Application of multiple mosaic callers improves post-zygotic mutation detection from exome sequencing data.

PURPOSE: The gold standard for identification of post-zygotic variants (PZVs) is droplet digital polymerase chain reaction or high-depth sequencing across multiple tissues types. These approaches are yet to be systematically implemented for monogenic disorders. We developed PZV detection pipelines for correct classification of de novo variants. METHOD: Our pipelines detect PZV in parents (gonosomal mosaicism [pGoM]) and children (somatic mosaicism, "M3"). We applied them to research exome sequencing (ES) data from the Australian Cerebral Palsy Biobank (n = 145 trios) and Simons Simplex Collection (n = 405 families). Candidate mosaic variants were validated using deep amplicon sequencing or droplet digital polymerase chain reaction. RESULTS: 69.2% (M3trio), 63.9% (M3single), and 92.7% (pGoM) of detected variants were validated, with 48.6%, 56.7%, and 26.2% of variants, respectively, meeting strict criteria for mosaicism. In the Australian Cerebral Palsy Biobank, 16.6% of probands and 20.7% of parents had at least 1 true-positive somatic or pGoM variant, respectively. A large proportion of PZVs detected in Simons Simplex Collection parents (79.8%) and child (94.5%) were not previously reported. We reclassified 3.7% to 8.0% of germline de novo variants as mosaic. CONCLUSION: Many PZVs were incorrectly classified as germline variants or missed by previous approaches. Systematic application of our pipelines could increase genetic diagnostic rate, improve estimates of recurrence risk in families, and benefit novel disease gene identification.

Cerebral Palsy and Motor Impairment After Extreme Prematurity: Prediction of Diagnoses at Ages 2 and 10 Years.

OBJECTIVE: To identify perinatal factors in children born extremely preterm (EP) that were associated with motor impairment (MI) at 2 and 10 years of age and develop a predictive algorithm to estimate the risk of MI during childhood. STUDY DESIGN: Participants of the Extremely Low Gestational Age Newborns Study (ELGANS) were classified as: no MI, MI only at 2 years, MI only at 10 years, and MI at both 2 and 10 years, based on a standardized neurological examination at 2 and the Gross Motor Function Classification System (GMFCS) at 10 years of age. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to develop the final predictive model. RESULTS: Of the 849 study participants, 64 (7.5%) had a diagnosis of MI at both 2 and 10 years and 63 (7.4%) had a diagnosis of MI at 1 visit but not the other. Of 22 total risk factors queried, 4 variables most reliably and accurately predicted MI: gestational age, weight z-score growth trajectory during neonatal intensive care unit (NICU) stay, ventriculomegaly, and cerebral echolucency on head ultrasound. By selecting probability thresholds of 3.5% and 7.0% at ages 2 and 10, respectively, likelihood of developing MI can be predicted with a sensitivity and specificity of 71.2%/72.1% at age 2 and 70.7%/70.7% at age 10. CONCLUSION: In our cohort, the diagnosis of MI at 2 years did not always predict a diagnosis of MI at 10 years. Specific risk factors are predictive of MI and can estimate an individual infant's risk at NICU discharge of MI at age 10 years.

The Knowledge Translation of Early Cerebral Palsy (KiTE CP) Study: Implementing Screening Among a High-Risk Prospective Cohort of Australian Infants.

OBJECTIVE: To describe the implementation of the international guidelines for the early diagnosis of cerebral palsy (CP) and engagement in the screening process in an Australian cohort of infants with neonatal risk factors for CP. STUDY DESIGN: Prospective cohort study of infants with neonatal risk factors recruited at <6 months corrected age from 11 sites in the states of Victoria, New South Wales, and Queensland, Australia. First, we implemented a multimodal knowledge translation strategy including barrier identification, technology integration, and special interest groups. Screening was implemented as follows: infants with clinical indications for neuroimaging underwent magnetic resonance imaging and/or cranial ultrasound. The Prechtl General Movements Assessment (GMA) was recorded clinically or using an app (Baby Moves). Infants with absent or abnormal fidgety movements on GMA videos were offered further assessment using the Hammersmith Infant Neurological Examination (HINE). Infants with atypical findings on 2/3 assessments met criteria for high risk of CP. RESULTS: Of the 597 infants (56% male) recruited, 95% (n = 565) received neuroimaging, 90% (n = 537) had scorable GMA videos (2% unscorable/8% no video), and 25% (n = 149) HINE. Overall, 19% of the cohort (n = 114/597) met criteria for high risk of CP, 57% (340/597) had at least 2 normal assessments (of neuroimaging, GMA or HINE), and 24% (n = 143/597) had insufficient assessments. CONCLUSIONS: Early CP screening was implemented across participating sites using a multimodal knowledge translation strategy. Although the COVID-19 pandemic affected recruitment rates, there was high engagement in the screening process. Reasons for engagement in early screening from parents and clinicians warrant further contextualization and investigation.

Neurodevelopmental outcomes in preterm or low birth weight infants with germinal matrix-intraventricular hemorrhage: a meta-analysis.

BACKGROUND: This meta-analysis aimed to identify the near- and long-term neurodevelopmental prognoses of preterm or low birth weight (LBW) infants with different severities of intraventricular hemorrhage (IVH). METHODS: Four databases were searched for observational studies that were qualified using the Newcastle-Ottawa Scale. RESULTS: 37 studies involving 32,370 children were included. Compared to children without IVH, children with mild IVH had higher incidences of neurodevelopmental impairment (NDI), cerebral palsy (CP), motor/cognitive delay, hearing impairment and visual impairment, as well as lower scores of the mental development index (MDI) and psychomotor development (PDI). Moreover, compared to mild IVH, severe IVH increased susceptibilities of children to NDI, motor delay, CP, hearing impairment and visual impairment, with worse performances in MDI, PDI, motor score and IQ. Mild IVH was not associated with seizures or epilepsy. CONCLUSIONS: Adverse neurodevelopmental outcomes positively associated with the occurrence and severity of IVH in preterm or LBW infants, providing evidence for counseling and further decisions regarding early therapeutic interventions. IMPACT: Adverse neurodevelopmental outcomes later in life were closely associated with the occurrence and severity of IVH in preterm or LBW infants. Our results highlight the importance to make prediction of the neurodevelopmental outcomes of children born preterm or LBW with a history of IVH, which will guide affected parents when their children need clinical interventions to reach the full potential. We emphasize the importance of identifying specific developmental delays that may exist in children with IVH, providing detailed information for the development of comprehensive intervention measures.

Symptomatic flatfoot in cerebral palsy.

PURPOSE OF REVIEW: The purpose of this review is to evaluate the current literature and best practices in the evaluation and treatment of symptomatic flatfoot in cerebral palsy. RECENT FINDINGS: While techniques to reconstruct the neuromuscular flatfoot and reestablish bony levers have remained similar over time, the concept of surgical dosing has helped guide appropriate interventions based on the magnitude of disease and functional level of the child. Moreover, the utilization of multisegment foot modeling in motion analysis has allowed quantitative description of such deformities and their impact on gait. SUMMARY: Future research should focus on refining operative indications and interventions with larger, multicenter, prospective cohorts to provide more robust evidence in surgical decision making. Long-term data are needed to confirm and compare efficacy of procedures. Radiographic data alone are not sufficient for describing functional foot position. Gait analysis with foot modeling and pedobarography along with patient-centered subjective outcomes will be needed in such investigations to make conclusive recommendations.

Neurological assessment tool for screening infants during the first year after birth: The Brief-Hammersmith Infant Neurological Examination.

AIM: To develop a short version of the original Hammersmith Infant Neurological Examination (HINE) to be used as a screening tool (Brief-HINE) and to establish if the short examination maintains good accuracy and predictive power for detecting infants with cerebral palsy (CP). METHOD: Eleven items were selected from the original HINE ('visual response'; 'trunk posture'; 'movement quantity'; 'movement quality'; 'scarf sign'; 'hip adductor angles'; 'popliteal angle'; 'pull to sit'; 'lateral tilting'; 'forward parachute reaction'; 'tendon reflexes') identifying those items previously found to be more predictive of CP in both low- and high-risk infants. In order to establish the sensitivity of the new module, the selected items were applied to existing data, previously obtained using the full HINE at 3, 6, 9, and 12 months, in 228 infants with typical development at 2 years and in 82 infants who developed CP. RESULTS: Brief-HINE scores showed good sensitivity and specificity, at each age of assessment, for detecting infants with CP. At 3 months, a score of less than 22 was associated with CP with a sensitivity of 0.88 and a specificity of 0.92; at 6, 9, and 12 months, the cut-off scores were less than 25 (sensitivity 0.93; specificity 0.87), less than 27 (sensitivity 0.95; specificity 0.81), and less than 27 (sensitivity 1; specificity 0.86) respectively. The presence of more than one warning sign, or items that are not optimal for the age of assessment, imply the need for a full examination reassessment. INTERPRETATION: These findings support the validity of the Brief-HINE as a routine screening method and the possibility of its use in clinical practice.

Prioritized strategies to improve diagnosis and early management of cerebral palsy for both Maori and non-Maori families.

AIM: To identify prioritized strategies to support improvements in early health service delivery around the diagnosis and management of cerebral palsy (CP) for both Maori and non-Maori individuals. METHOD: Using a participatory approach, health care professionals and the parents of children with CP attended co-design workshops on the topic of early diagnosis and management of CP. Health design researchers facilitated two 'discovery' (sharing experiences and ideas) and two 'prototyping' (solution-focused) workshops in Aotearoa, New Zealand. A Maori health service worker co-facilitated workshops for Maori families. RESULTS: Between 7 and 13 participants (14 health care professionals, 12 parents of children with CP across all functional levels) attended each workshop. The discovery workshops revealed powerful stories about early experiences and needs within clinician-family communication and service provision. The prototyping workshops revealed priorities around communication, and when, what, and how information is provided to families; recommendations were co-created around what should be prioritized within a resource to aid health care navigation. INTERPRETATION: There is a critical need for improved communication, support, and guidance, as well as education, for families navigating their child with CP through the health care system. Further input from families and health care professionals partnering together will continue to guide strategies to improve health care service delivery using experiences as a mechanism for change.

Baby Observational Selective Control AppRaisal (BabyOSCAR): Convergent and discriminant validity and reliability in infants with and without spastic cerebral palsy.

AIM: To describe the development of an observational measure of spontaneous independent joint motion in infants with spastic cerebral palsy (CP), the Baby Observational Selective Control AppRaisal (BabyOSCAR), and to test its convergent validity and reliability. METHOD: A retrospective sample of 75 infants (45 with spastic CP and 30 without CP) at 3 months of age were scored with the BabyOSCAR and compared with diagnosis of spastic CP, limbs affected, and Gross Motor Function Classification level at 2 years of age or later for convergent validity using t-tests, Kruskal-Wallis tests, and Spearman's rank correlation coefficients. BabyOSCAR interrater and test-retest reliability was also evaluated using intraclass correlation coefficients. RESULTS: Infants with spastic CP had significantly lower BabyOSCAR scores than children without CP (p < 0.001) and scores were significantly correlated with Gross Motor Function Classification System levels (p < 0.001). Children with unilateral CP had significantly higher asymmetry scores than children with bilateral CP or no CP (p < 0.01). Interrater and test-retest reliabilities were good to excellent. INTERPRETATION: Reductions in independent joint control measured in infancy are a hallmark of eventual diagnosis of spastic CP, and influence gross motor function later in childhood (with or without a diagnosis of CP). WHAT THIS PAPER ADDS: Early brain injury causing spastic cerebral palsy results in fewer independent joint movements in infants. Baby Observational Selective Control AppRaisal (BabyOSCAR) score at 3 months depends on limbs affected by early brain injury. BabyOSCAR scores at 3 months correlate with Gross Motor Function Classification System level at ≥2 years. BabyOSCAR has excellent interrater reliability. BabyOSCAR, scored with a 1-minute video recording, has good to excellent test-retest reliability.

Baby Observational Selective Control AppRaisal (BabyOSCAR): Scores at 3 months predict functional ability, spastic cerebral palsy distribution, and diagnosis at 2 years.

AIM: To assess the predictive capabilities of the Baby Observational Selective Control AppRaisal (BabyOSCAR) tool, administered at 3 months corrected age, in determining spastic cerebral palsy (CP) outcome, functional abilities, and body topography at 2 years of age or later. METHOD: Independent joint motions were measured at age 10 to 16 weeks from video recordings of spontaneous movement using BabyOSCAR in a sample of 75 infants. All included infants had known 2-year outcomes (45 with spastic CP and 30 without CP) including Gross Motor Functional Classification System (GMFCS) levels and CP body distribution. Receiver operating characteristic curves and cut points indicating greatest sensitivity and specificity were generated for predictive performance. RESULTS: Total BabyOSCAR score was a strong predictor of future outcome of spastic CP (cut score of 22.5, sensitivity = 98%, specificity = 100%, area under the curve = 0.99), and was able to distinguish children classified in GMFCS levels I and II from those in III to V (cut score of 13.5, sensitivity = 92%, specificity = 89%, area under the curve = 0.94). Having an (absolute) asymmetry score on the BabyOSCAR of more than 5 was a predictor of having unilateral CP at age 2 years (sensitivity = 56%, specificity = 100%, area under the curve = 0.86). INTERPRETATION: BabyOSCAR scores are predictors of diagnosis, body distribution, and future gross motor function in infants with spastic CP at 2 years of age or later. WHAT THIS PAPER ADDS: Decreased independent joint movement at 3 months predicts spastic cerebral palsy (CP) at 2 years. Baby Observational Selective Control AppRaisal (BabyOSCAR) scores ≤13 are predictive of Gross Motor Function Classification System (GMFCS) levels III to V. BabyOSCAR scores of 14 to 22 are predictive of GMFCS levels I and II. A BabyOSCAR total asymmetry score >5 predicts unilateral CP. Stereotyped movements are more prominent in those who will be diagnosed with spastic CP at 2 years.

Measurement of surface electromyography activity during swallowing in paediatrics: a scoping literature review.

Surface electromyography (sEMG) could be used for diagnostic and therapeutic purposes in various health conditions. For example, sEMG biofeedback is shown to be beneficial in adults with swallowing disorders (dysphagia), whereas there are no easily identifiable studies to support such evidence in paediatrics. The current review aimed to evaluate the feasibility of implementing sEMG during swallowing tasks in paediatric populations with various diagnoses. Additionally, the review aimed to describe findings in publications involving participants with cerebral palsy (CP) and dysphagia. Paediatric-related publications were sourced using English keywords and phrases across the following seven databases: PubMed, EMBASE, CINAHL, Web of Science, PsycINFO, and ProQuest Dissertations and Theses Global. The search included all available publications without language and date restrictions. Publications using sEMG during chewing tasks were also accepted in the review as chewing is considered to be part of the act of swallowing. The feasibility of measuring sEMG during swallowing in children with various health conditions was supported by 116 publications (n = 6 literature reviews) that met the inclusion criteria for the final full-text review. However, a few publications described some difficulties occurring directly during the sEMG data collection sessions. The review identified 15 publications involving 177 participants with CP who underwent sEMG while swallowing (n = 1 publication focused solely on the assessment of chewing). Ten publications described studies that recruited children with dysphagia. Children with CP who had dysphagia were recruited in five of these studies. CONCLUSIONS: The acquisition of sEMG measurements while performing swallowing tasks was shown to be feasible in children with various diagnoses including those who have CP and dysphagia. Future studies should investigate the implementation of sEMG as a part of paediatric dysphagia therapy alongside biofeedback swallowing skill training. WHAT IS KNOWN: • Surface electromyography (sEMG) could be implemented for diagnostic and therapeutic purposes in various health conditions. • Biofeedback using sEMG is beneficial in adults with swallowing disorders (dysphagia). WHAT IS NEW: • Implementation of sEMG was shown to be feasible during swallowing tasks in paediatric populations with various diagnoses, including dysphagia and cerebral palsy. • The usage of sEMG biofeedback as a part of paediatric dysphagia management should be investigated in future studies.

'We did everything by phone': a qualitative study of mothers' experience of smartphone-aided screening of cerebral palsy in Kathmandu, Nepal.

BACKGROUND: International guidelines recommend early intervention to all children at risk of cerebral palsy, but targeted screening programs are often lacking in low- and middle-income settings with the highest burden of disease. Smartphone applications have the potential to improve access to early diagnostics by empowering parents to film their children at home followed by centralized evaluation of videos with General Movements Assessment. We explored mothers' perceptions about participating in a smartphone aided cerebral palsy screening program in Kathmandu, Nepal. METHODS: This is an explorative qualitative study that used focus group discussions (n = 2) and individual interviews (n = 4) with mothers of term-born infants surviving birth asphyxia or neonatal seizures. Parents used the NeuroMotion™ smartphone app to film their children at home and the videos were analysed using Precthl's General Movements Assessment. Sekhon et al.'s framework on the acceptability of health care interventions guided the design of the group discussions and interviews, and the deductive qualitative content analysis. RESULTS: Mothers were interested in engaging with the programme and expressed hope it would benefit their children. Most felt using the app was intuitive. They were, however, unclear about the way the analysis was performed. Support from the research team was often needed to overcome an initial lack of self-confidence in using the technology, and to reduce anxiety related to the follow-up. The intervention was overall perceived as recommendable but should be supplemented by a face-to-face consultation. CONCLUSION: Smartphone aided remote screening of cerebral palsy is acceptable in a lower middle-income population but requires additional technical support.

Signs of perceptual disorder during movement were reliably assessed in children with cerebral palsy in Sweden.

AIM: The aim of this Swedish study was to evaluate the assessment of clinical signs of perceptual disorder in children with cerebral palsy (CP). METHODS: Three experienced raters assessed 56 videos of 19 children from 1 to 18 years of age with bilateral spastic CP, which were recorded by colleagues at an Italian hospital. Six signs were evaluated for inter-rater reliability and criterion validity. Clinical applicability was evaluated by assessing inter-rater reliability between 47 Swedish clinicians, who examined 15 of the videos during face-to-face and online education seminars. There were 41 physiotherapists, two occupational therapists and four doctors, with 1-37 years of clinical experience and a median of 10 years. RESULTS: The experienced raters demonstrated moderate to almost perfect inter-rater reliability (kappa 0.54-0.81) and criterion validity (0.54-0.87) for startle reaction, upper limbs in startle position, averted eye gaze and eye blinking. The clinicians recognised these signs with at least moderate reliability (0.56-0.88). Grimacing and posture freezing were less reliable (0.22-0.35) and valid (0.09-0.50). CONCLUSION: Four of the six signs of perceptual disorder were reliably recognised by experienced raters and by clinicians after education seminars. Extended education and larger study samples are needed to recognise all the signs.

The Danish child and parent Gait Outcomes Assessment List questionnaires were reliable and valid for cerebral palsy.

AIM: We investigated the reliability and validity of the Danish child and parent versions of the Gait Outcomes Assessment List (GOAL) questionnaires for ambulatory children with cerebral palsy (CP). METHODS: Translation and cultural adaptations were performed and content validity evaluated. Participants were enrolled between 2016 and 2018 from Aarhus University Hospital, Denmark. Children and parents completed the GOAL questionnaires twice for test-retest reliability. Discriminative validity was evaluated by comparing the child and parent GOAL scores between children with Gross Motor Function Classification System (GMFCS) levels I and II. The concurrent validity of the GOAL questionnaires were investigated by comparing them with Challenge-20, which assesses motor skills in children with CP. RESULTS: We studied 59 children (57% boys) with CP and GMFCS I-II at a mean age of 10.6 years. Test-retest intra-class correlations were excellent for the children (0.91, 95% confidence interval (CI) 0.83-0.96) and good for the parents (0.83, 95% CI 0.67-0.91). GOAL scores decreased with increasing GMFCS (p < 0.05). Both versions correlated well. The mean children's scores were significantly (6.2/100) higher than the parents' (p < 0.001). The GOAL scores correlated positively with Challenge-20. CONCLUSION: The Danish GOAL child and parent questionnaires demonstrated good reliability and content and discriminative and concurrent validity.

Sit-to-stand performance in children with cerebral palsy: a population-based cross-sectional study.

BACKGROUND: Sit-to-stand (STS) is one of the most commonly performed functional movements in a child's daily life that enables the child to perform functional activities such as independent transfer and to initiate walking and self-care. Children with cerebral palsy (CP) often have reduced STS ability. The aim of this study was to describe STS performance in a national based total population of children with CP and its association with age, sex, Gross Motor Function Classification System (GMFCS) level, and CP subtype. METHODS: This cross-sectional study included 4,250 children (2,503 boys, 1,747 girls) aged 1-18 years from the Swedish Cerebral Palsy Follow-Up Program (CPUP). STS performance was classified depending on the independence or need for support into "without support," "with support," or "unable." "With support" included external support from, e.g., walls and furniture. Physical assistance from another person was classified as "unable" (dependent). Ordinal and binary logistic regression analyses were used to identify associations between STS and age, GMFCS level, and CP subtype. RESULTS: 60% of the children performed STS without support, 14% performed STS with support, and 26% were unable or needed assistance from another person. STS performance was strongly associated with GMFCS level and differed with age and subtype (p < 0.001). For all GMFCS levels, STS performance was lowest at age 1-3 years. Most children with GMFCS level I (99%) or II (88%) performed STS without support at the age of 4-6 years. In children with GMFCS level III or IV, the prevalence of independent STS performance improved throughout childhood. CP subtype was not associated with STS performance across all GMFCS levels when adjusted for age. CONCLUSIONS: Independent STS performance in children with CP is associated with GMFCS level and age. Children with CP acquire STS ability later than their peers normally do. The proportion of children with independent STS performance increased throughout childhood, also for children with GMFCS level III or IV. These findings suggest the importance of maintaining a focus on STS performance within physiotherapy strategies and interventions for children with CP, including those with higher GMFCS level.

Incidence and sequence of scoliosis and windswept hip deformity: which comes first in 4148 children with cerebral palsy? A longitudinal cohort study.

BACKGROUND: The aim was to analyse whether scoliosis or windswept hip deformity (WSH) occurs first for children with cerebral palsy (CP). METHODS: This longitudinal cohort study using data from 1994 - 2020 (26 years) involved 41,600 measurements of 4148 children (2419 [58.3%] boys) with CP born 1990 - 2018 and registered into the Swedish CP follow-up program. Children were followed from a mean age of 2.8 [SD 1.4] years, until they developed either scoliosis or WSH or were removed at surgery. RESULTS: WSH developed first in 16.6% of the children (mean age 8.1 [SD 5.0] years), and scoliosis in 8.1% (mean age 8.1 [SD 4.9] years). The incidence of WSH was higher than scoliosis across all levels I-V of the Gross Motor Function Classification System (GMFCS), both sexes, and for those with dyskinetic (20.0%) or spastic (17.0%) CP. The incidence of scoliosis was highest (19.8%) and developed earliest in children with GMFCS level V (mean age 5.5 [SD 3.5] years), and in children with dyskinetic (17.9%) CP (mean age 7.0 [SD 4.7] years). CONCLUSIONS: WSH presents earlier than scoliosis in most children with CP. Children with higher GMFCS level or dyskinetic CP are more likely to develop these deformities at a younger age.

Feasibility and usefulness of video-based markerless two-dimensional automated gait analysis, in providing objective quantification of gait and complementing the evaluation of gait in children with cerebral palsy.

BACKGROUND: Gait analysis aids in evaluation, classification, and follow-up of gait pattern over time in children with cerebral palsy (CP). The analysis of sagittal plane joint kinematics is of special interest to assess flexed knee gait and ankle joint deviations that commonly progress with age and indicate deterioration of gait. Although most children with CP are ambulatory, no objective quantification of gait is currently included in any of the known international follow-up programs. Is video-based 2-dimensional markerless (2D ML) gait analysis with automated processing a feasible and useful tool to quantify deviations, evaluate and classify gait, in children with CP? METHODS: Twenty children with bilateral CP with Gross Motor Function Classification Scale (GMFCS) levels I-III, from five regions in Sweden, were included from the national CP registry. A single RGB-Depth video camera, sensitive to depth and contrast, was positioned laterally to a green walkway and background, with four light sources. A previously validated markerless method was employed to estimate sagittal plane hip, knee, ankle kinematics, foot orientation and spatio-temporal parameters including gait speed and step length. RESULTS: Mean age was 10.4 (range 6.8-16.1) years. Eight children were classified as GMFCS level I, eight as II and four as III. Setup of the measurement system took 15 min, acquisition 5-15 min and processing 50 min per child. Using the 2D ML method kinematic deviations from normal could be determined and used to implement the classification of gait pattern, proposed by Rodda et al. 2001. CONCLUSION: 2D ML assessment is feasible, since it is accessible, easy to perform and well tolerated by the children. The 2D ML adds consistency and quantifies objectively important gait variables. It is both relevant and reasonable to include 2D ML gait assessment in the evaluation of children with CP.

Children Newly Diagnosed with Fetal and Neonatal Alloimmune Thrombocytopenia: Neurodevelopmental Outcome at School Age.

OBJECTIVE: To evaluate the neurodevelopmental outcome at school age in children newly diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT). STUDY DESIGN: This observational cohort study included children diagnosed with FNAIT between 2002 and 2014. Children were invited for cognitive and neurological testing. Behavioral questionnaires and school performance results were obtained. A composite outcome of neurodevelopmental impairment (NDI) was used, defined, and subdivided into mild-to-moderate and severe NDI. Primary outcome was severe NDI, defined as IQ <70, cerebral palsy with Gross Motor Functioning Classification System level ≥ III, or severe visual/hearing impairment. Mild-to-moderate NDI was defined as IQ 70-85, minor neurological dysfunction or cerebral palsy with Gross Motor Functioning Classification System level ≤ II, or mild visual/hearing impairment. RESULTS: In total, 44 children were included at a median age of 12 years (range: 6-17 years). Neuroimaging at diagnosis was available in 82% (36/44) of children. High-grade intracranial hemorrhage (ICH) was detected in 14% (5/36). Severe NDI was detected in 7% (3/44); two children had high-grade ICH, and one had low-grade ICH and perinatal asphyxia. Mild-to-moderate NDI was detected in 25% (11/44); one child had high-grade ICH, and eight children were without ICH, yet for two children, neuroimaging was not performed. Adverse outcome (perinatal death or NDI) was 39% (19/49). Four children (9%) attended special needs education, three of whom had severe NDI and one had mild-to-moderate NDI. Total behavioral problems within the clinical range were reported in 12%, which is comparable with 10% in the general Dutch population. CONCLUSION: Children who are newly diagnosed with FNAIT are at increased risk for long-term neurodevelopmental problems, even those without ICH. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (Identifier: NCT04529382).

Severe Congenital Heart Defects and Cerebral Palsy.

OBJECTIVE: To report the prevalence of cerebral palsy (CP) in children with severe congenital heart defects (sCHD) and the outcome/severity of the CP. METHODS: Population-based, data linkage study between CP and congenital anomaly registers in Europe and Australia. The EUROCAT definition of severe CHD (sCHD) was used. Linked data from 4 regions in Europe and 2 in Australia were included. All children born in the regions from 1991 through 2009 diagnosed with CP and/or sCHD were included. Linkage was completed locally. Deidentified linked data were pooled for analyses. RESULTS: The study sample included 4989 children with CP and 3684 children with sCHD. The total number of livebirths in the population was 1 734 612. The prevalence of CP was 2.9 per 1000 births (95% CI, 2.8-3.0) and the prevalence of sCHD was 2.1 per 1000 births (95% CI, 2.1-2.2). Of children with sCHD, 1.5% (n = 57) had a diagnosis of CP, of which 35 (61%) children had prenatally or perinatally acquired CP (resulting from a brain injury at ≤28 days of life) and 22 (39%) children had a postneonatal cause (a brain injury between 28 days and 2 years). Children with CP and sCHD more often had unilateral spastic CP and more intellectual impairments than children with CP without congenital anomalies. CONCLUSIONS: In high-income countries, the proportion of children with CP is much higher in children with sCHD than in the background population. The severity of disease in children with CP and sCHD is milder compared with children with CP without congenital anomalies.

Integrative Multi-Omics Research in Cerebral Palsy: Current Progress and Future Prospects.

Cerebral palsy (CP) describes a heterogeneous group of non-progressive neurodevelopmental disorders affecting movement and posture. The etiology and diagnostic biomarkers of CP are a hot topic in clinical research. Recent advances in omics techniques, including genomics, epigenomics, transcriptomics, metabolomics and proteomics, have offered new insights to further understand the pathophysiology of CP and have allowed for identification of diagnostic biomarkers of CP. In present study, we reviewed the latest multi-omics investigations of CP and provided an in-depth summary of current research progress in CP. This review will offer the basis and recommendations for future fundamental research on the pathogenesis of CP, identification of diagnostic biomarkers, and prevention strategies for CP.

Risk factors for cerebral palsy and movement difficulties in 5-year-old children born extremely preterm.

BACKGROUND: Motor impairment is common after extremely preterm (EPT, <28 weeks' gestational age (GA)) birth, with cerebral palsy (CP) affecting about 10% of children and non-CP movement difficulties (MD) up to 50%. This study investigated the sociodemographic, perinatal and neonatal risk factors for CP and non-CP MD. METHODS: Data come from a European population-based cohort of children born EPT in 2011-2012 in 11 countries. We used multinomial logistic regression to assess risk factors for CP and non-CP MD (Movement Assessment Battery for Children - 2nd edition ≤5th percentile) compared to no MD (>15th percentile) among 5-year-old children. RESULTS: Compared to children without MD (n = 366), young maternal age, male sex and bronchopulmonary dysplasia were similarly associated with CP (n = 100) and non-CP MD (n = 224) with relative risk ratios (RRR) ranging from 2.3 to 3.6. CP was strongly related to severe brain lesions (RRR >10), other neonatal morbidities, congenital anomalies and low Apgar score (RRR: 2.4-3.3), while non-CP MD was associated with primiparity, maternal education, small for GA (RRR: 1.6-2.6) and severe brain lesions, but at a much lower order of magnitude. CONCLUSION: CP and non-CP MD have different risk factor profiles, with fewer clinical but more sociodemographic risk factors for non-CP MD. IMPACT: Young maternal age, male sex and bronchopulmonary dysplasia similarly increased risks of both cerebral palsy and non-cerebral palsy movement difficulties. Cerebral palsy was strongly related to clinical risk factors including severe brain lesions and other neonatal morbidities, while non-cerebral palsy movement difficulties were more associated with sociodemographic risk factors. These results on the similarities and differences in risk profiles of children with cerebral palsy and non-cerebral palsy movement difficulties raise questions for etiological research and provide a basis for improving the identification of children who may benefit from follow-up and early intervention.