This thesis reinforce that children born preterm are at risk for long-term impairments. Being able to predict who is at risk, by neonatal neuroimaging or early assessment, remains difficult,... Show moreThis thesis reinforce that children born preterm are at risk for long-term impairments. Being able to predict who is at risk, by neonatal neuroimaging or early assessment, remains difficult, especially in children who have milder forms of brain injury and/or experience milder difficulties at two years of age. Currently, most follow-up assessments use standardized outcome measures that might not show the full extent of a child’s daily functioning. Additional measurements and/or the implementation of qualitative research can be of great additional value. Show less
Background: Psychosocial development in monochorionic (MC) twins born after selective fetal growth restriction (sFGR) has been unreported to date, despite its importance for daily functioning and... Show moreBackground: Psychosocial development in monochorionic (MC) twins born after selective fetal growth restriction (sFGR) has been unreported to date, despite its importance for daily functioning and future relationships. Aims: To investigate psychosocial development, attachment and school functioning in MC twins with sFGR and compare outcomes with the general population and between smaller and larger twins. Study design: Observational cohort study. Subjects: MC twins with sFGR (defined as a birth weight discordance >= 20 %) born between 2002 and 2017 and aged 3-17 years. Outcome measures: Multiple parent report questionnaires: the Child Behavior Checklist (social-emotional devel-opment and behavior), the (Early) Childhood Behavior Questionnaire Very Short Form (temperament), the Attachment Insecurity Screening Inventory (attachment) and a school functioning questionnaire. Results: Median age for the 48 twin pairs was 11 (interquartile range (IQR) 8-13) years. Attachment insecurity for both twins was higher than in the general population for ambivalence/resistance (34 % (21/62) vs. 16 %, p = 0.024) and total attachment insecurity (35 % (22/62) vs. 16 %, p = 0.016). Smaller twins had more internalizing behavioral problems, i.e. negative emotions and behaviors turned inwards (22 % (10/46) vs. 11 % (5/46), p = 0.021) and a higher negative affect, i.e. more likely to experience negative emotions (3.2 (2.9-3.7) vs. 2.9 (2.2-3.2), p = 0.009) than larger twins, as well as a lower secondary school level (p = 0.031). Conclusion: MC twins with sFGR have more ambivalent/resistant attachment insecurity following the compli-cated pregnancy course. Smaller twins have a tendency towards negative emotions and internalizing behaviors compared to larger twins, indicating an increased sensitivity for depression and anxiety. Show less
Jansen, L.; Steggerda, S.; Rijken, M.; Steenis, A. van; Vries, L. de; Peeters-Scholte, C.; ... ; Klink, J. van 2022
Preterm infants are at risk of developing social-emotional and behavioural difficulties. To understand the experiences of their caregivers in day-to-day life, parents (at 2 and 10 years) and... Show morePreterm infants are at risk of developing social-emotional and behavioural difficulties. To understand the experiences of their caregivers in day-to-day life, parents (at 2 and 10 years) and teachers (at 10 years) completed a behavioural questionnaire and answered two open-ended questions addressing their concerns and the most positive aspects regarding their child and/or pupil (born <32 weeks gestation). Their answers were analyzed using thematic content analysis. Parental concerns at two years related equally to themes in the clusters Developmental Milestones, Physical Development and Development in Relation to the Self and Others. At 10 years, both parents and teachers reported mainly within the cluster Development in Relation to the Self and Others, but the underlying themes differed. While parents more often mentioned their child's emotional development, teachers were more concerned about their pupils' difficulties interacting with their peers, due to a lack of social skills. In-depth qualitative analysis of what parents and teachers experience from day-to-day improves our understanding of the social-emotional and behavioural development of children born very preterm, revealing important topics that should be addressed during follow-up. Show less
Huang, L.; Jansen, L.; Verhoeven, R.H.A.; Ruurda, J.P.; Eycken, L. van; Schutter, H. de; ... ; Brenner, H. 2022
Background We previously observed decreasing resection rates of non-metastatic gastric adenocarcinoma (GaC) in the US and some European countries. If and to what extent these trends affect the... Show moreBackground We previously observed decreasing resection rates of non-metastatic gastric adenocarcinoma (GaC) in the US and some European countries. If and to what extent these trends affect the trends in overall survival (OS) of patients with non-metastatic GaC at the population level remain unclear. This large international population-based cohort study aimed to assess the impact of the previously observed decreasing resection rates on multivariable-adjusted trends in the long-term OS of patients with non-metastatic GaC. Methods Individual-level data of patients with non-metastatic GaC were obtained from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, and Slovenia, and the US Surveillance, Epidemiology, and End Results database. We analyzed data for each country separately. Associations between year of diagnosis and OS were assessed using Cox proportional hazards regression model with adjustment for multiple prognostic variables, with and without including resection and chemotherapy as potential explanatory variables. Results A total of 66,398 non-metastatic GaC patients diagnosed in 2003-2016 were analyzed, with an accumulated follow-up of 172,357 person-years. Without adjustment for resection, OS was improved only slightly in the US [hazard ratio (HR)(per year) = 0.99; HR >= (vs.) (<2010) = 0.96], and no improvement was observed in the investigated European countries, with OS even worsening in Sweden (HRper year = 1.03; HR >= (vs.) (<2010) = 1.17). After adjusting for resection, the increasing OS trend became stronger in the US (HRper year = 0.98; HR >= (vs.) (<2010) = 0.88), and the temporal trend became insignificant in Sweden. In Slovenia (HRper year = 0.99; HR >= (vs.) (<2010) = 0.92) and Norway (HRper year = 0.97; HR >= (vs.) (<2010) = 0.86), improved OS over time emerged after resection adjustment. Improved OS in patients undergoing resection was observed in the US, the Netherlands, and Norway. Adjustment for chemotherapy did not alter the observed associations. Stratified analyses by tumor location showed mostly similar results with the findings in all patients with non-metastatic GaCs regarding the associations between year of diagnosis and survival. Conclusions OS of patients with non-metastatic GaC mostly did not improve in selected European countries and was even worsened in Sweden, while it was slightly increased in the US in the early 21(st) century. Progress in OS of patients with non-metastatic GaC seems to have been impeded to a large extent by decreasing rates of resection. Show less
Erken, R.; Loukachov, V.; Dort, K.; Hurk, A. den; Takkenberg, R.B.; Niet, A.; ... ; Kootstra, N. 2022
Background and Aims: HBV can integrate in the host genome of the hepat-ocyte and recent findings suggest that integrated HBV contributes to the per-sistent production of viral proteins. Here, we... Show moreBackground and Aims: HBV can integrate in the host genome of the hepat-ocyte and recent findings suggest that integrated HBV contributes to the per-sistent production of viral proteins. Here, we quantified the levels of integratedHBV in patients with chronic hepatitis B (CHB) and analyzed the relation be-tween HBV integration, virological activity (plasma HBV DNA and HBsAg lev-els), and clinical outcomes.Approach and Results: We developed and validated a multistep Arthrobacterluteus (Alu)- PCR that specifically amplifies integrated HBV and RT-Alu- PCRdetecting mRNA transcripts derived from integrated HBV. Pretreatment liverbiopsy samples and baseline characteristics of 124 patients with CHB eithertreated for 48 weeks with pegylated interferon plus adefovir or tenofovir or re-ceiving no treatment were available for analysis. Integrated HBV sequencescontaining open reading frame S and X (but not C) and S and X mRNA tran-scripts derived from integrated HBV could be detected and quantified in liverbiopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanineaminotransferase plasma levels, and the liver histology activity index but notto levels of intrahepatic covalently closed circular DNA (cccDNA), plasmapregenomic RNA, or hepatitis B core-related antigen. Multivariable logisticregression analysis showed that lower baseline HBV integration levels wereindependently associated with HBsAg loss (functional cure) within 5 yearsfollow-up.Conclusions: Integrated HBV levels are strongly correlated with surrogatemarkers for virological activity but not to cccDNA levels and are predictivefor HBsAg loss. Our data suggest that integrated HBV is closely related toHBV replication and may therefore be an important tool in the evaluation anddevelopment of treatment modalities aiming to cure CHB. Show less
Knijnenburg, P.J.C.; Spruijt, M.S.; Jansen, L.; Rijken, M.; Tan, R.N.G.B.; Slaghekke, F.; ... ; Klink, J.M.M. van 2022
Objective: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or... Show moreObjective: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or small for gestational age. Study design: At 2 and 5 years of age, standardized neurologic, motor, and cognitive assessments were performed by a neonatologist, a pediatric physical therapist, and a psychologist. Behavior was assessed using a validated questionnaire completed by parents. Results: Neurodevelopmental assessment at both time points was available for 73 survivors of TITS. Mild to moderate neurodevelopmental impairment (NDI) was detected in 34% of survivors (25 of 73) at 5 years, compared with 25% (18 of 73) at 2 years (P = .178). Severe NDI was observed in 12% (9 of 73) at 5 years and in 3% (2 of 73) at 2 years (P = .035). Mean cognitive score was lower at the 5-year follow-up (90.7 +/- 12.3 vs 95.6 +/- 13.1 at 2 years; P = .001), and more children were diagnosed with mild cognitive impairment at 5 years (29% vs 11 % at 2 years; P = .007). When comparing individual outcomes at both time points, 35% (25 of 71) moved from a normal outcome or mild to moderate impairment at 2 years toward more severe impairment at 5 years. Conclusions: A high rate of mild to moderate cognitive impairment and severe NDI at age 5 years was not identified at age 2 years. Our data highlight the importance of longitudinal follow-up of survivors of TTTS beyond age 2 years and emphasize the precautions that should be taken when diagnosing an absence of impairment before school age. Show less
Jansen, L.; Steenis, A. van; Berg-Huysmans, A.A. van den; Wiggers-de Bruine, S.T.; Rijken, M.; Vries, L.S. de; ... ; Steggerda, S.J. 2021
Objective To assess associations between neonatal brain injury assessed by magnetic resonance imaging and cognitive, motor, and behavioral outcomes at 2 and 10 years of age, in a longitudinal... Show moreObjective To assess associations between neonatal brain injury assessed by magnetic resonance imaging and cognitive, motor, and behavioral outcomes at 2 and 10 years of age, in a longitudinal cohort of children born very preterm.Study design There were 112 children born at <32 weeks of gestation who participated in a longitudinal prospective study on brain injury and neurodevelopmental outcome. Using the Kidokoro score, neonatal brain injury and altered brain growth in white matter, cortical and deep gray matter, and the cerebellum were assessed. Cognitive, motor, and behavioral outcomes were assessed during follow-up visits at both 2 (corrected) and 10 years of age.Results After adjusting for perinatal factors and level of maternal education, the global brain abnormality score was associated with cognition (B = -1.306; P = .005), motor skills (B = -3.176; P < .001), and behavior (B = 0.666; P = .005) at 2 years of age, but was not associated with cognition at 10 years of age. In the subgroup of children with a moderate-severe global brain abnormality score, magnetic resonance imaging was independently associated with cognitive impairment at 10 years of age. For children with milder forms of brain injury, only birth weight and level of maternal education were associated with cognitive outcomes.Conclusions Neonatal brain injury, assessed by a standardized scoring system, was associated with short-term neurodevelopmental outcomes, but only with motor skills and behavior in childhood. Environmental factors, such as level of maternal education, become more important for cognitive development as children grow older, especially for children with relatively mild neonatal brain injury. Show less
Objective: To investigate the rate and stability of impairments in children born preterm by assessing (1) early and school-age outcome in four developmental domains and (2) individual changes in... Show moreObjective: To investigate the rate and stability of impairments in children born preterm by assessing (1) early and school-age outcome in four developmental domains and (2) individual changes in outcome at both timepoints. Design: Prospective, longitudinal cohort study in children born in 2006-2007, <32 weeks' gestation. Follow-up at 2 and 10 years of age included standardized neurological, motor, cognitive and behavioral assessments. Children were categorized as having no, mild or moderate-severe impairment in these four domains. A composite impairment score was composed and the number of domains with impairments counted. For each child, individual outcomes at both timepoints were compared. Results: Follow-up at both time-points was available in 71/113(63%) children. At group level, there were no significant changes in the severity of impairments per domain. However, at individual level, there were less children with a mild abnormal composite score at 10 years of age (44 vs. 20%; p = 0.006), and more with a moderate-severe abnormal composite score (12 vs. 35%; p = 0.001). Especially children with normal/mild outcome at 2 years were likely to shift to other outcome categories over time. Conclusions: Children with early severe impairment are likely experiencing impairments later on, but early normal/mild abnormal outcomes should be interpreted with care, considering the large individual shifts over time. Long-term follow-up in all children born very preterm should therefore be continued to at least school-age. Show less
Ree, I.M.C.; Oever, R.M. van 't; Jansen, L.; Lopriore, E.; Haas, M. de; Klink, J.M.M. van 2021
Background Preterm born children are at high risk for adverse motor neurodevelopment. The aim of this study was to establish the relationship between motor outcome and advanced magnetic resonance... Show moreBackground Preterm born children are at high risk for adverse motor neurodevelopment. The aim of this study was to establish the relationship between motor outcome and advanced magnetic resonance imaging (MRI) and electroencephalography (EEG) measures. Methods In a prospective cohort study of 64 very preterm born children, the motor outcome was assessed at 9.83 (SD 0.70) years. Volumetric MRI, diffusion tensor imaging (DTI), and EEG were acquired at 10.85 (SD 0.49) years. We investigated associations between motor outcome and brain volumes (white matter, deep gray matter, cerebellum, and ventricles), white matter integrity (fractional anisotropy and mean, axial and radial diffusivity), and brain activity (upper alpha (A2) functional connectivity and relative A2 power). The independence of associations with motor outcome was investigated with a final model. For each technique, the measure with the strongest association was selected to avoid multicollinearity. Results Ventricular volume, radial diffusivity, mean diffusivity, relative A2 power, and A2 functional connectivity were significantly correlated to motor outcome. The final model showed that ventricular volume and relative A2 power were independently associated with motor outcome (B = -9.42 x 10(-5), p = 0.027 and B = 28.9, p = 0.007, respectively). Conclusions This study suggests that a lasting interplay exists between brain structure and function that might underlie motor outcome at school age. ImpactThis is the first study that investigates the relationships between motor outcome and brain volumes, DTI, and brain function in preterm born children at school age. Ventricular volume and relative upper alpha power on EEG have an independent relation with motor outcome in preterm born children at school age. This suggests that there is a lasting interplay between structure and function that underlies adverse motor outcome. Show less
Ree, I.M.C.; Oever, R.M. van 't; Jansen, L.; Lopriore, E.; Haas, M. de; Klink, J.M.M. van 2021
Aim: To investigate the school performance and behavioral difficulties in children with hemolytic disease of the fetus and newborn (HDFN) treated with intrauterine transfusion (IUT) compared to... Show moreAim: To investigate the school performance and behavioral difficulties in children with hemolytic disease of the fetus and newborn (HDFN) treated with intrauterine transfusion (IUT) compared to Dutch norm data.Study design: Cros-sectional cohort study. Subjects: Children who received one or multiple IUTs for severe Rh-or K (Kell)-mediated HDFN between January 2008 and January 2015 at the LUMC.Outcome measures: School performance reports were assessed as well as behavioral difficulties as assessed with the Dutch child behavioral checklist (CBCL) by parents and caregivers and the Teacher Report Form (TRF) completed by teachers.Results: A response rate of 56% (70 children, aged 5-12 years) was obtained. Grade repetition occurred in 13 cases (19%), 16 children (23%) received some form of additional help, most often support by a speech therapist (n = 8), but also support for dyslexia (n = 4), physical therapy (n = 2) and social-emotional support (n = 2). None of the children in our study group attended special-needs education. School performance levels for reading comprehension, spelling and mathematics according to the Dutch National Pupil Monitoring System were similar for the study population and Dutch norm data. The incidence of behavioral problems as reported by parents was similar to the Dutch norm data, teachers reported less behavioral difficulties in the study group. Conclusion: This study shows favorable and reassuring school development in children treated with IUT in an experienced fetal-therapy center. A normal distribution in school and behavioral development is to be expected for children with HDFN treated with IUTs. Show less
Background: Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from... Show moreBackground: Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients. Methods: HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 mg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time. Results: Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups. Conclusions: This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation. ( J CLIN EXP HEPATOL 2022;12:735–744) Show less
Prematurely born children are at higher risk for long-term adverse motor and cognitive outcomes. The aim of this paper was to compare quantitative measures derived from electroencephalography (EEG)... Show morePrematurely born children are at higher risk for long-term adverse motor and cognitive outcomes. The aim of this paper was to compare quantitative measures derived from electroencephalography (EEG) between extremely (EP) and very prematurely (VP) born children at 9-10 years of age.Fifty-five children born < 32 weeks' of gestation underwent EEG at 9-10 years of age and were assessed for motor development and cognitive outcome. Relative frequency power and functional connectivity, as measured by the Phase Lag Index (PLI), were calculated for all frequency bands. Per subject, power spectrum and functional connectivity results were averaged over all channels and pairwise PLI values to explore differences in global frequency power and functional connectivity between EP and VP children. Brain networks were constructed for the upper alpha frequency band using the Minimum Spanning Tree method and were compared between EP and VP children. In addition, the relationships between upper alpha quantitative EEG results and cognitive and motor outcomes were investigated.Relative power and functional connectivity were significantly higher in VP than EP children in the upper alpha frequency band, and VP children had more integrated networks. A strong positive correlation was found between relative upper alpha power and motor outcome whilst controlling for gestational age, age during EEG recording, and gender (p = 0.493, p = 0.004).These results suggest that 9-10 years after birth, the effects of the degree of prematurity can be observed in terms of alterations in functional brain activity and that motor deficits are associated with decreases in relative upper alpha power. Show less
Jansen, L.; Peeters-Scholte, C.; Wiggers-de Bruine, S.; Berg-Huysmans, A. van den; Klink, J. van; Steenis, A. van; ... ; Steggerda, S. 2020
Objective: To determine classroom-evaluated school performance nine years after preterm birth, predicted by perinatal risk factors and neonatal brain abnormalities.Study design: Children were... Show moreObjective: To determine classroom-evaluated school performance nine years after preterm birth, predicted by perinatal risk factors and neonatal brain abnormalities.Study design: Children were recruited from a consecutive cohort of 113 preterm infants ( < 32 weeks' gestation), participating in a longitudinal prospective study, investigating brain injury and neurodevelopmental outcome. Data on perinatal risk factors, presence of brain injury at term-equivalent age, and maternal education were collected. Information on school performance included enrollment in special (primary) education, grade repetition and school results from the nationwide standardized Dutch Pupil Monitoring System regarding reading comprehension, spelling, and mathematics.Results: Information on school enrollment was available for 87 children (77%), of whom 7 (8%) were in special primary education and 19 (22%) repeated a grade. This was significantly higher compared to national rates (p <= .05). Results on school performance were available for 74 children (65%) and showed clearly below average scores in reading comprehension (p = .006), spelling (p = .014) and mathematics (p < .001). Univariate analysis showed that lower performance in reading comprehension was predicted by male sex and low maternal education; spelling by male sex; and mathematics by Bronchopulmonary Dysplasia, white matter injury and maternal education. In a multivariate model, male sex and maternal education were predictive for reading comprehension and white matter injury for mathematics.Conclusion: Preterm born children more often need special primary education and have higher grade repeat rates. They perform poorer on reading comprehension, spelling and mathematics. Regular follow-up remains important for preterm born children during school age. Show less
Gink, K. van; Domburgh, L. van; Jansen, L.; Goddard, N.; Ottenbros, R.; Stegen, B. van der; ... ; Vermeiren, R. 2020
Non-violent Resistance (NVR) is a method to manage child and adolescent aggressive behavior and to decrease parental helplessness. Although developed for a family setting, this paper describes the... Show moreNon-violent Resistance (NVR) is a method to manage child and adolescent aggressive behavior and to decrease parental helplessness. Although developed for a family setting, this paper describes the adaptation of NVR for child and adolescent residential settings, reports on the possible hampering and facilitating elements of implementing NVR in four different institutions and finally presents seclusion and restraint rates before and after implementation. Retrospective analysis of the different implementation processes suggested the following dements to facilitate implementation: awareness that NVR is not a quick fix, a considerable amount of time and financial investment, a team-wide perspective, support from all levels in an organization and influential team members committed to NVR to decrease the risk of falling back into more familiar patterns. Seclusion and restraint figures pre-post point in the direction that the implementation of an adapted version of NVR in residential settings could result in decreased seclusion and restraint. Furthermore, this decrease was most pronounced in sites with a successful implementation process. This observational study provides a starting point for an empirical basis for the use of NVR within child and adolescent residential settings. Further research on successful implementation processes for multi-level, milieu-based interventions, such as NVR, is required. Show less
Not only are childhood onset offenders at high risk of becoming serious persistent offenders, they are also at high risk of becoming victimized themselves. Furthermore, studies in the general... Show moreNot only are childhood onset offenders at high risk of becoming serious persistent offenders, they are also at high risk of becoming victimized themselves. Furthermore, studies in the general population suggest that a combined perpetrator-victim group can be distinguished from a perpetrator-only and a victim-only group on individual and family risk factors. The current study investigated the co-occurrence of offending and victimization among first-time arrestees and the 2-year predictive value of previously found clusters of dynamic risk factors of offending. Childhood first-time arrestees (N = 308; M-age = 10.3, SD = 1.45) were clustered into three groups based on dynamic risk factors of offending in the individual, peer, school, and family domains: a pervasive high, an externalizing intermediate, and a low problem group. Police records and self-report data on re-offending and victimization of these children were collected over a 2-year follow-up period. Compared with the low problem group, the prevalence of re-offending was higher in both the externalizing intermediate group and the pervasive high group. The pervasive high group was most likely to display co-occurring future antisocial behavior and victimization. These findings emphasize that attention should be paid to victimization in addition to future antisocial behavior, especially if additional internalizing and family problems are present. Furthermore, the differences in re-offending and victimization between subgroups of childhood onset offenders stress the need for specific interventions tailored to the risk profile of a child. Show less
Gink, K. van; Vermeiren, R.; Goddard, N.; Domburgh, L. van; Stegen, B. van der; Twisk, J.; ... ; Jansen, L. 2018
