH DESIGN AND METHODS-This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. PPARy2 was genotyped in DNA obtained from cord blood samples in 3,432 children. Information about breast-feeding was available from questionnaires. Weight, head circumference, and femur length were repeatedly measured in second and third trimesters of pregnancy, at birth, and at the ages of 1.5, 6, 11, 14, and 18 months. RESULTS-Genotype frequency distribution was 77.6% (Pro12Pro), 20.7% (Pro12Ala), and 1.7% (Ala12Ala). Growth rates in weight from second trimester of pregnancy to 18 months were higher for Pro12Ala and Ala12Ala than for Pro12Pro carriers (differences 1.11 g/week [95% CI 0.47-1.74] and 2.65 g/week [0.45-4.87], respectively). We found an interaction between genotype and breast-feeding duration (P value for interaction <0.0001). In infants who were breast-fed for >nths, PPARy2 Pro12Ala was not associated with growth rate. When breast-feeding duration was <2 months or 2-4 months, growth rate was higher in Ala12Ala than Pro12Pro carriers (differences 9.80 g/week [3.97-15.63] and 6.32 g/week [-1.04 to 13.68], respectively). CONCLUSIONS-The PPAR7gamma;2 Ala12 allele is associated with an increased growth rate in early life. This effect may be influenced by breast-feeding duration. Further studies should replicate these findings, identify the underlying mechanisms, and assess whether these effects persist into later life.

Reliability of renal ultrasound measurements in children (Article)

2009-03-12T00:00:00Z

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.

Tracking and Determinants of Kidney Size From Fetal Life Until the Age of 2 Years: The Generation R Study (Article)

2009-02-01T00:00:00Z

Background: 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. Study Design: Prospective cohort study from fetal life onward. Setting & Participants: The study was conducted in a group of 688 infants in Rotterdam, The Netherlands. Entry criteria were singleton, noncomplicated pregnancies, and Dutch ethnicity. Predictors: 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. Outcomes & Measurements: 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. Results: 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. Limitations: Kidney measurements successfully performed in only 86% of children. Conclusions: 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.

Fetal growth influences lymphocyte subset counts at birth: The generation R study (Article)

2009-02-01T00:00:00Z

Background: Preterm born and low-birth-weight infants are at risk for severe infections in infancy. It has been suggested that these infants have an immature immune system. Objective:To assess the associations of gestational age, birth weight and fetal growth with absolute lymphocyte subset counts at birth. Methods: This study was conducted in 571 infants participating in the Generation R Study, a population-based prospective cohort study from fetal life onwards. Gestational age and birth weight were obtained from midwives and hospital registries. Fetal growth was defined as increase in weight between late pregnancy and birth. Lymphocytes and T lymphocyte subset counts in cord blood were determined by 6-color flow cytometry. Multivariate linear regression models with adjustment for gender, maternal education, smoking, alcohol use, fever and mode of delivery were applied. Results: Per week increase of gestational age, T, B and NK lymphocyte counts increased with 3, 5 and 6%, respectively (p < 0.05). Helper, cytotoxic and naive T lymphocyte counts increased with 3, 4 and 5%, respectively (p < 0.05), but memory T lymphocyte counts did not. Increased birth weight and fetal growth were significantly associated with higher B lymphocyte counts, independent of gestational age, but not with the other lymphocyte subset counts. Conclusions: Lymphocyte subset counts increase with prolonged gestation, suggesting an ongoing development of the immune system. Birth weight and fetal growth seem to influence only B lymphocyte counts. Copyright

Socioeconomic inequalities in infant temperament: The Generation R Study (Article)

2009-01-01T00:00:00Z

Background: A low socioeconomic status (SES) has consistently been associated with behavioural problems during childhood. The studies of SES and behaviour in infants used temperament as a behavioural measure. However, these studies in younger children yielded inconsistent findings. Furthermore, they generally did not examine explanatory mechanisms underlying the association between SES and temperament. We investigated the association between SES and temperament in infancy. Methods: The study was embedded in the Generation R study, a population-based cohort in The Netherlands. Maternal and paternal education, family income, and maternal occupational status were used as indicators of SES. At the age of 6 months, 4,055 mothers filled out six scales of the Infant Behaviour Questionnaire-Revised. Results: Lower SES was associated with more difficult infant temperament as measured by five of the six temperament dimensions (e.g. Fear: unadjusted z-score difference between lowest and highest education: 0.57 (95%CI: 0.43, 0.71)). Only the direction of the association between SES and Sadness was reversed. The effect of SES on Distress to Limitations, Recovery from Distress, and Duration of Orienting scores was largely explained by family stress and maternal psychological well-being. These covariates could not explain the higher levels of Activity and Fear nor the lower Sadness scores of infants from low SES groups. Conclusions: SES inequalities in temperament were already present in six months old infants and could partially be explained by family stress and maternal psychological well-being. The results imply that socioeconomic inequalities in mental health in adults may have their origin early in life.

Maternal folic acid supplement use in early pregnancy and child behavioural problems: The Generation R Study (Article)

2009-01-01T00:00:00Z

Folate deficiency during embryogenesis is an established risk factor for neural tube defects in the fetus. An adequate folate nutritional status is also important for normal fetal growth and brain development. The aim of the present research was to study the association between folic acid use of the mother during pregnancy and child behavioural development. Within a population-based cohort, we prospectively assessed folic acid supplement use during the first trimester by questionnaire. Child behavioural and emotional problems were assessed with the Child Behaviour Checklist at the age of 18 months in 4214 toddlers. Results showed that children of mothers who did not use folic acid supplements in the first trimester had a higher risk of total problems (OR 1·44; 95 % CI 1·12, 1·86). Folic acid supplement use protected both from internalising (OR of no supplement use 1·65; 95 % CI 1·24, 2·19) and externalising problems (OR 1·45; 95 % CI 1·17, 1·80), even when adjusted for maternal characteristics. Birth weight and size of the fetal head did not mediate the association between folic acid use and child behaviour. In conclusion, inadequate use of folic acid supplements during early pregnancy may be associated with a higher risk of behavioural problems in the offspring. Folic acid supplementation in early pregnancy, aimed to prevent neural tube defects, may also reduce mental health problems in children.

Induction of antibodies by Staphylococcus aureus nasal colonization in young children (Article)

2009-01-01T00:00:00Z

Abstract In order to develop novel anti-staphylococcal strategies, understanding the determinants of carriage and how humans respond to Staphylococcus aureus exposure is essential. Here, the primary S. aureus-specific humoral immune response and its association with nasal colonization was studied in young children. Sera of fifty-seven (non) colonized children serially collected at birth, 6, 14 and 24 months, were analyzed for IgG, IgA and IgM binding to 19 staphylococcal proteins using flow-cytometry based technology. The antibody responses showed extensive inter-individual variability. On average, the levels of anti-staphylococcal IgA and IgM increased from birth until the age of two years (P<0.05), whereas the levels of IgG decreased (P<0.001). Placentally transferred maternal IgG did not protect against colonization. In colonized children, IgG and IgA levels to a number of proteins were higher than in non-colonized children. At both 14 and 24 months, IgG levels to Chemotaxis Inhibitory Protein of S. aureus (at 24 months, Median fluorescence intensity; 4928 vs. 13, P<0.01), Extracellular fibrinogen-binding protein (987 vs. 440, P<0.01), Clumping factor B (63 vs. 2, P<0.05) and Iron-surface determinant H (100 vs. 3, P<0.01) were significantly higher in colonized children. Therefore, these proteins seem to play a role in nasal colonization of young children.

Folic acid is positively associated with uteroplacental vascular resistance: The Generation R Study (Article)

2009-01-01T00:00:00Z

Background and aims: Periconception folic acid supplementation may influence early placentation processes and thereby the occurrence of hypertensive pregnancy disorders. For this reason we examined the associations between periconception folic acid supplementation and uteroplacental vascular resistance, blood pressure, and the risks of gestational hypertension and preeclampsia, in 5993 pregnant women, participating in a population-based cohort study. Methods and results: Folic acid supplementation was assessed by questionnaire. Mean pulsatility index (PI) and resistance index (RI) of the uterine (UtA) and umbilical arteries (UmA) were measured by Doppler ultrasound in mid- and late pregnancy. Systolic and diastolic blood pressures (SBP, DBP) were measured in early, mid- and late pregnancy. Compared to women who did not use folic acid, preconception folic acid users had a slightly lower UtA-RI in mid-pregnancy [β -0.02, 95% confidence interval (CI) -0.03, -0.01] and late pregnancy [β -0.02, 95% CI -0.03, -0.001], a lower UtA-PI in mid-pregnancy [β -0.06, 95% CI -0.1, -0.03] and late pregnancy [β -0.03, 95% CI -0.05, -0.01], as well as tendencies towards a lower UmA-PI in mid-pregnancy [β -0.02, 95% CI -0.04, -0.001] and late pregnancy [β -0.01, 95% CI -0.02, 0.01]. Additionally, these women had slightly higher SBP and DBP throughout pregnancy. Neither the patterns of blood-pressure change during pregnancy, nor the risk of gestational hypertension and preeclampsia differed between the folic acid categories. Conclusion: Periconception folic acid supplementation is associated with lower uteroplacental vascular resistance and higher blood pressures during pregnancy. The effects are small and within physiologic ranges and seem not associated with the risk of hypertensive pregnancy disorders.

Medical record validation of maternally reported history of preeclampsia (Article)

2009-01-01T00:00:00Z

Objective: In this study, we assessed the validity of maternally self-reported history of preeclampsia. Study Design and Setting: This study was embedded in the Generation R Study, a population-based prospective cohort study. Data were obtained from prenatal questionnaires and one questionnaire obtained 2 months postpartum from the mother. All women who delivered in hospital and returned a 2-month postpartum questionnaire (n = 4,330) were selected. Results: Of the 4,330 women, 76 out of 152 (50%) women who self-reported preeclampsia appeared not to have had the disease according to the definition (International Society for the Study of Hypertension in Pregnancy). From the women who self-reported not to have experienced preeclampsia, 11 out of 4,178 (0.3%) had suffered from preeclampsia. Sensitivity and specificity were 0.87 and 0.98, respectively. Higher maternal education level and parity were associated with a better self-reported diagnosis of preeclampsia. Conclusion: The validity of maternal-recall self-reported preeclampsia is moderate. The reduced self-reported preeclampsia might suggest a lack of accuracy in patient-doctor communication with regard to the diagnostic criteria of the disease. Therefore, doctors have to pay attention to make sure that women understand the nature of preeclampsia.

Variation in the IGF-1 gene is associated with lymphocyte subset counts in neonates: The Generation R Study (Article)

2009-01-01T00:00:00Z

Objective: IGF-1 stimulates growth, development and function of lymphocytes. The aim of this study was to examine whether functional variants of the IGF-1 gene are associated with absolute lymphocyte subset counts in neonates. Study design and measurements: This study was embedded in the Generation R Study, a prospective cohort study from foetal life onwards. A polymorphism in the IGF-1 promoter region was genotyped in cord blood DNA. Lymphocytes (T, B and NK) and T lymphocyte subsets (helper, cytotoxic, naïve and memory) in cord blood were immunophenotyped in 380 neonates by six-colour flow cytometry. Results: In total, 39% of the neonates were homozygous for the 192-bp allele (wild-type), 48% were heterozygous and 13% were noncarrier. No differences in absolute lymphocyte and T lymphocyte subset counts were observed between the 192-bp allele heterozygous and homozygous groups. In noncarriers, we found 15% lower T lymphocyte (P = 0.03), 22% lower B lymphocyte (P = 0.04) and 10% lower NK lymphocyte counts (P = 0.36) than in the 192-bp allele homozygous group. Analyses of T lymphocyte subsets showed 16% lower helper T lymphocyte counts (P = 0.01) in noncarriers. No significant differences were found for cytotoxic, naïve and memory T lymphocyte counts. All associations were adjusted for gravidity, mode of delivery, gestational age, birth weight, gender and 1- and 5- min Apgar scores. Conclusions: Our study showed associations between this IGF-1 promoter region polymorphism and absolute lymphocyte subset counts in neonates. These results should be regarded as hypothesis generating until they have been replicated in other studies.

Factors Associated with Pneumococcal Carriage in Healthy Dutch Infants: The Generation R Study (Article)

2008-12-01T00:00:00Z

Objective: To study the prevalence, risk factors, and dynamics of pneumococcal carriage in infancy. Study design: In a population-based prospective cohort study conducted in Rotterdam, the Netherlands between June 2003 and November 2006, nasopharyngeal swabs were obtained from children at age of 1.5, 6, and 14 months. Data on risk factors were obtained from midwives, hospital registries, and questionnaires. Results: The prevalence of pneumococcal carriage increased from 8.3% at age 1.5 months (n = 627) to 31.3% at age 6 months (n = 832) and 44.5% at age 14 months (n = 757). The prevalence of serotypes covered by the 7-valent conjugate increased from 3.0% to 16.2% and 27.7% at these respective ages. Having siblings (adjusted odds ratio [aOR] = 4.33; 95% confidence interval [CI] = 1.22 to 15.35) and day care attendance (aOR = 3.05, 95% CI = 1.88 to 4.95 at 6 months; aOR = 2.78, 95% CI 1.= 70 to 4.55 at 14 months) were associated with pneumococcal carriage. Pneumococcal carriage at age 6 months was associated with pneumococcal carriage at age 14 months (aOR = 2.43; 95% CI = 1.50 to 3.94). Pneumococcal carriage was not associated with sex, maternal smoking, maternal educational level, or breast-feeding. Conclusions: The prevalence of serotypes covered by the 7-valent conjugate vaccine increased in the first year of life. Siblings, day care attendance, and previous pneumococcal carriage were independent factors associated with pneumococcal carriage.

Fetal nutritional origins of adult diseases: Challenges for epidemiological research (Article)

2008-12-01T00:00:00Z

The generation R study: Design and cohort update until the age of 4 years (Article)

2008-12-01T00:00:00Z

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. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Of all eligible children at birth, 61% participate in the study. In addition, more detailed assessments are conducted in a subgroup of 1,232 pregnant women and their children. Data collection in the prenatal phase and postnatal phase until the age of 4 years includes questionnaires, detailed physical and ultrasound examinations, behavioural observations and biological samples. This paper gives an update of the study design and cohort profile until the children's age of 4 years. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

Demographic, emotional and social determinants of cannabis use in early pregnancy: The Generation R study (Article)

2008-12-01T00:00:00Z

Aims: To ascertain demographic, emotional and social determinants of cannabis use in early pregnancy. Design: This study was embedded in the Generation R study, a multiethnic population-based cohort of parents and their children, followed from pregnancy to childhood. Setting: Rotterdam, The Netherlands. Participants: Mothers enrolled in pregnancy who answered questions about their own and their partners substance use before and during pregnancy (n = 7610). Measurements: Using self-report questionnaires, information was collected on maternal demographics, psychopathology, delinquency, childhood trauma, social stress, family functioning, and parental alcohol, tobacco and substance use. Multinomial logistic regression analysis was used, with non-using women as reference. Findings: 246 (3.2%) women used cannabis before pregnancy and 220 (2.9%) women used cannabis both before and during pregnancy. The strongest determinant for maternal cannabis use during pregnancy was cannabis use by the biological father of the child (OR = 38.56; 95%CI = 26.14-58.88). Maternal cannabis use during pregnancy was also independently associated with being single (OR = 4.25; 95%CI = 2.33-7.75) or having a partner without being married (OR = 2.75; 95%CI = 1.56-4.85), childhood trauma (OR = 1.39; 95%CI = 1.22-1.57) and delinquency (OR = 3.37; 95%CI = 1.90-5.98), but not with maternal age, ethnicity, psychopathology, family functioning and perceived stress. Being religious was protective (Islam: OR = 0.25; 95%CI = 0.09-0.65) for maternal cannabis use during pregnancy. Additionally, lower educational level determined continued cannabis use in ever-users (OR = 3.22; 95%CI = 1.54-6.74). Conclusions: Our results showed that multiple demographic, emotional and social characteristics were associated with maternal cannabis use. These characteristics should be considered when investigating offspring exposed to cannabis in utero, as they may play an important role in mother-child interaction and child development.

What is spared by fetal brain-sparing? Fetal circulatory redistribution and behavioral problems in the general population (Article)

2008-11-01T00:00:00Z

Intrauterine growth restriction has been linked to infant behavioral problems. While typically only birth weight is examined, here the authors assessed fetal circulatory redistribution, also called the "brain-sparing effect," which is a fetal adaptive reaction to placental insufficiency. They aimed to investigate whether fetal circulatory redistribution protects against behavioral problems. Within the Generation R Study (Rotterdam, the Netherlands, 2003-2007), fetal circulation variables for the umbilical artery and the middle and anterior cerebral arteries were assessed with Doppler ultrasound in late pregnancy. Ratios between placental resistance and cerebral resistance were related to behavioral problems, as measured by the Child Behavior Checklist, in 935 toddlers aged 18 months. The umbilical/anterior cerebral ratio was associated with the Total Problems summary score from the Child Behavior Checklist (per standard-deviation increase, odds ratio = 1.2, 95% confidence interval: 1.0, 1.5). Children with higher umbilical/anterior cerebral ratios had higher risks of internalizing problems, emotional reactivity, somatic complaints, and attention problems. A high umbilical/middle cerebral ratio was related to higher scores on the Internalizing and Somatic Complaints scales. The authors conclude that infants with circulatory redistribution in gestation are more likely to have behavioral problems. This suggests that "brain-sparing" does not completely spare the brain and indicates underlying pathology with consequences for later behavior.

No midpregnancy fall in diastolic blood pressure in women with a low educational level: The generation R study (Article)

2008-10-01T00:00:00Z

Low socioeconomic status has been associated with preeclampsia. The underlying mechanism, however, is unknown. Preeclampsia is associated with relatively high blood pressure levels in early pregnancy and with an absent midpregnancy fall in blood pressure. At present, little is known about the associations among socioeconomic status, blood pressure level in early pregnancy, blood pressure change during pregnancy, and preeclampsia. We studied these associations in 3142 pregnant women participating in a population-based cohort study. Maternal educational level (high, midhigh, midlow, and low) was used as an indicator of socioeconomic status. Systolic and diastolic blood pressure was measured in early, mid-, and late pregnancy. Relative to women with high education, those with low and midlow education had higher mean systolic and diastolic blood pressure levels in early pregnancy; this was explained largely by a higher prepregnancy body mass index. Although women with high, midhigh, and midlow education had a significant midpregnancy fall in diastolic blood pressure, those with low education did not (change from early to midpregnancy: -0.38 mm Hg; 95% CI: -1.33 to 0.58). The latter could not be explained by prepregnancy body mass index, smoking, or alcohol consumption during pregnancy. The absence of a midpregnancy fall also tended to be related to the development of preeclampsia, especially among women with a low educational level (OR: 3.8; 95% CI: 0.80 to 18.19). The absence of a midpregnancy fall in diastolic blood pressure in women with a low education level may be a sign of endothelial dysfunction that is manifested during pregnancy. This might partly explain these women's susceptibility to preeclampsia.

Does gestational duration within the normal range predict infant neuromotor development? (Article)

2008-10-01T00:00:00Z

Aim: To examine the extent to which infant neuromotor development is determined by gestational duration and birth weight within the normal range. Methods: The study was embedded within the Generation R Study, a population-based cohort in Rotterdam, the Netherlands. An adapted version of Touwen's Neurodevelopmental Examination was used to assess 3224 infants (1576 males and 1648 females) at corrected ages between 9 and 15 weeks. Non-optimal neuromotor development was defined as a score in the highest tertile. Results: Infant neuromotor development was significantly affected by gestational duration (odds ratio 0.8, 95% confidence interval 0.7;0.8). Adding a quadratic term of gestational duration to the model revealed a highly significant curvilinear association between gestational duration and neuromotor development; after adjusting for post-conceptional age this was still significant. Although babies with a 1 kg lower birth weight had a 30% higher risk of non-optimal neuromotor development, this association disappeared after adjustment for post-conceptional age. Conclusions: Our findings indicate that differences in infant neuromotor development can be explained even by variations in gestational duration within the normal range. If an infant is found to have minor neuromotor delays, account should be taken of this.

Dynamics and determinants of Staphylococcus aureus carriage in infancy: the Generation R Study (Article)

2008-10-01T00:00:00Z

Serial nasal swabs were collected at the ages of 1.5, 6, and 14 months from 443 infants in the Generation R Study. The objective was to study the dynamics and determinants of Staphylococcus aureus nasal carriage in the first year of life. The prevalence of S. aureus carriage decreased in the first year of life, from 52.1% at the age of 1.5 months to 12.9% at 14 months. Persistent carriage, defined as continuous carriage of the same S. aureus strain at the three sampling moments, was rarely detected in early infancy.

Determinants of folic acid use in early pregnancy in a multi-ethnic urban population in The Netherlands: The Generation R study (Article)

2008-10-01T00:00:00Z

Objective: Recommendations on folic acid use to prevent neural tube defects have been launched in several countries. Adequate folic acid use seems to be low. This study assesses the prevalence of folic acid use and identifies its determinants. Methods: The study was embedded in the Generation R Study Rotterdam, the Netherlands, a population-based prospective cohort study between 2002 and 2006. Complete information of 6940 women was available. Information on folic acid use and potential determinants was obtained by questionnaires and physical examination. Results: Of all women 37% adequately used folic acid during the preconception period. Most important risk factors for inadequate use were unplanned pregnancy (OR 9.5, CI 7.2-12.4, p < 0.001), low educational level (OR 2.5, CI 1.8-3.6, p < 0.001) and non-western ethnicity, (OR 3.5, CI 2.9-4.3, p < 0.001). After stratification for ethnicity, unplanned pregnancy remained the most important risk factor for inadequate use. Other risk factors for inadequate use were younger age, single marital status, smoking, multiparity (all p < 0.001) and alcohol use (p < 0.05). In contrast, previous spontaneous abortion decreased the risk of inadequate folic acid use (p < 0.001). Conclusion: Adequate preconception folic acid supplementation is still too low. Implementation of preconception programs and other public health strategies are strongly needed.

Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: The Generation R study (Article)

2008-09-05T00:00:00Z

Concern about potential health impacts of low-level exposures to organophosphorus (OP) pesticides, bisphenol A (BPA), and phthalates among the general population is increasing. We measured levels of six dialkyl phosphate (DAP) metabolites of OP pesticides, a chlorpyrifos-specific metabolite (3,5,6-trichloro-2-pyridinol, TCPy), BPA, and 14 phthalate metabolites in urine samples of 100 pregnant women from the Generation R study, the Netherlands. The unadjusted and creatinine-adjusted concentrations were reported, and compared to National Health and Nutrition Examination Survey and other studies. In general, these metabolites were detectable in the urine of the women from the Generation R study and compared with other groups, they had relatively high-level exposures to OP pesticides and several phthalates but similar exposure to BPA. The median concentrations of total dimethyl (DM) metabolites was 264.0 nmol/g creatinine (Cr) and of total DAP was 316.0 nmol/g Cr. The median concentration of mono-ethyl phthalate (MEP) was 222.0 μg/g Cr; the median concentrations of mono-isobutyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were above 50 μg/g Cr. The median concentrations of the three secondary metabolites of di-2-ethylhexyl phthalate (DEHP) were greater than 20 μg/g Cr. The data indicate that the Generation R study population provides a wide distribution of selected environmental exposures. Reasons for the relatively high levels and possible health effects need investigation.

A variant of the IGF-I gene is associated with blood pressure but not with left heart dimensions at the age of 2 years: The Generation R Study (Article)

2008-09-01T00:00:00Z

Background and objective: A common variant of the IGF-I gene has been shown to be associated with cardiovascular disease in adulthood. The objective of this study was to examine whether this variant of the IGF-I gene is associated with blood pressure and left heart dimensions in early childhood. Research design and methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life onwards. IGF-I promoter region was genotyped in DNA obtained from cord blood. Blood pressure (systolic and diastolic) and echocardiography (left ventricular mass, left atrial diameter and aortic root diameter) measurements were performed at the age of 2 years. Analyses were performed in 538 subjects. Results: Eight alleles of the IGF-I promoter region were identified. In total, 43% of the subjects were homozygous for the 192 bp allele (wild type), 46% were heterozygous and 11% were non-carriers. Significantly lower systolic and diastolic blood pressures were found in non-carrier subjects (difference compared with homozygous subjects: - 4.4 (95% confidence interval (CI) - 7.8 to - 1.1) mmHg and - 3.5 (95% CI: - 6.9 to - 0.1) mm respectively). No significant differences were found for left heart dimensions at the age of 2 years. No association was found when we used a previously proposed alternative classification of the IGF-I gene. Conclusion: The variant type of the IGF-I promoter region is associated with lower blood pressure but not with left heart dimensions at the age of 2 years. Follow-up studies are needed to examine whether these differences persist in later life.

Maternal smoking in prenatal and early postnatal life and the risk of respiratory tract infections in infancy. the Generation R study (Article)

2008-08-01T00:00:00Z

Objective: To assess the associations of maternal smoking during pregnancy and in the postnatal period with respiratory tract infections in young infants. Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onwards. All data were assessed by questionnaires. Maternal smoking was assessed in pregnancy (no, stopped when pregnancy was known, continued during pregnancy) and at 6 months postnatally. Doctor-attended respiratory tract infections were recorded at the age of 6 months. The present analyses were based on 3,418 subjects. Results: Continued maternal smoking during pregnancy was not associated with respiratory tract infections in young infants. Maternal smoking in the postnatal period showed a tendency for an increased risk of lower respiratory tract infections in infants (adjusted odds ratio (aOR) 1.61 (95% confidence interval: 0.99, 2.63)). Dose-response effects for maternal smoking during pregnancy or in the postnatal period on the risk of respiratory tract infections were not observed. In infants of mothers who smoked neither during pregnancy nor in the postnatal period, environmental smoking during pregnancy and in the postnatal period together was associated with upper respiratory tract infections (aOR 1.58 (95% CI: 1.07, 2.35)). Conclusions: No effect of maternal smoking during pregnancy with respiratory tract infections was observed. Weak evidence for the association between maternal smoking in the postnatal period and lower respiratory tract infections were found. Exposure to non-maternal environmental smoking during pregnancy and in the postnatal period together increases the risk of upper respiratory tract infections in young infants.

Smoke exposure, airway symptoms and exhaled nitric oxide in infants: The Generation R study (Article)

2008-08-01T00:00:00Z

The effect of pre- and post-natal smoke exposure on exhaled nitric oxide fraction (FeNO) in infants was evaluated and the association between respiratory symptoms and FeNO in the first 2 months of life was investigated. The Generation R study is a population-based, prenatally recruited birth cohort. Exposures were assessed by means of questionnaires prospectively administered during pregnancy and after birth. Successful off-line FeNO measurements during tidal breathing were obtained in 187 infants (median age 6.9 weeks). The association between possible determinants and log FeNO was investigated with multiple linear regression analysis. Infants exposed pre- and post-natally to smoke showed lower FeNO than infants exposed only after birth (geometric mean difference (95% confidence interval) 1.5 (1.0-2.1) ppb) and never-exposed infants (1.4 (1.0-1.8) ppb). FeNO was reduced in infants with severe upper respiratory symptoms compared with infants with nonsevere symptoms (1.6 (1.0-2.4) ppb). Infants with symptoms of the lower respiratory tract had lower FeNO than asymptomatic infants (1.2 (1.0-1.50) ppb). In conclusion, the nature of the association between smoke exposure and exhaled nitric oxide fraction is dependent on timing and intensity of exposure. The occurrence and the severity of respiratory symptoms in the first 2 months of life are associated with lower exhaled nitric oxide fraction. Copyright

Smoking during pregnancy in ethnic populations: The Generation R study (Article)

2008-08-01T00:00:00Z

Patterns and correlates of maternal smoking could differ according to ethnic background, and these differences might have consequences for intervention strategies. In the Generation R study, we examined patterns of smoking during pregnancy and the associations of socioeconomic (educational level), demographic (maternal age, marital status, generational status, parity) and lifestyle (alcohol consumption, partner smoking) correlates with smoking during pregnancy in 5,748 women of Dutch, Turkish, Moroccan, Surinamese-Hindustani, Surinamese-Creole, Capeverdean and Antillean ethnic background. Smoking rates before pregnancy were highest in the Turkish group (43.7%) and lowest in the Moroccan group (7.0%). Compared with Dutch women (24.1%), Turkish and Moroccan women were less likely to quit smoking before pregnancy (17.0% and 5.9%, respectively; p<.001). Turkish and Moroccan women (72.0% and 70.6%, respectively) were more likely to continue smoking during pregnancy compared to Dutch women (58.6%, p<.001). Lower education was associated with smoking during pregnancy only in the Dutch group. No significant association of education with smoking was seen in the non-Dutch groups. Second-generation (i.e., foreign-born) Turkish and Capeverdean women were more likely to smoke during pregnancy compared with first-generation women. Partner smoking was associated with smoking during pregnancy in all ethnic groups except for Surinamese-Creole and Antillean. Maternal alcohol consumption was associated with smoking during pregnancy in all ethnic groups except for Capeverdean. Smoking rates and correlates of smoking during pregnancy varied by ethnic background. These observations should be considered when designing maternal smoking prevention and intervention strategies.

Tracking and determinants of subcutaneous fat mass in early childhood: The Generation R Study (Article)

2008-07-01T00:00:00Z

Objectives: To examine the development and tracking of subcutaneous fat mass in the first 2 years of life and to examine which parental, fetal and postnatal characteristics are associated with subcutaneous fat mass. Design: This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. Subcutaneous fat mass was measured by skinfold thickness (biceps, triceps, suprailiacal, subscapular) at the ages of 1.5, 6 and 24 months in 1012 children. Information about parental, fetal and postnatal growth characteristics was collected by physical and fetal ultrasound examinations and questionnaires. Results: Normal values of subcutaneous fat mass are presented. Total subcutaneous fat mass was higher in girls than in boys at the age of 24 months (P=0.01). Subjects in the lowest and highest quartiles at the age of 6 months tended to keep their position in the same quartile at the age of 24 months (odds ratios 1.86 (95% confidence interval (CI) 1.3, 2.7)) and 1.84 (95% CI: 1.3, 2.6), respectively). Maternal height and weight, paternal weight, fetal weight at 30 weeks, birth weight and weight at the age of 6 weeks were each inversely associated with subcutaneous fat mass at the age of 24 months after adjustment for current weight at 24 months. Conclusion: This study shows for the first time that subcutaneous fat mass tends to track in the first 2 years of life. Furthermore, the results suggest that an adverse fetal environment and growth are associated with increased subcutaneous fat mass at the age of 24 months. Further studies are needed to examine whether these associations persist in later life.

Explaining Educational Inequalities in Preterm Birth. The Generation R Study (Article)

2008-06-18T00:00:00Z

BACKGROUND: Although a low socioeconomic status has consistently been associated with an increased risk of preterm birth, little is known about the pathways through which socioeconomic disadvantage influences preterm birth. AIM: To examine mechanisms that might underlie the association between the educational level of pregnant women as an indicator of socioeconomic status, and preterm birth. METHODS: The study was nested in a population-based cohort study in the Netherlands. Information was available for 3830 pregnant women of Dutch origin. FINDINGS: The lowest-educated pregnant women had a statistically significant higher risk of preterm birth (odds ratio (OR) = 1.89 (95% CI 1.28 to 2.80)) than the highest educated women. This increased OR was reduced by up to 22% after separate adjustment for age, height, preeclampsia, intrauterine growth restriction, financial concerns, long-lasting difficulties, psychopathology, smoking habits, alcohol consumption, and body mass index (BMI) of the pregnant women. Joint adjustment for these variables resulted in a reduction of 89% of the increased risk of preterm birth among low-educated pregnant women (fully adjusted OR = 1.10 (95% CI 0.66 to 1.84)). CONCLUSIONS: Pregnant women with a low educational level have a nearly twofold higher risk of preterm birth than women with a high educational level. This elevated risk could largely be explained by pregnancy characteristics, indicators of psychosocial well-being, and lifestyle habits. Apparently, educational inequalities in preterm birth go together with an accumulation of multiple adverse circumstances among women with a low education. A number of explanatory mechanisms unravelled in the present study seem to be modifiable by intervention programmes.

Intra- and interobserver reproducibility study of early fetal growth parameters (Article)

2008-04-01T00:00:00Z

Objective: To assess the intra- and interobserver reproducibility of fetal biometry measurements by transabdominal ultrasound in early pregnancy. Methods: The study consisted of 21 singleton pregnancies with a gestational age between 9 and 14 weeks. Intraclass correlation coefficients (ICCs) and coefficients of variation (CVs) were calculated. Bland and Altaian plots were computed to analyze agreement for measurements between and among observers. Limits of agreement ±2 SD for the differences in fetal biometry measurements in proportions of the mean of the measurements were derived. Results: High intra- and interobserver ICCs were found, ranging from 0.998, crown-rump length (CRL) to 0.982, femur length (FL) and CVs ranging from 1.4% (CRL) to 5.9% (FL). Limits of agreement in the Bland and Altman plots ranged from -2.7 to 2.3% (CRL) difference from the mean to -13 to 23% (FL) difference. Agreement for fetal biometry increased with fetal size. Conclusions: This study demonstrated good reproducibility of most measurements of fetal biometry in early pregnancy by abdominal ultrasound. CRL and biparietal diameter (BPD) showed high reproducibility and agreement, and head circumference (HC) to a lesser extend, from 9 weeks of gestational age onwards, abdominal circumference (AC) is only reliable from circa 11 weeks onwards. FL has a poor reproducibility before 14 weeks of gestational age. Copyright

New charts for ultrasound dating of pregnancy and assessment of fetal growth: Longitudinal data from a population-based cohort study (Article)

2008-04-01T00:00:00Z

Objectives: Correct assessment of gestational age and fetal growth is essential for optimal obstetric management. The objectives of this study were, first, to develop charts for ultrasound dating of pregnancy based on crown-rump length and biparietal diameter and, second, to derive reference curves for normal fetal growth based on biparietal diameter, head circumference, transverse cerebellar diameter, abdominal circumference and femur length from 10 weeks of gestational age onwards. Methods: A total of 8313 pregnant women were included for analysis in this population-based prospective cohort study. All women had repeated ultrasound assessments to examine fetal growth. Results: Charts for ultrasound dating of pregnancy, based on crown-rump length and biparietal diameter, were derived. Internal validation with the actual date of delivery showed that ultrasound imaging provided reliable gestational age estimates. Up to 92% of deliveries took place within 37-42 weeks of gestation if gestational age was derived from ultrasound data, compared with 87% based on a reliable last menstrual period. The earlier the ultrasound assessment the more accurate the prediction of date of delivery. After 24 weeks of gestation a reliable last menstrual period provided better estimates of gestational age. Reference curves for normal fetal growth from 10 weeks of gestational age onwards were derived. Conclusions: Charts for ultrasound dating of pregnancy and reference curves for fetal biometry are presented. The results indicate that, up to 24 weeks of pregnancy, dating by ultrasound examination provides a better prediction of the date of delivery than does last menstrual period. The earlier the ultrasound assessment in pregnancy, preferably between 10 and 12 weeks, the better the estimate of gestational age. Copyright

Perinatal stress influences lymphocyte subset counts in neonates. The generation R study (Article)

2008-03-01T00:00:00Z

In the general population, it is unknown whether stress-related perinatal factors influence lymphocyte subset counts in neonates. The aim of this study was to assess the associations of perinatal factors related to stress and hypoxia (mode of delivery, Apgar scores, and umbilical cord blood pH) with absolute lymphocyte subset counts (T, B, NK, helper T, cytotoxic T, naïve, memory T) in cord blood of 571 neonates. This study was embedded in a population-based prospective cohort study from fetal life onwards. All models were adjusted for gestational age, birth weight, gender, maternal fever, and each of the other perinatal stress-relating factors. Our results showed that increasing stress-related mode of delivery was positively associated with NK and memory T-lymphocyte subset counts (all p < 0.01). Effects of Apgar scores on lymphocyte subsets were explained by umbilical cord blood pH. Lower umbilical cord blood pH was associated with higher B, NK, and memory T-lymphocyte counts (all p < 0.05). Effects of mode of delivery and umbilical cord blood pH on other lymphocyte subsets were not observed. We conclude that, in the general population, lymphocyte subset counts in neonates increase with increasing stress- and hypoxia-related perinatal factors.

Active and passive maternal smoking during pregnancy and the risks of low birthweight and preterm birth: The generation R study (Article)

2008-03-01T00:00:00Z

The objective of this study was to examine the associations between active and passive smoking in different periods of pregnancy and changing smoking habits during pregnancy, with low birthweight and preterm birth. The study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards in Rotterdam, The Netherlands. Active and passive smoking were assessed by questionnaires in early, mid- and late pregnancy. Analyses were based on 7098 pregnant women and their children. Active smoking until pregnancy was ascertained and was not associated with low birthweight and preterm birth. Continued active smoking after pregnancy was also recorded and was associated with low birthweight (adjusted odds ratio 1.75 [95% CI 1.20, 2.56]) and preterm birth (adjusted odds ratio 1.36 [95% CI 1.04, 1.78]). The strongest associations were found for active maternal smoking in late pregnancy. Passive maternal smoking in late pregnancy was associated with continuously measured birthweight (P for trend <0.001). For all active smoking categories in early pregnancy, quitting smoking was associated with a higher birthweight than continuing to smoke. Tendencies towards smaller non-significant beneficial effects on mean birthweight were found for reducing the number of cigarettes without quitting completely. This study shows that active and passive smoking in late pregnancy are associated with adverse effects on weight and gestational age at birth. Smoking in early pregnancy only, seems not to affect fetal growth adversely. Health care strategies for pregnant women should be aimed at quitting smoking completely rather than reducing the number of cigarettes.

Variation in the IGF1 gene and growth in foetal life and infancy. The Generation R Study (Article)

2008-03-01T00:00:00Z

Objective: 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. Results: 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). Conclusions: 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.

Foetal growth determines cerebral ventricular volume in infants. The Generation R Study (Article)

2008-02-15T00:00:00Z

The cerebral ventricular system is a marker of brain development and a predictor of neurodevelopmental outcome. In premature or dysmature neonates, neuroanatomical structures including the ventricular system appear to be altered. The present study aims to provide information on the association between foetal growth and neonatal cerebral ventricular size in the normal population. Within the Generation R Study, a population-based cohort study, we used three-dimensional cranial ultrasound to determine lateral ventricular volume in 778 term infants aged 4-12 weeks. Foetal growth characteristics were repeatedly measured in early, mid- and late pregnancy and analysed in relation to ventricular volume divided by head circumference. Results revealed positive associations between foetal head circumference in late pregnancy and log-transformed ventricular volume (β = 0.077, 95% confidence interval (0.017; 0.136), equivalent to a 7.7% increase in ventricular volume per standard deviation of head circumference). Similarly, in a per week-longer gestational duration, ventricular volume in infancy was 6.0% larger. Multilevel modelling demonstrated that reduced growth of foetal head circumference and biparietal diameter during pregnancy were associated with decreased ventricular volume in infancy. In conclusion, foetal maturation is positively associated to cerebral ventricular size in term infants. Larger ventricular size in term infants needs to be distinguished from ventricular enlargement due to intraventricular haemorrhage or white matter damage in premature or dysmature infants. Moreover, the naturally occurring enlargement of ventricles during infancy should be considered in interpreting reports on increased ventricular volumes in several neuropsychiatric disorders.

Fetal hemodynamic adaptive changes related to intrauterine growth the generation R study (Article)

2008-02-05T00:00:00Z

Background-It has been suggested that an adverse fetal environment increases susceptibility to hypertension and cardiovascular disease in adult life. This increased risk may result from suboptimal development of the heart and main arteries in utero and from adaptive cardiovascular changes in conditions of reduced fetal growth. The aim of the present study was to evaluate whether reduced fetal growth is associated with fetal circulatory changes and cardiac dysfunction. Methods and Results-This study was embedded in a population-based, prospective cohort study starting in early fetal life. Fetal growth characteristics and fetal circulation variables were assessed with ultrasound and Doppler examinations in 1215 healthy women. The fetal circulation was examined in relation to estimated fetal weight. Higher placental resistance indices were strongly associated with decreased fetal growth. Cerebral resistance showed a gradual decline with reduced fetal growth. Cardiac output, peak systolic velocity of the outflow tracts, and cardiac compliance showed a gradual reduction with diminished fetal growth, whereas intraventricular pressure gradually increased. Conclusions-Decreased fetal growth is associated with adaptive fetal cardiovascular changes. Cardiac remodeling and cardiac output changes are consistent with a gradual increase in afterload and compromised arterial compliance in conditions of decreased fetal growth. These changes have already begun to occur before the stage of clinically apparent fetal growth restriction and may contribute to the increased risk of cardiovascular disease in later life. (Circulation. 2008;117:649-659.).

Maternal smoking in pregnancy is associated with cholesterol development in the offspring: A 27-years follow-up study (Article)

2008-01-01T00:00:00Z

Objective: To examine the associations of maternal smoking in pregnancy with development of cholesterol levels from childhood to adulthood. Methods: Total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were measured annually from 1975 to 1993 and in 2002 in 350 subjects aged 5-19 years at baseline who participate in a prospective cohort study. Pregnancy and birth data were obtained through questionnaires sent to the parents. Results: Children of mothers who smoked in pregnancy showed a higher annual change in total cholesterol of 0.12 mmol/l per 10 years (95% confidence interval (CI): 0, 0.23) compared to children whose mothers did not smoke in pregnancy. Larger effect estimates were found in children with moderate overweight (0.39 mmol/l per 10 years (95% CI: 0.14, 0.63). HDL-cholesterol and LDL-cholesterol showed tendencies towards a decrease and increase, respectively, in children of mothers who smoked in pregnancy compared to children whose mothers did not smoke in pregnancy. Adjustment for potential confounders did not materially change the effect estimates. Conclusion: This study suggests for the first time that maternal smoking in pregnancy is associated with an increased rise in total cholesterol levels and a tendency towards an adverse lipoprotein profile in the offspring.

Maternal anthropometrics in pregnancy are associated with left ventricular mass in infancy. The generation R study (Article)

2008-01-01T00:00:00Z

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.

The Generation R Study Biobank: A resource for epidemiological studies in children and their parents (Article)

2007-12-01T00:00:00Z

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.

Insulin gene variable number of tandem repeats is not associated with weight from fetal life until infancy: The Generation R Study (Article)

2007-12-01T00:00:00Z

Objective: 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. Design and methods: 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. Results: The genotype distribution was I/1 50.8%, I/III40.0%, and III/ III9.2%. 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. Conclusions: 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.

Explaining differences in birthweight between ethnic populations. The Generation R Study (Article)

2007-12-01T00:00:00Z

Objective: To examine whether differences in birthweight of various ethnic groups residing in the Netherlands can be explained by determinants of birthweight. Design: Population-based birth cohort study. Setting: Data of pregnant women and their partners in Rotterdam, the Netherlands. Population: We examined data of 6044 pregnant women with a Dutch, Moroccan, Turkish, Capeverdean, Antillean, Surinamese-Creole, Surinamese-Hindustani and Surinamese-other ethnic background. Methods: Regression analyses were used to assess the impact of biomedical, socio-demographic and lifestyle-related determinants on birthweight differences. Main outcome measure: Birthweight was established immediately after delivery in grams. Results: Compared with mean birthweight of offspring of Dutch women (3485 g, SD 555), the mean birthweight was lower in all non-Dutch populations, except in Moroccans. Differences ranged from an 88-g lower birthweight in offspring of the Turkish women to a 424-g lower birthweight in offspring of Surinamese-Hindustani women. Differences in gestational age, maternal and paternal height largely explained the lower birthweight in the Turkish, Antillean, Surinamese-Creole and Surinamese-other populations. Differences in birthweight between the Dutch and the Capeverdean and Surinamese-Hindustani populations could only partly be explained by the studied determinants. Conclusions: These results confirm significant differences in birthweight between ethnic populations that can only partly be understood from established determinants of birthweight. The part that is understood points to the importance of determinants that cannot easily be modified, such as parental height. Further study is necessary to obtain a fuller understanding.

Moderate Alcohol Consumption During Pregnancy and the Risk of Low Birth Weight and Preterm Birth. The Generation R Study (Article)

2007-10-01T00:00:00Z

Purpose: To examine the associations of alcohol consumption in different periods of pregnancy with the risks of low birth weight and preterm birth. Methods: This study was based on 7141 subjects participating in a population-based prospective cohort study from early pregnancy. Alcohol consumption was assessed in early, mid, and late pregnancy. Birth outcomes were birth weight in grams, low birth weight (<2500 g), small size for gestational age at birth (< -2 standard deviation scores) and preterm birth (gestational age <37 weeks). Results: Overall, alcohol consumption during pregnancy was not associated with adverse birth outcomes. However, dose-response analyses showed tendencies toward adverse effects of average consumption of 1 or more alcoholic drinks per day in early pregnancy on birth weight (difference -129 g [95% confidence interval (CI): -271, 12]), low birth weight (adjusted odds ratio [aOR] 4.81 [95% CI: 1.10, 21.08]), small size for gestational age at birth (aOR 1.45 [95% CI: 0.33, 6.44]) and preterm birth (aOR 2.51 [95% CI: 0.92, 6.81]). Similar effects were found in late pregnancy. Conclusion: Average consumption of one or more but not less than one alcoholic drink per day in early or late pregnancy seems to be associated with adverse birth outcomes in the offspring.

Fetal kidney volume and its association with growth and blood flow in fetal life: The Generation R Study (Article)

2007-09-01T00:00:00Z

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.

Maternal smoking and fetal growth characteristics in different periods of pregnancy: The Generation R Study (Article)

2007-05-01T00:00:00Z

The authors examined the associations of maternal smoking in pregnancy with various fetal growth characteristics among 7,098 pregnant women participating in the Generation R Study (2002-2006), a population-based prospective cohort study of pregnant women and their children in Rotterdam, the Netherlands. Maternal smoking was assessed by questionnaires administered in early, mid-, and late pregnancy. Fetal growth characteristics evaluated included head circumference, abdominal circumference, and femur length measured repeatedly in mid- and late pregnancy. Maternal smoking during pregnancy was associated with reduced growth in head circumference (-0.56 mm/week; 95% confidence interval (CI): -0.73, -0.40), abdominal circumference (-0.58 mm/week; 95% CI: -0.81, -0.34), and femur length (-0.19 mm/week; 95% CI: -0.23, -0.14). This reduced growth resulted in a smaller femur length from midpregnancy (gestational age 18-24 weeks) onwards and smaller head and abdominal circumferences from late pregnancy (gestational age ≥25 weeks) onwards. Analyses using standard deviation scores for the growth characteristics demonstrated the largest effect estimates for femur length. The authors concluded that maternal smoking during pregnancy is associated with reduced growth in fetal head circumference, abdominal circumference, and femur length. The larger effect on femur length suggests that smoking during pregnancy affects primarily peripheral tissues. Copyright

Effects of maternal smoking in pregnancy on prenatal brain development. The generation R study (Article)

2007-02-01T00:00:00Z

Nicotine, as has been shown in animal studies, is a neuroteratogen, even in concentrations that do not cause growth retardation. In humans, there is only indirect evidence for negative influences of nicotine on brain development from studies on the association between maternal smoking in pregnancy and behavioural and cognitive development in the offspring. We investigated the associations of maternal smoking in pregnancy with foetal head growth characteristics in 7042 pregnant women. This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life until adulthood. Maternal smoking was assessed by questionnaires in early, mid- and late pregnancy. Head circumference, biparietal diameter, transcerebellar diameter and atrial width of lateral ventricles were repeatedly measured by ultrasound. When mothers continued to smoke during pregnancy, foetal head circumference showed a growth reduction of 0.13 mm [95% confidence interval (CI): -0.18, -0.09] per week compared to foetuses of mothers who never smoked during pregnancy. Biparietal diameter of foetuses with smoking mothers grew 0.04 mm (95% CI: -0.05, -0.02) less per week than that of foetuses of nonsmoking mothers. Atrial width of lateral ventricle was 0.12 mm (95% CI: -0.22, -0.02) smaller and transcerebellar diameter was 0.08 mm (95% CI: -0.15, -0.00) smaller if mothers smoked, but growth per week of these characteristics was not affected by maternal smoking in pregnancy. In conclusion, continuing to smoke during pregnancy leads to reduced growth of the foetal head. Further research should focus on the causal pathway from prenatal cigarette exposure via brain development to behavioural and cognitive functions.

Maternal and fetal origins of cardiovascular disease: The Generation R Study (Doctoral Thesis)

2006-05-24T00:00:00Z

In de afgelopen twintig jaar zijn in epidemiologisch onderzoek associaties aangetoond tussen een laag geboortegewicht en de ontwikkeling van hart en vaatziekten en de risicofactoren daarvoor op latere leeftijd. De ‘foetale origine van volwassen aandoeningen’ hypothese veronderstelt dat een ongunstige foetale omgeving leidt tot aanpassingen in de ontwikkeling die permanent de structuur, fysiologie en het metabolisme van de foetus beïnvloeden. Dit leidt tot foetale groeivertraging en een laag geboortegewicht en zou ten gunste zijn voor de overleving op korte termijn. Lange termijn eff ecten zouden echter schadelijk zijn en leiden tot hart en vaatziekten. Door deze hypothese is recent de zoektocht naar de oorsprong van hart en vaatziekten uitgebreid van epidemiologisch onderzoek bij volwassenen en kinderen naar onderzoek gericht op het foetale en vroege postnatale leven. Hoewel het geboortegewicht makkelijk te meten is en beschikbaar is uit obstetrische dossiers, is het waarschijnlijk niet de beste afspiegeling van een ongunstige foetale omgeving of blootstelling. Hetzelfde geboortegewicht kan het resultaat zijn van verschillende foetale blootstellingen en groeipatronen. Roken van moeder tijdens de zwangerschap is de belangrijkste determinant van laag geboortegewicht in westerse landen. Een ongunstige foetale omgeving als gevolg van roken van moeder kan door de directe effecten van nicotine en de geassocieerde maternale levensstijl en voedingsgewoonten leiden tot veranderingen in de ontwikkeling. Om die reden zou roken van moeder tijdens de zwangerschap een betere afspiegeling kunnen zijn van een nadelige foetale omgeving dan het geboortegewicht. De ‘foetale origine van volwassen aandoeningen’ hypothese was de belangrijkste aanleiding tot het doen van het onderzoek dat beschreven wordt in dit proefschrift. Het doel van dit onderzoek was om mechanismen te identificeren die leiden van ongunstige foetale blootstellingen, tot suboptimale foetale groeipatronen en vervolgens tot de ontwikkeling van risicofactoren voor hart en vaatziekten. Hierbij hebben we ons gericht op roken van moeder tijdens de zwangerschap als ongunstige foetale blootstelling. Er zijn verschillende hypothesen voorgesteld voor mechanismen die de associaties tussen een laag geboortegewicht en ziekten op de volwassen leeftijd zouden kunnen verklaren. Deze hypothesen stellen een centrale rol voor voor 1) foetale ondervoeding; 2) toegenomen foetale blootstelling aan cortisol; 3) genetische aanleg voor zowel laag geboortegewicht als ziekten op de volwassen leeftijd; en 4) versnelde postnatale groei van kinderen met een laag geboortegewicht. In hoofdstuk 2 worden resultaten beschreven van eerder verricht epidemiologisch onderzoek, dat opgezet was om deze hypothesen te testen. Het is nog niet bekend welke mechanismen de associaties tussen laag geboortegewicht en ziekten op de volwassen leeftijd verklaren.