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1.  Use of alarm features in referral of febrile children to the emergency department: an observational study 
The diagnostic value of alarm features of serious infections in low prevalence settings is unclear.
To explore to what extent alarm features play a role in referral to the emergency department (ED) by GPs who face a febrile child during out-of-hours care.
Design and setting
Observational study using semi-structured, routine clinical practice data of febrile children (<16 years) presenting to GP out-of-hours care.
Logistic regression analyses were performed to assess the association between alarm features of serious infections (selected from two guidelines and one systematic review) and referral to the ED. Adherence to the guideline was explored by a 2×2 contingency table.
In total 794 (8.1%) of 9794 eligible patients were referred to the ED. Alarm signs most strongly associated with referral were ‘age <1 month’, ‘decreased consciousness’, ‘meningeal irritation’, and ‘signs of dehydration’. Nineteen percent of 3424 children with a positive referral indication according to the guideline were referred to the ED. The majority of those not referred had only one or two alarm features present. A negative referral indication was adhered to for the majority of children. Still, in 20% of referred children, alarm features were absent.
In contrast to guidance, GPs working in primary out-of-hours care seem more conservative in referring febrile children to the ED, especially if only one or two alarm features of serious infection are present. In addition, in 20% of referred children, alarm features were absent, which suggests that other factors may be important in decisions about referral of febrile children to the hospital ED.
PMCID: PMC3876161  PMID: 24567576
bacterial infections; child; fever; general practice; infant; referral and consultation; signs and symptoms
2.  Alarm signs and antibiotic prescription in febrile children in primary care: an observational cohort study 
The British Journal of General Practice  2013;63(612):e437-e444.
Although fever in children is often self-limiting, antibiotics are frequently prescribed for febrile illnesses. GPs may consider treating serious infections by prescribing antibiotics.
To examine whether alarm signs and/or symptoms for serious infections are related to antibiotic prescription in febrile children in primary care.
Design and setting
Observational cohort study involving five GP out-of-hours services.
Clinical information was registered and manually recoded. Children (<16 years) with fever having a face-to-face contact with a GP were included. Children who were already using antibiotics or referred to secondary care were excluded. The relation between alarm signs and/or symptoms for serious infections and antibiotic prescription was tested using multivariate logistic regression.
Of the 8676 included patients (median age 2.4 years), antibiotics were prescribed in 3167 contacts (36.5%). Patient characteristics and alarm signs and/or symptoms positively related to antibiotic prescription were: increasing age (odds ratio [OR] = 1.03; 95% confidence interval [95% CI] = 1.02 to 1.05), temperature measured by GP (OR = 1.72; 95% CI = 1.59 to 1.86), ill appearance (OR = 3.93; 95% CI = 2.85 to 5.42), being inconsolable (OR = 2.27; 95% CI = 1.58 to 3.22), shortness of breath (OR = 2.58; 95% CI = 1.88 to 3.56), duration of fever (OR = 1.31; 95% CI = 1.26 to 1.35). Negative associations were found for neurological signs (OR = 0.45; 95% CI = 0.27 to 0.76), signs of urinary tract infection (OR = 0.63; 95% CI = 0.49 to 0.82), and vomiting and diarrhoea (OR = 0.65; 95% CI = 0.57 to 0.74). These variables explained 19% of the antibiotic prescriptions.
Antibiotics are often prescribed for febrile children. These data suggest that treatment of a supposed serious bacterial infection is a consideration of GPs. However, the relatively low explained variation indicates that other considerations are also involved.
PMCID: PMC3693800  PMID: 23834880
antibacterial agents; child; child, preschool; family practice; fever; infant; signs and symptoms; primary health care
3.  Alarming Signs and Symptoms in Febrile Children in Primary Care: An Observational Cohort Study in The Netherlands 
PLoS ONE  2014;9(2):e88114.
Febrile children in primary care have a low risk for serious infection. Although several alarming signs and symptoms are proposed to have predictive value for serious infections, most are based on research in secondary care. The frequency of alarming signs/symptoms has not been established in primary care; however, in this setting differences in occurrence may influence their predictive value for serious infections.
To determine the frequency of alarming signs/symptoms in febrile children in primary care.
Observational cohort study. Clinical information was registered in a semi-structured way and manually recoded.
General practitioners' out-of-hours service.
Face-to-face patient contacts concerning children (aged ≤16 years) with fever were eligible for inclusion.
Main outcome measures
Frequency of 18 alarming signs and symptoms as reported in the literature.
A total of 10,476 patient contacts were included. The frequency of alarming signs/symptoms ranged from n = 1 (ABC instability; <0.1%) to n = 2,207 (vomiting & diarrhea; 21.1%). Of all children, 59.7% had one or more alarming signs and/or symptoms. Several alarming signs/symptoms were poorly registered with the frequency of missing information ranging from 1,347 contacts (temperature >40°C as reported by the parents; 12.9%) to 8,647 contacts (parental concern; 82.5%).
Although the prevalence of specific alarming signs/symptoms is low in primary care, ≥50% of children have one or more alarming signs/symptoms. There is a need to determine the predictive value of alarming signs/symptoms not only for serious infections in primary care, but as well for increased risk of a complicated course of the illness.
PMCID: PMC3929539  PMID: 24586305
4.  Improving the Manchester Triage System for Pediatric Emergency Care: An International Multicenter Study 
PLoS ONE  2014;9(1):e83267.
This multicenter study examines the performance of the Manchester Triage System (MTS) after changing discriminators, and with the addition use of abnormal vital sign in patients presenting to pediatric emergency departments (EDs).
International multicenter study
EDs of two hospitals in The Netherlands (2006–2009), one in Portugal (November–December 2010), and one in UK (June–November 2010).
Children (<16years) triaged with the MTS who presented at the ED.
Changes to discriminators (MTS 1) and the value of including abnormal vital signs (MTS 2) were studied to test if this would decrease the number of incorrect assignment. Admission to hospital using the new MTS was compared with those in the original MTS. Likelihood ratios, diagnostic odds ratios (DORs), and c-statistics were calculated as measures for performance and compared with the original MTS. To calculate likelihood ratios and DORs, the MTS had to be dichotomized in low urgent and high urgent.
60,375 patients were included, of whom 13% were admitted. When MTS 1 was used, admission to hospital increased from 25% to 29% for MTS ‘very urgent’ patients and remained similar in lower MTS urgency levels. The diagnostic odds ratio improved from 4.8 (95%CI 4.5–5.1) to 6.2 (95%CI 5.9–6.6) and the c-statistic remained 0.74. MTS 2 did not improve the performance of the MTS.
MTS 1 performed slightly better than the original MTS. The use of vital signs (MTS 2) did not improve the MTS performance.
PMCID: PMC3893080  PMID: 24454699
5.  Socioeconomic and Sociodemographic Factors Associated with Asthma Related Outcomes in Early Childhood: The Generation R Study 
PLoS ONE  2013;8(11):e78266.
Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied.
The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models.
At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18–2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24–2.15, aOR = 1.85, 95% CI:1.11–3.09, aOR = 1.58, 95% CI:1.24–2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained.
This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6 years. Several socioeconomic and sociodemographic factors were independently associated with wheezing and asthma. Child's ethnicity was the only factor independently associated with FeNO. We encourage further studies on underlying pathways and public health intervention programs, focusing on reducing socioeconomic or sociodemographic inequalities in asthma.
PMCID: PMC3823924  PMID: 24244299
6.  Air pollution, fetal and infant tobacco smoke exposure, and wheezing in preschool children: a population-based prospective birth cohort 
Environmental Health  2012;11:91.
Air pollution is associated with asthma exacerbations. We examined the associations of exposure to ambient particulate matter (PM10) and nitrogen dioxide (NO2) with the risk of wheezing in preschool children, and assessed whether these associations were modified by tobacco smoke exposure.
This study was embedded in the Generation R Study, a population-based prospective cohort study among 4,634 children. PM10 and NO2 levels were estimated for the home addresses using dispersion modeling. Annual parental reports of wheezing until the age of 3 years and fetal and infant tobacco smoke exposure was obtained by questionnaires.
Average annual PM10 or NO2 exposure levels per year were not associated with wheezing in the same year. Longitudinal analyses revealed non-significant tendencies towards positive associations of PM10 or NO2 exposure levels with wheezing during the first 3 years of life (overall odds ratios (95% confidence interval): 1.21 (0.79, 1.87) and 1.06 (0.92, 1.22)) per 10 μg/m3 increase PM10 and NO2, respectively). Stratified analyses showed that the associations were stronger and only significant among children who were exposed to both fetal and infant tobacco smoke (overall odds ratios 4.54 (1.17, 17.65) and 1.85 (1.15, 2.96)) per 10 μg/m3 increase PM10 and NO2, respectively (p-value for interactions <0.05).
Our results suggest that long term exposure to traffic-related air pollutants is associated with increased risks of wheezing in children exposed to tobacco smoke in fetal life and infancy. Smoke exposure in early life might lead to increased vulnerability of the lungs to air pollution.
PMCID: PMC3533997  PMID: 23231783
Cohort study; Asthma; Pediatrics; Environmental tobacco smoke exposure; Air pollution
7.  Facilitators and barriers to screening for child abuse in the emergency department 
BMC Pediatrics  2012;12:167.
To identify facilitators of, and barriers to, screening for child abuse in emergency departments (ED) through interviews with ED staff, members of the hospital Board, and related experts.
This qualitative study is based on semi-structured interviews with 27 professionals from seven Dutch hospitals (i.e. seven pediatricians, two surgeons, six ED nurses, six ED managers and six hospital Board members). The resulting list of facilitators/barriers was subsequently discussed with five experts in child abuse and one implementation expert. The results are ordered using the Child Abuse Framework of the Dutch Health Care Inspectorate that legally requires screening for child abuse.
Lack of knowledge of child abuse, communication with parents in the case of suspected abuse, and lack of time for development of policy and cases are barriers for ED staff to screen for child abuse. For Board members, lack of means and time, and a high turnover of ED staff are impediments to improving their child abuse policy. Screening can be promoted by training ED staff to better recognize child abuse, improving communication skills, appointing an attendant specifically for child abuse, explicit support of the screening policy by management, and by national implementation of an approved protocol and validated screening instrument.
ED staff are motivated to work according to the Dutch Health Care Inspectorate requirements but experiences many barriers, particularly communication with parents of children suspected of being abused. Introduction of a national child abuse protocol can improve screening on child abuse at EDs.
PMCID: PMC3502173  PMID: 23092228
Child abuse; Emergency department; Screening; Qualitative study
8.  Head Circumference of Infants Born to Mothers with Different Educational Levels; The Generation R Study 
PLoS ONE  2012;7(6):e39798.
Head circumference (HC) reflect growth and development of the brain in early childhood. It is unknown whether socioeconomic differences in HC are present in early childhood. Therefore, we investigated the association between socioeconomic position (SEP) and HC in early childhood, and potential underlying factors.
The study focused on Dutch children born between April 2002 and January 2006 who participated in The Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Maternal educational level was used as indicator of SEP. HC measures were concentrated around 1, 3, 6 and 11 months. Associations and explanatory factors were investigated using linear regression analysis, adjusted for potential mediators.
The study included 3383 children. At 1, 3 and 6 months of age, children of mothers with a low education had a smaller HC than those with a high education (difference at 1 month: −0.42 SD; 95% CI: −0.54,−0.30; at 3 months: −0.27 SD; 95% CI −0.40,−0.15; and at 6 months: −0.13 SD; 95% CI −0.24,−0.02). Child’s length and weight could only partially explain the smaller HC at 1 and 3 months of age. At 6 months, birth weight, gestational age and parental height explained the HC differences. At 11 months, no HC differences were found.
Educational inequalities in HC in the first 6 months of life can be mainly explained by pregnancy-related factors, such as birth weight and gestational age. These findings further support public health policies to prevent negative birth outcomes in lower socioeconomic groups.
PMCID: PMC3387269  PMID: 22768125
9.  Children of Low Socioeconomic Status Show Accelerated Linear Growth in Early Childhood; Results from the Generation R Study 
PLoS ONE  2012;7(5):e37356.
People of low socioeconomic status are shorter than those of high socioeconomic status. The first two years of life being critical for height development, we hypothesized that a low socioeconomic status is associated with a slower linear growth in early childhood. We studied maternal educational level (high, mid-high, mid-low, and low) as a measure of socioeconomic status and its association with repeatedly measured height in children aged 0–2 years, and also examined to what extent known determinants of postnatal growth contribute to this association.
This study was based on data from 2972 mothers with a Dutch ethnicity, and their children participating in The Generation R Study, a population-based cohort study in Rotterdam, the Netherlands (participation rate 61%). All children were born between April 2002 and January 2006. Height was measured at 2 months (mid-90% range 1.0–3.9), 6 months (mid-90% range 5.6–11.4), 14 months (mid-90% range 13.7–17.9) and 25 months of age (mid-90% range 23.6–29.6).
At 2 months, children in the lowest educational subgroup were shorter than those in the highest (difference: −0.87 cm; 95% CI: −1.16, −0.58). Between 1 and 18 months, they grew faster than their counterparts. By 14 months, children in the lowest educational subgroup were taller than those in the highest (difference at 14 months: 0.40 cm; 95% CI: 0.08,0.72). Adjustment for other determinants of postnatal growth did not explain the taller height. On the contrary, the differences became even larger (difference at 14 months: 0.61 cm; 95% CI: 0.26,0.95; and at 25 months: 1.00 cm; 95% CI: 0.57,1.43)
Compared with children of high socioeconomic status, those of low socioeconomic status show an accelerated linear growth until the18th month of life, leading to an overcompensation of their initial height deficit. The long-term consequences of these findings remain unclear and require further study.
PMCID: PMC3359354  PMID: 22649522
10.  Early respiratory morbidity in a multicultural birth cohort: the Generation R Study 
European Journal of Epidemiology  2012;27(6):453-462.
Ethnic disparities in the prevalence of asthma symptoms in children have been described. We evaluated to what extent the association between ethnic background and respiratory symptoms during the first 2 years of life could be explained by the mediating effect of risk factors for respiratory morbidity. The Generation R Study is a multiethnic, population-based birth cohort study. Pre and postnatal risk factors for respiratory morbidity were prospectively assessed by questionnaires. Information about ethnicity was available for 5,684 infants. The associations between ethnic background and lower respiratory symptoms at 12 and 24 months were evaluated with log-binomial regression models. Relative risks and 95 % confidence intervals (RR [95 % CI]) were computed for Cape Verdean, Moroccan, Antillean, Surinamese and Turkish ethnicity with Dutch ethnicity as the reference category. We found an increased risk of lower respiratory symptoms at 24 months in Antillean infants (1.32 [95 % CI 1.12–1.57]) that was mediated by early postnatal exposures (pets keeping, siblings, breastfeeding, daycare attendance, smoke exposure). Turkish infants also had an increased risk of lower respiratory symptoms at 12 and 24 months (1.14 [95 % CI 1.02–1.27] and 1.21 [95 % CI 1.07–1.38], respectively), partly explained by previous morbidity (eczema, infections and upper respiratory symptoms). There were no differences for Cape Verdean, Moroccan or Surinamese, as compared to Dutch infants. Hence, ethnic background was associated with respiratory symptoms during the first 2 years of life and this association was largely explained by mediating effects of known pre and postnatal risk factors for respiratory morbidity.
PMCID: PMC3382637  PMID: 22476729
Ethnicity; Infants; Pre and postnatal exposures; Prospective birth cohort; Respiratory symptoms
11.  The proxy problem anatomized: child-parent disagreement in health related quality of life reports of chronically ill adolescents 
Discrepancy between self-reports and parent-proxy reports of adolescent health-related quality of life (HRQoL) has been repeatedly acknowledged in the literature as the proxy problem. However, little is known about the extent and direction of this discrepancy. The purpose of this study is to explore to what extent and in what direction HRQoL self-reports of adolescents with chronic conditions and those of their parents differ.
A cross-sectional survey was conducted among adolescents suffering from chronic conditions and their parents. Socio-demographic and disease-related characteristics were collected and information about consequences of the chronic condition was assessed. HRQoL was measured with KIDSCREEN-10 and DISABKIDS condition generic measure (DCGM-10). Agreement was analysed through defining a threshold of agreement based on half of the standard deviation of the HRQoL score with the highest variance. Agreement occurred if the difference between adolescent and parent scores was less than or equal to half of the standard deviation. Intra-class correlation coefficients and Bland-Altman plots were also computed. The characteristics associated with direction of disagreement were statistically tested with one-way ANOVA and Chi-square tests.
584 paired HRQoL scores were obtained. Ratings from both adolescents and parents were high, compared to European norm data. Differences between adolescents and parents were statistically significant, yet relatively small. Disagreement existed in both directions: in 24.5% (KIDSCREEN-10) and 16.8% (DCGM-10) of the cases adolescents rated their HRQoL lower than did their parent, while in 32.2% (KIDSCREEN-10) and 31.7% (DCGM-10) of the cases the opposite was true. Adolescent's age, educational level and type of education, parent's educational level, number of hospital admissions and several other disease-related factors influenced direction of disagreement.
In a reasonable proportion of cases the adolescent and parent agreed on the adolescent's HRQoL (43-51% of the cases) and most disagreement tended to be minor. Thus, the proxy problem may be smaller than presented in the literature and its extent may differ per population. As adolescents are expected to become partners in their own health care, it is recommended to focus on adolescents' own perceptions of HRQoL.
PMCID: PMC3299605  PMID: 22276974
Adolescent; Chronic Illness; Self Report; Quality of Life; Parent; Proxy Report; KIDSCREEN-10; DCGM-10
12.  Individually customised fetal weight charts derived from ultrasound measurements: the Generation R Study 
European Journal of Epidemiology  2011;26(12):919-926.
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-011-9629-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3253277  PMID: 22083366
Customised fetal growth curves; Ultrasound; Fetal weight; Biometry; Ethnicity; Maternal anthropometrics
13.  Detection of child abuse in emergency departments: a multi-centre study 
Archives of Disease in Childhood  2011;96(5):422-425.
This study examines the detection rates of suspected child abuse in the emergency departments of seven Dutch hospitals complying and not complying with screening guidelines for child abuse.
Data on demographics, diagnosis and suspected child abuse were collected for all children aged ≤18 years who visited the emergency departments over a 6-month period. The completion of a checklist of warning signs of child abuse in at least 10% of the emergency department visits was considered to be compliance with screening guidelines.
A total of 24 472 visits were analysed, 54% of which took place in an emergency department complying with screening guidelines. Child abuse was suspected in 52 children (0.2%). In 40 (77%) of these 52 cases, a checklist of warning signs had been completed compared with a completion rate of 19% in the total sample. In hospitals complying with screening guidelines for child abuse, the detection rate was higher (0.3%) than in those not complying (0.1%, p<0.001).
During a 6-month period, emergency department staff suspected child abuse in 0.2% of all children visiting the emergency department of seven Dutch hospitals. The numbers of suspected abuse cases detected were low, but an increase is likely if uniform screening guidelines are widely implemented.
PMCID: PMC3075563  PMID: 21278429
14.  The Generation R Study: design and cohort update 2010 
European Journal of Epidemiology  2010;25(11):823-841.
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.
PMCID: PMC2991548  PMID: 20967563
Cohort study; Pregnancy; Child; Design
15.  Motor Learning in Children with Neurofibromatosis Type I 
Cerebellum (London, England)  2010;10(1):14-21.
The aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed substantial problems in visuo-motor integration (Beery VMI). Prism-induced hand movement adaptation seemed to be mildly affected. However, no significant impairments in the accuracy of simple eye or hand movements were observed. Also, saccadic eye movement adaptation, a cerebellum dependent task, appeared normal. These results suggest that the motor problems of children with NF1 in daily life are unlikely to originate solely from impairments in motor learning. Our findings, therefore, do not support a general dysfunction of the cerebellum in children with NF1.
PMCID: PMC3038237  PMID: 20927664
Neurofibromatosis type 1; Children; Motor deficits; Motor control; Eye movements; Hand movements
16.  Early detection and counselling intervention of asthma symptoms in preschool children: study design of a cluster randomised controlled trial 
BMC Public Health  2010;10:555.
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.
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.
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.
PMCID: PMC2944378  PMID: 20843313
17.  Risk factors for otitis media in children with special emphasis on the role of colonization with bacterial airway pathogens: the Generation R study 
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.
PMCID: PMC3018595  PMID: 20821039
Otitis media; Risk factors; Streptococcus pneumoniae; Haemophilus influenzae; Moraxella catarrhalis
18.  Correlation of Bacterial Colonization Status between Mother and Child: the Generation R Study ▿  
Journal of Clinical Microbiology  2009;48(3):960-962.
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.
PMCID: PMC2832455  PMID: 19940045
19.  Breast-Feeding Modifies the Association of PPARγ2 Polymorphism Pro12Ala With Growth in Early Life 
Diabetes  2009;58(4):992-998.
We examined whether the PPARγ2 Ala12 allele influences growth in early life and whether this association is modified by breast-feeding.
This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. PPARγ2 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.
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 ≥4 months, PPARγ2 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).
The PPARγ2 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.
PMCID: PMC2661583  PMID: 19188432
20.  Reliability and validity of the Infant and Toddler Quality of Life Questionnaire (ITQOL) in a general population and respiratory disease sample 
Quality of Life Research  2006;16(3):445-460.
To evaluate feasibility, internal consistency, test–retest reliability, and concurrent and discriminative validity of the Infant and Toddler Quality of Life Questionnaire (ITQOL) for parents of pre-school children with 12 scales (103-items) covering physical and psychosocial domains and impact of child health on parents, in comparison with the TNO-AZL Pre-school Children Quality of Life Questionnaire (TAPQOL).
Parents of children from a random general population sample (2 months–4 years old; n = 500) and of an outpatient clinic sample of children with respiratory disease (5 months–5 1/2 years old; n = 217) were mailed ITQOL and TAPQOL questionnaires; a retest was sent after two weeks.
Feasibility: The response was ≥80% with few missing and non-unique ITQOL-answers (<2%) in both study populations. Some ITQOL-scales (3–4 scales) showed a ceiling effect (>25% at maximum score). Internal consistency: All Cronbach’s α >0.70. Test–retest Intraclass Correlation Coefficients (ICCs) were moderate or adequate (≥0.50; p lt; 0.01) for 10 ITQOL-scales. Validity: ITQOL-scales, with a few exceptions, correlated better with predefined parallel TAPQOL scales than with non-parallel scales. Five to eight ITQOL-scales discriminated clearly between children with few and with many parent-reported chronic conditions, between children with and without doctor-diagnosed respiratory disease and with a low and a high parent-reported medical consumption (p <0.05).
This study supported the evidence that the ITQOL is a feasible instrument with adequate psychometric properties. The study provided reference ITQOL scores for gender/age subgroups. We recommend repeated evaluations of the ITQOL in varied populations, especially among very young children, including repeated assessments of test–retest characteristics and evaluations of responsiveness to change. We recommend developing and evaluating a shortened ITQOL version.
PMCID: PMC2792359  PMID: 17111231
Asthma; General population; Health-related quality of life; Infant and Toddler Quality of Life Questionnaire (ITQOL); Pre-school children; Reference/norm scores; Reliability; TNO-AZL Pre-school Children Quality of Life Questionnaire (TAPQOL); Validity
21.  Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies 
BMC Medical Genetics  2009;10:67.
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.
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.
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.
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.
PMCID: PMC2722586  PMID: 19615048
22.  Effect of Simvastatin on Cognitive Functioning in Children With Neurofibromatosis Type 1 
Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model.
To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1.
Design, Setting, and Participants
Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital.
Simvastatin or placebo treatment once daily for 12 weeks.
Main Outcome Measures
Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex.
No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β=0.10; 95% confidence interval [CI], −0.36 to 0.56); cancellation test (β=−0.19; 95% CI, −0.67 to 0.29); prism adaptation (odds ratio=2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β=0.06; 95% CI, −0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β=0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β =0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment.
In this 12-week trial, simvastatin did not improve cognitive function in children with NF1.
PMCID: PMC2664742  PMID: 18632543
23.  Randomized Trial of a Clinical Decision Support System: Impact on the Management of Children with Fever without Apparent Source 
To assess compliance with a clinical decision support system (CDSS) for diagnostic management of children with fever without apparent source and to study the effects of application of the CDSS on time spent in the emergency department (ED) and number of laboratory tests.
The CDSS was used by ED nursing staff to register children presenting with fever. The CDSS identified children that met inclusion criteria (1–36 months and fever without apparent source (FWS)) and provided patient-specific diagnostic management advice. Children at high risk for serious bacterial infection were randomized for the ‘intervention’ (n = 74) or the ‘control’ (n = 90) group. In the intervention group, the CDSS provided the advice to immediately order laboratory tests and in the control group the ED physician first assessed the children and then decided on ordering laboratory tests.
Compliance with registration of febrile children was 50% (683/1,399). Adherence to the advice to order laboratory tests was 82% (61/74). Children in the intervention group had a median (25th–75th percentile) length of stay at the ED of 138 (104–181) minutes. The median length of stay at the ED in the control group was 123 (83–179) minutes. Laboratory tests were significantly more frequently ordered in the intervention group (82%) than in the control group (44%, p < 0.001, χ2 test).
Implementation of a CDSS for diagnostic management of young children with fever without apparent source was successful regarding compliance and adherence to CDSS recommendations, but had unexpected effects on patient outcome in terms of ED length of stay and number of laboratory tests. The use of the current CDSS was discontinued.
PMCID: PMC2273109  PMID: 17947627
24.  The Generation R Study Biobank: a resource for epidemiological studies in children and their parents 
European Journal of Epidemiology  2007;22(12):917-923.
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.
PMCID: PMC2190786  PMID: 18095172
Cohort study; Biobank; Child; Parents
25.  Human Bocavirus in Febrile Children, the Netherlands 
Emerging Infectious Diseases  2007;13(1):180-182.
PMCID: PMC2725834  PMID: 17370546
parvoviridae infections; human bocavirus; child; fever; communicable diseases, emerging; family practice; letter

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