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Objective To evaluate the long‐term outcomes of children born to women with a short cervix and otherwise low risk for preterm birth, after antenatal exposure to vaginal progesterone vs placebo. Methods This was a follow‐up study of the Triple P trial, which randomized 80 low‐risk women with a short cervix (≤ 30 mm) at 18–22 weeks' gestation to progesterone (n = 41) or placebo (n = 39). At 2 years of corrected age, children were invited for a neurodevelopmental assessment, using the Bayley Scales of Infant and Toddler Development, third edition (BSID‐III), and a neurological and physical examination by an assessor blinded to the allocated treatment. Parents filled out the Ages and Stages Questionnaire, the Child Behavior Checklist (CBCL) and a general‐health questionnaire. The main outcome of interest was mean BSID‐III cognitive and motor scores. Additionally, a composite score of mortality and abnormal developmental outcome, including BSID‐III ≤–1 SD, CBCL score in the clinical range and/or parental reported physical problems (at least two operations or at least two hospital admissions in the previous 2 years), was evaluated. Our sample size, dictated by the original sample of the Triple P trial, provided 80% power to detect a mean difference (MD) of 15 points (1 SD) between groups for the BSID‐III tests. Results Of the 80 children born to the randomized women, one in the progesterone group and two in the placebo group died in the neonatal period. Follow‐up data were obtained for 59/77 (77%) children and BSID‐III outcomes in 57 children (n = 28 in the progesterone group and n = 29 in the placebo group) born at a median gestational age of 38 + 6 weeks (interquartile range (IQR), 37 + 3 to 40 + 1 weeks) with a median birth weight of 3240 g (IQR, 2785–3620 g). In the progesterone vs placebo groups, mean BSID‐III cognitive development scores were 101.6 vs 105.0 (MD, –3.4 (95% CI, –9.3 to 2.6); P = 0.29) while mean motor scores were 102.4 vs 107.3 (MD, –4.9 (95% CI, –11.2 to 1.4); P = 0.13). No differences were seen between the two groups in physical (including genital and neurological examination), behavioral and health‐related outcomes. Conclusion In this sample of children born to low‐risk women with a short cervix at screening, no relevant differences in neurodevelopmental, behavioral, health‐related and physical outcomes were found between offspring exposed to vaginal progesterone and those exposed to placebo. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Long-term results after non-operative treatment for children with simple appendicitis seem promising, possibly avoiding appendicectomy in 70 per cent of children after a median follow-up of 5 years. The need for delayed appendicectomy more than 2 years after the initial treatment is rare (0–5 per cent) and no complications occurred past 1 year, including children who underwent delayed appendicectomy.

In clinical trials, it is relevant to ask patients and/or their caregivers which aspects concerning their disease they consider important to measure when a new intervention is being investigated. Those aspects, useful as outcome measures in a trial, are of pivotal importance for the result of the trial and the subsequent decision-making. In rare diseases the choice of outcome measures may be even more important, due to the small numbers and heterogeneity of the patients that are included. We have developed a tool to involve patients in the determination of outcome measures and the choice of measurement instruments. This tool was developed together with a patient think tank, consisting of a group of rare disease patient representatives, and by interviewing end users. We have road-tested our tool in an ongoing trial, and evaluated it during a focus group meeting. The tool consists of three steps: 1) Preparation, 2) Consultation of patients, 3) Follow-up during which the consultation results are implemented in the trial design. The tool provides guidelines for researchers to include the patient's opinion in the choice of outcome measures in the trial design stage. We describe the development of the POWER-tool (Patient participation in Outcome measure WEighing for Rare diseases), and first experiences of the tool in an ongoing trial.

Contains fulltext : 215531.pdf (Publisher’s version ) (Open Access) Goal Attainment Scaling is an assessment instrument to evaluate interventions on the basis of individual, patient-specific goals. The attainment of these goals is mapped in a pre-specified way to attainment levels on an ordinal scale, which is common to all goals. This approach is patient-centred and allows one to integrate the outcomes of patients with very heterogeneous symptoms. The latter is of particular importance in clinical trials in rare diseases because it enables larger sample sizes by including a broader patient population. In this paper, we focus on the statistical analysis of Goal Attainment Scaling outcomes for the comparison of two treatments in randomised clinical trials. Building on a general statistical model, we investigate the properties of different hypothesis testing approaches. Additionally, we propose a latent variable approach to generate Goal Attainment Scaling data in a simulation study, to assess the impact of model parameters such as the number of goals per patient and their correlation, the choice of discretisation thresholds and the type of design (parallel group or cross-over). Based on our findings, we give recommendations for the design of clinical trials with a Goal Attainment Scaling endpoint. Furthermore, we discuss an application of Goal Attainment Scaling in a clinical trial in mastocytosis.

Objective A recent randomized clinical trial (ProTWIN) showed that a cervical pessary prevented preterm birth and improved neonatal outcome in women with multiple pregnancy and cervical length (CL)

Introduction: In phenylketonuria (PKU), a natural protein-restricted dietary treatment prevents severe cognitive impairment. Nutrient deficiencies may occur due to strict diet. This study is aimed at evaluating the dietary intake and blood concentrations of micronutrients and essential fatty acids (FA), bone mineral density (BMD) and fracture history in patients on long-term dietary treatment. Methods: Sixty early diagnosed Dutch patients (aged 1-39 years) were included in a multi-center cross-sectional study. Their dietary intake, blood concentrations of micronutrients, FA, fracture history and BMD were assessed. Results: Selenium dietary intake and serum concentrations were low in 14 and 46% of patients, respectively. The serum 25-OH vitamin D2 + D3 concentration was low in 14% of patients while 20% of patients had a low vitamin D intake. Zinc serum concentrations were below normal in 14% of patients, despite adequate intake. Folic acid serum concentrations and intake were elevated. Despite safe total protein and fat intake, arginine plasma concentrations and erythrocyte eicosapentaenoic acid were below reference values in 19 and 6% of patients, respectively. Low BMD (Z-score Conclusions: Dutch patients with PKU on long-term dietary treatment have a near normal nutrient status. Supplementation of micronutrients of which deficiency may be deleterious (e.g., vitamin D and selenium) should be considered. BMD warrants further investigation.

Background High levels of maltreatment are found in children who are identified because their parents visit the emergency department due to partner violence, substance abuse or suicide attempt. However, it is unknown if these children experience psychosocial problems. This study aims to assess their levels of post-traumatic stress, anxiety, depression, behavioural problems and health-related quality of life. Methods A cross-sectional study was conducted in six hospitals. All consecutive families of which a parent visited the emergency department due to partner violence, substance abuse or suicide attempt between 1 July 2012 and 1 March 2014 with children aged 1.5–17 years were approached for participation. Parents and children aged 8 years and older filled out questionnaires measuring post-traumatic stress [13-item version of Children's Revised Impact of Event Scale (CRIES-13)], anxiety, depression (Revised Child Anxiety and Depression Scale), behavioural problems [Child Behavior Checklist (CBCL) and Youth Self-Report (YSR)] and health-related quality of life (PedsQL). Scores of participants were compared with reference data obtained in children in similar age ranges from representative Dutch community samples (CRIES-13, Revised Child Anxiety and Depression Scale, PedsQL and CBCL) and to a normed cutoff score (CRIES-13). Results Of 195 eligible families, 89 (46%) participated in the study. Participating children did not score different from community children, both on child-reported and parent-reported instruments. Standardized mean differences of total sum scores were 0 (CRIES-13 and CBCL 1.5–5), 0.1 (YSR), 0.2 (CBCL 6–18) and −0.3 (PedsQL) and not statistically different from community children. Thirty-five percent of the participating children scored above the cutoff score on the CRIES-13, indicating post-traumatic stress disorder, but this difference was not statistically significant from community children (mean difference 8%; 95% CI −4–22%). Conclusions We found no differences in psychosocial problems between children whose parents visited the emergency department due to partner violence, substance abuse or suicide attempt and children from community samples. Because 35% of the children scored in the range of post-traumatic stress disorder, we advise healthcare providers to pay attention to post-traumatic stress symptoms

Aim(s) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic-ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients. Methods Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the 'PharmaCool Study') were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. Results A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg-1 h-1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg-1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). Conclusions This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg-1 every 36 h or every 24 h for patients with GA 36-40 weeks and GA 42 weeks, respectively.

A recent randomized clinical trial (ProTWIN) showed that a cervical pessary prevented preterm birth and improved neonatal outcome in women with multiple pregnancy and cervical length (CL) 38 mm. In this follow-up study, the long-term developmental outcome of these children was evaluated at 3 years' corrected age.This was a follow-up study of ProTWIN, a multicenter trial conducted between 2009 and 2012 in which asymptomatic women with a multiple pregnancy were randomized to placement of a cervical pessary or no intervention. Current follow-up and analysis were limited to mothers with a mid-trimester CL 38 mm (78 women (157 children) in the pessary group and 55 women (111 children) in the control group). At 3 years of corrected age, surviving children were invited for a Bayley Scales of Infant and Toddler Development-third edition (Bayley-III) assessment. Death after randomization or neurodevelopmental disability (Bayley-III score of ≤ 85, 1 SD below mean) rates were compared between the pessary and control groups, according to the intention-to-treat principle and using multiple imputation for missing data. Mean Bayley-III scores in surviving children were also assessed. A linear mixed-effects model was used to adjust for correlation between children of one mother.From the time of entry in the ProTWIN trial until follow-up at 3 years of age, a total of 27 children had died (six (5%) in the pessary vs 21 (26%) in the control group; odds ratio (OR), 0.13; 95% CI, 0.04-0.48). Bayley-III outcomes were collected for 173/241 (72%) surviving children (114 (75%) in the pessary vs 59 (66%) in the control group). The cumulative incidence of death or survival with a neurodevelopmental disability was 12 (10%) in the pessary vs 23 (29%) in the control group (OR, 0.26; 95% CI, 0.09-0.73). No statistical or clinically relevant differences were found with respect to cognitive, language and motor development among surviving children between the groups. Comparable results were found after multiple imputation.In women with twin pregnancy and a CL 38 mm, the use of a cervical pessary strongly improved survival of the children without affecting neurodevelopment at 3 years' corrected age. Copyright © 2018 ISUOG. Published by John WileySons Ltd.

Background There is increasing evidence that neonatal seizures in term neonates with stroke, asphyxia or brain haemorrhage might be associated with adverse neurodevelopment and development of epilepsy. The extent of this association is not known. The objective of this study was to assess the possible impact of neonatal seizures on these outcomes and if possible calculate a relative risk. Methods A systematic review and meta-analysis was performed (study period January 2000–June 2015). PubMed, Medline and Embase were searched for cohort studies evaluating neurodevelopmental outcome at the age of at least 18 months or development of epilepsy in surviving term neonates with or without neonatal seizures. The methodological quality of included studies was assessed and data extractions were performed in a standardized manner by independent reviewers. Pooled Relative Risks (RR) with 95% confidence intervals for adverse outcome were calculated if possible. Results Out of 1443 eligible studies 48 were selected for full text reading leaving 9 cohort studies for the final analyses (4 studies on stroke, 4 on perinatal asphyxia and one on cerebral hemorrhage). For all cases with stroke or asphyxia combined the pooled risk ratio (RR) for adverse outcome when suffering neonatal seizures was 7.42 (3.84–14.34); for neonates with perinatal asphyxia: 8.41 (4.07–17.39) and for neonates with stroke: 4.95 (1.07–23.0). The pooled RR for development of late onset epilepsy could only be determined for infants suffering from stroke: 1.48 (0.82–2.68). Results were biased and evidence sparse. Conclusions The presence of neonatal seizures in term newborns with vascular or hypoxic brain injury may have an impact on or be a predictor of neurodevelopmental outcome. The biased available data yield insufficient evidence about the true size of this association. Electronic supplementary material The online version of this article (10.1186/s12887-018-1116-9) contains supplementary material, which is available to authorized users.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene ( ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C>T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1,000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy.

High levels of maltreatment are found in children who are identified because their parents visit the emergency department due to partner violence, substance abuse or suicide attempt. However, it is unknown if these children experience psychosocial problems. This study aims to assess their levels of post-traumatic stress, anxiety, depression, behavioural problems and health-related quality of life.A cross-sectional study was conducted in six hospitals. All consecutive families of which a parent visited the emergency department due to partner violence, substance abuse or suicide attempt between 1 July 2012 and 1 March 2014 with children aged 1.5-17 years were approached for participation. Parents and children aged 8 years and older filled out questionnaires measuring post-traumatic stress [13-item version of Children's Revised Impact of Event Scale (CRIES-13)], anxiety, depression (Revised Child Anxiety and Depression Scale), behavioural problems [Child Behavior Checklist (CBCL) and Youth Self-Report (YSR)] and health-related quality of life (PedsQL). Scores of participants were compared with reference data obtained in children in similar age ranges from representative Dutch community samples (CRIES-13, Revised Child Anxiety and Depression Scale, PedsQL and CBCL) and to a normed cutoff score (CRIES-13).Of 195 eligible families, 89 (46%) participated in the study. Participating children did not score different from community children, both on child-reported and parent-reported instruments. Standardized mean differences of total sum scores were 0 (CRIES-13 and CBCL 1.5-5), 0.1 (YSR), 0.2 (CBCL 6-18) and -0.3 (PedsQL) and not statistically different from community children. Thirty-five percent of the participating children scored above the cutoff score on the CRIES-13, indicating post-traumatic stress disorder, but this difference was not statistically significant from community children (mean difference 8%; 95% CI -4-22%).We found no differences in psychosocial problems between children whose parents visited the emergency department due to partner violence, substance abuse or suicide attempt and children from community samples. Because 35% of the children scored in the range of post-traumatic stress disorder, we advise healthcare providers to pay attention to post-traumatic stress symptoms.

High plasma C-reactive protein (CRP) levels are associated with favorable outcome in adults with acute lung injury (ALI). The association between CRP levels and outcome has not been studied in ALI in children. We performed a historical cohort study in 93 mechanically ventilated children (0–18 years) with ALI. The CRP level within 48 h of disease onset was tested for association with 28-day mortality and ventilator-free days (VFD). Clinical parameters and ventilator settings were evaluated for possible confounding. Fourteen patients died within 28 days. The median (interquartile range) CRP level in nonsurvivors was 126 mg/L (64; 187) compared with 56 mg/L (20; 105) in survivors (p = 0.01). For every 10-mg/L rise in CRP level, the unadjusted odds (95 % confidence interval (95 % CI)) for mortality increased 8.7 % (2.1–15.8 %). Cardiovascular organ failure at onset of ALI was the strongest predictor for mortality (odds ratio, 30.5 (6.2–152.5)). After adjustment for cardiovascular organ failure, for every 10-mg/L rise in CRP level, the OR (95 % CI) for mortality increased 4.7 % (−2.7–12.6 %; p = 0.22). Increased CRP levels were associated with a decrease in VFD (ρ = −0.26, p = 0.01). Conclusion: increased plasma CRP levels are not associated with favorable outcome in ALI in children. This is in contrast with findings in adults with ALI.

In this paper studies conducted in the Netherlands on quality of life and social status of children and young adults who have grown up with a chronic disease are summarized. Only for 21 diseases studies could be found. Growing up with a chronic disease has negative consequences in terms of social functioning, schooling and intellectual functioning. Problems in quality of life domains are reported for children with congenital heart disease, inflammatory bowel disease, spina bifida and for children with end-stage renal disease. Little is known about predictive factors such as medical determinants, personality or family factors which are related to the later functioning. Research with a psychological-theoretical background in this area should be promoted, also to contribute to the development of necessary interventions for these children and young adults.

Objective: To develop an observational instrument that can be used to evaluate the quality of arm and hand skills in daily functional activities in children with obstetric brachial plexus lesion (OBPL). A set of functional activities was constructed and standardized, and the intra-observer reliability of the assessment of this set of activities was studied. Setting: Department of Occupational Therapy and Department of Rehabilitation Medicine, VU University Medical Centre. Subjects: Twenty-six children with OBPL in the age range of 4 -6 years. Interventions: The children were asked to perform 47 bimanual activities, which were recorded on videotape. Main measures: The videotapes were scored twice by the same occupational therapist. Results: The percentage of agreement in scoring ‘hand-use’, ‘speed’ and ‘assistance’ was over 80% for a substantial number of activities, indicating a strong agreement. However, in scoring ‘deviations in movements and body posture’ the percentage of agreement was insufficient in most activities. Conclusions: This set of activities has good potential for assessment of the performance of functional activities in children with OBPL. This study, however, showed a number of difficulties in observing and scoring the activities that have to be considered when developing a standardized video observation.

In a large study project we tried to determine the number of children and adolescents in the Netherlands with a chronic disease, and to evaluate the consequences of living with this. Therefore we defined and operationalised chronic diseases and health conditions in childhood, in a consensus procedure. Consensus was attained on a definition consisting of four criteria. A disease or condition is considered to be a chronic condition in childhood if (i) it occurs in children aged 0 up to 18 years, (2) the diagnosis is based on medical scientific knowledge and it can be diagnosed using reproducible and valid methods or instruments according to professional standards, (3) it is not (yet) curable, and (4) it has been present longer than three months or it will very probably last longer than three months, or it has occurred three times or more during the past year and will probably reoccur. Adding upon research findings and prevalence rates we estimated that at least 14% of children in the Netherlands are growing up with a chronic disease; counting for at least 500.000 children and adolescents. This is definitely an underestimation because for only a limited number of diseases reliable information was available. We also paid attention to studies on the social consequences of young adults who have been growing up with a chronic disease. Studies in the Netherlands in this area are limited as well. To evaluate the effects of pediatric and child health care on a societal level, and for the planning of health care facilities and other services for children and young adults with chronic conditions, valid and reliable prevalence estimates are needed.

The aim of the study by Lee et al. (ref) was to evaluate determinants (co-morbidities) and outcomes of in-hospital delay in treatment of children with acute appendicitis. This retrospective evaluation was done using a database of 683,016 children hospitalised with appendicitis between 2000 and 2008 in the USA. Out of these, 17,737 children (2.6 %) experienced a delay in treatment of 2 days or more (Median 3 days; IQR 2–5 days). The underlying hypothesis is that ‘Increased time interval from the onset of symptoms to intervention is associated with increased rate of rupture’ as the authors state in their introduction. This hypothesis, however, has never been proven, and has even been disputed by several investigators [1–3]. It has been demonstrated that the majority of patients with ruptured appendicitis have the perforation already at the time of presentation at the hospital [3]. Several authors envisage two types of appendicitis: simple (non-perforated) appendicitis, with no tendency to progress, and complex (perforated) appendicitis, in which perforation occurs early in the course of the disease [3, 4]. The authors reported significant differences between the groups with and without delay in terms of age, sex, ethnicity and presence of co-morbidities (Table 1). Significantly more patients with a delay in treatment (57.3 %) had a complicated disease course, including perforation, than was seen in the early treatment group (28.9 %) (Table 3). Not surprisingly, therefore, the authors demonstrate an association between delayed treatment and adverse outcome, such as mortality, length of stay and increased cost (Table 4). The implicit but not proven assumption of the authors is that perforation of the appendix occurred during the delay between admission and treatment and, therefore, could have been prevented. There is no argument that early diagnosis and treatment (whether operative or antibiotic) of acute appendicitis actually results in reduction of pain, anxiety, complications and costs.

Background and aims: Increased risk for chromosomal abnormalities in embryos is considered as a cause of low pregnancy rate with advanced maternal age. PGS has been suggested to improve pregnancy outcome. Since PGS includes extensive embryo manipulation, PGS could have an effect on morphological outcome in children. A follow-up study of a RCT comparing IVF/ICSI with PGS (PGS+) and without (PGS-) was performed to evaluate morphological abnormalities of live born children at 2 years of age. Methods: 408 women were included in a multicenter RCT on the efficacy of PGS. There were 120 women with ≥1 live births, 119 mothers with 142 children alive (57 PGS+; 85 PGS-) were available for follow-up. A reference group of 67 children conceived naturally was formed. At 2 years of age a body-surface examination and anthropometry was performed. Morphological abnormalities were classified as major abnormalities, minor anomalies or common variants according to Merks (Am J Med Genet 2003;123A:211-230). Results: No significant association was found between PGS and any specific minor anomaly or major abnormality. The proportions [95% CI] of children with ≥1 minor anomalies and ≥1 major abnormalities for PGS+ versus PGS- were 64 % [50 -76] vs 67 % [55 - 77] and 28 % [18 - 42] vs 35 % [25 - 46], respectively. No significant differences were found between the randomized and reference groups. Conclusions: This study found no differences in morphological abnormalities between children conceived after IVF/ICSI with PGS and children conceived after regular treatment.

In this study the prevalence of nocturnal enuresis defined according to the DSM III criteria was determined in a random sample of 2070 children aged from 4 to 16 years. Nocturnal enuresis declines in prevalence with age and is more frequent in boys than in girls. Moreover, the decline in prevalence with age was found to take place earlier in girls than in boys. It is therefore argued that the DSM III age limit for enuresis should be raised to 8 years for boys.