Cognitive Training for Visuospatial Processing in Children Aged 5½ to 6 Years Born Very Preterm With Working Memory Dysfunction: A Randomized Clinical Trial.

Importance: Compared with term-born peers, children born very preterm generally perform poorly in executive functions, particularly in working memory and inhibition. By taking advantage of neuroplasticity, computerized cognitive training of working memory in those children could improve visuospatial processing by boosting visual inhibition via working memory. Objective: To evaluate the long-term effect of cognitive working memory training on visuospatial processing in children aged 5½ to 6 years born very preterm who have working memory impairment. Design, Setting, and Participants: This multicenter (18 French university hospitals), open-label randomized clinical trial with 2 parallel groups (EPIREMED) was conducted from November 2016 to April 2018, with the last follow-up during August 2019. Eligible children from the EPIPAGE 2 cohort were aged 5½ to 6 years, were born between 24 and 34 weeks' gestation, and had a global intelligence quotient greater than 70 and a working memory index less than 85. Data were analyzed from February to December 2020. Intervention: Children were randomized 1:1 to standard care management and a working memory cognitive training program (Cogmed software) for 8 weeks (25 sessions) (intervention) or to standard management (control). Main Outcomes and Measures: The primary outcome was the visuospatial index score from the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition. Secondary outcomes were working memory, intellectual functioning, executive and attention processes, language skills, behavior, quality of life, and schooling. Neurobehavioral assessments were performed at inclusion and after finishing training at 6 months (intermeditate assessment; secondary outcomes) and at 16 months (final assessment; primary outcome). Results: There were 169 children randomized, with a mean (SD) age of 5 years 11 months (2 months); 91 (54%) were female. Of the participants, 84 were in the intervention group (57 of whom [68%] completed at least 15 cognitive training sessions) and 85 were in the control group. The posttraining visuospatial index score was not different between groups at a mean (SD) of 3.0 (1.8) months (difference, -0.6 points; 95% CI, -4.7 to 3.5 points) or 12.9 (2.6) months (difference, 0.1 points; 95% CI, -5.4 to 5.1 points). The working memory index score in the intervention group significantly improved from baseline at the intermediate time point (difference, 4.7 points; 95% CI, 1.2-8.1 points), but this improvement was not maintained at the final assessment. Conclusions and Relevance: This randomized clinical trial found no lasting effect of a cognitive training program on visuospatial processing in children aged 5½ to 6 years with working memory disorders who were born very preterm. The findings suggest that this training has limited long-term benefits for improving executive function. Transient benefits seemed to be associated with the developmental state of executive functions. Trial Registration: ClinicalTrials.gov Identifier: NCT02757794.

Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): A multicentric French national observational cross-sectional study based on the FranceCoag registry.

INTRODUCTION: It is necessary to gain insights into adherence to healthcare in people with severe haemophilia (PwSH), especially during the transition from paediatric to adult care, which is an important phase in lives of young people with childhood chronic disease. This adherence can be considered as a marker of successful transition. OBJECTIVES: The main objective of the quantitative phase of the TRANSHEMO project was to compare the adherence to healthcare between adolescents and young adults (YAs) with severe haemophilia. The secondary objective was to identify the determinants (facilitators and barriers) of this adherence and associations between these determinants. METHODS: A multicentre, observational, cross-sectional study was conducted in 2017-2019 on PwSH aged between 14 and 17 years (adolescents) or between 20 and 29 years (YAs), included in the FranceCoag registry and having completed the questionnaires. The adherence to healthcare (treatment regimens and clinical follow-up) was compared between adolescents and YAs using the chi-squared test. The determinants of this adherence were analysed by structural equation modelling. RESULTS: There were 277 participants, 107 adolescents, and 170 YAs. The rate of adolescents adhering to healthcare was 82.2%, while the rate of YAs was 61.2% (p < .001). The barriers to the adherence to healthcare were being YA, having repeated at least one school grade and presenting mental health concerns. CONCLUSION: Adolescents had better adherence to healthcare than YAs. According to the determinants enlightened in this project, targeted supportive strategies and adapted therapeutic education programs can be developed for young PwSH to facilitate their adherence to healthcare.

Occupational integration of adults with severe haemophilia (INTHEMO): A study based on the FranceCoag registry.

INTRODUCTION: Health of people with severe haemophilia (PwSH) improves thanks to the advancements in haemophilia care, giving them more opportunities in occupational integration. However, there is little literature on the occupational integration of PwSH. OBJECTIVES: The main objective of our study was to assess the occupational integration of PwSH and to compare it with that of the general population. The secondary objective was to study the association between individual characteristics (sociodemographic, clinical and psycho-behavioural) and occupational integration of PwSH. METHODS: A multicentre, non-interventional, cross-sectional study was conducted in 2018-2020 on PwSH, aged over 18 and under 65 years and included in the FranceCoag registry. Measurements included indicators of occupational integration, sociodemographic, clinical and psycho-behavioural characteristics. The indicators of occupational integration were compared with those of the general population, using indirect standardization. The data of the general population were available from the National Institute of Statistics and Economic Studies (INSEE). Determinants of occupational integration were explored using structural equation modelling. RESULTS: Of 1262 eligible people, 588 were included. PwSH had a lower employment rate than the general population (standardized ratio, .85; 95% CI, .77-.94). There were more PwSH at tertiary education level than expected (standardized ratio, 1.38; 95% CI, 1.17-1.61). HIV infection, poor physical health and mental health concerns were associated with a higher risk of unemployment in PwSH. CONCLUSION: Employment rate of PwSH is lower than that of the general population despite their higher education level. Target interventions focusing on determinants of difficult occupational integration could be helpful for PwSH.

The French EVAL-PLH cohort of persons with polyhandicap.

Polyhandicap is characterized by a combination of profound intellectual disability and serious motor deficit, resulting in the extreme restriction of autonomy and communication. The aim of the EVAL-PLH (EVALuation PoLyHandicap) study is to identify the impact of socioeconomic, environmental, and epidemiological determinants on the health status of the persons with polyhandicap and the daily lives of their caregivers. EVAL-PLH is a prospective cohort study. The study involved persons with severe polyhandicap (who were cared for at reeducation centers, residential facilities, and one specialized pediatric/neurological department of a university hospital), their familial caregivers and the institutional caregivers. Data collection included sociodemographics, heath status, and psychocomportemental information. Data have been collected at 2 points (2015-2016 and 2020-2021). The French EVAL-PLH cohort is the first cohort study focusing on persons with polyhandicap, their families, and the health care workers caring for them. The sustainability of the device is essential to assist patients, families, clinicians, and health decision-making authorities in the optimization of care management.

Effect of Massage with Oil Balanced in Essential Fatty Acids on Development and Lipid Parameters in Very Premature Neonates: A Randomized, Controlled Study.

Background: Oil massage versus only massage can increase preterm newborn development, especially weight gain, via a supposed percutaneous absorption of oil lipids, but data are contradictory. Aims: Investigating whether massage with a vegetable oil balanced in essential fatty acids improves neonatal weight gain, and digestive autonomy as proxy for neuro-development outcomes. Methods: A prospective monocentric randomized study was conducted in very premature newborns who received massage with oil (isio4 10 mL/kg/day, n = 18) versus with no oil (n = 18) for five consecutive days (10-min session twice daily) at a corrected gestational age of 34−35 weeks. Anthropometrics and clinical characteristics were recorded. Plasma triglyceride and total cholesterol concentrations were analyzed with an enzymatic kit. The fatty acid composition (weight%, mg/mL) of total plasma lipids and of red blood cell (RBC) membrane was analyzed by gas chromatography. Results: Weight gain velocity at the end of massage period was 12.3 ± 1.4 g/kg/day with oil vs. 9.8 ± 1.4 g/kg/day with no oil (p = 0.1). Digestive autonomy, plasma lipid parameters, polyunsaturated fatty acids in plasma total lipids or in RBC were comparable. The no oil group displayed a higher RBC level in nervonic acid at discharge (4.3 ± 0.2 vs. 3.4 ± 0.2%; p = 0.025) and in C18:1n-9 plasmalogen species at the end of the massage period and at discharge (0.73 ± 0.06 vs. 0.48 ± 0.06; 0.92 ± 0.06 vs. 0.69 ± 0.06%; p < 0.01), two molecules that are involved in neurodevelopment. Conclusions: The use of isio4 oil did not provide additional benefits for the development of very premature newborns, neither changed lipid metabolism nor polyunsaturated fatty acid biological status, which did not corroborate the existence of a percutaneous route for oil lipid absorption. The reason for different levels of nervonic acid and plasmalogen in RBC remains to be explored.

Neurobehavioral Phenotype and Dysexecutive Syndrome of Preterm Children: Comorbidity or Trigger? An Update.

Premature birth is a worldwide public health priority. One in ten children is born before 37 weeks of gestational age and, in developed countries, survival rates without major neonatal morbidity are increasing. Although severe sequelae associated with these births have decreased, their neurobehavioral difficulties, often associated in multiple fields, remain stable but still widespread. These neurobehavioral difficulties hamper the normal development of academic achievements and societal integration and intensify the children's needs for rehabilitation during their preschool and academic years. Severe sequelae increase when gestational age decreases. This is even truer if the socio-cultural background is impeded by low income, education and language skills as compared with defined averages. However, moderate and/or minor neurocognitive and/or behavioral difficulties are almost identical for a moderate or a late preterm birth. Obtaining a better clinical description of neurobehavioral characteristics of those pretermly born, once they reach preschool age, is essential to detect behavioral issues as well as early specific cognitive difficulties (working memory, planning, inhibition, language expression and reception, attention and fine motor skills, etc.). Such information would provide a better understanding of the executive functions' role in brain connectivity, neurodevelopment and neuroanatomical correlation with premature encephalopathy.

The Neurobehavioral Phenotype of School-Aged, Very Prematurely Born Children with No Serious Neurological Sequelae: A Quality of Life Predictor.

School-aged extremely preterm (EPT) children have multiple specific neurocognitive/behavioral disorders that are often associated with other disorders; this manifests a true neurobehavioral "phenotype" of prematurity. To determine a profile of cognitive/behavioral impairments in a population of school-aged EPT children (7-10 years-old) without major disabilities, a cross-sectional study was conducted in five medical centers. An algorithm distributed the study population according to four WISC-IV subtests, five NEPSY-2 subtests, and two variables of figure of Rey. The behavior (SDQ), anxiety (Spielberg STAI-C), and generic QoL (Kidscreen 10 and VSP-A) were also evaluated. The study included 231 school-aged EPT children. Three neurobehavioral "phenotypes" were defined according to their severity: 1 = moderately, 2 = minor, and 3 = unimpaired. In all the profiles, the working memory, perceptual reasoning, as well as mental flexibility, were close to or below average, and their emotional behavior was always troubled. Self-esteem and school-work were the most impacted QoL areas. The unimpaired neurobehavior exhibited emotional behavioral impairment and executive dysfunction. The profile analysis defined distinct outcome groups and provided an informative means of identifying factors related to developmental outcomes. The QoL deterioration is determined by the severity of the three neurobehavioral "phenotypes", which is defined as well as by dysexecutive and/or behavioral disorders.

A randomized EPIREMED protocol study on the long-term visuo spatial effects of very preterm children with a working memory deficit.

BACKGROUND: Very preterm children generally perform poorly in executive functions and particularly in working memory. Adaptive training tasks encouraging these children to work continuously on their personal working memory capacity can be very useful. Above all in preschool-age children, several cognitive training programs focused on improving working memory capacity. Cogmed is a computerized visuospatial cognitive training program that improves working memory in children and adolescents with attention-deficit/hyperactivity disorder. The main objective is to assess the long-term effects (18 months) of cognitive training (Cogmed) on visuospatial processing in preschool-age very preterm children with working memory impairment. METHODS: The EPIREMED study is a prospective, randomized, controlled, multicentric trial nested in a population based epidemiological survey. An intervention group (Cogmed cognitive training) and a control group (standard care management) will compare children aged 5½ to 6 years, born between 24- and 34-weeks' gestational age, with a global intelligence quotient > 70 and a working memory index < 85. The study will include 166 children from national study EPIPAGE-2 (Epidemiological Study on Small Gestational Ages). The intervention consists of 25 sessions administered over a 5- to 8-week period. The primary endpoint will be the visuospatial processing, assessed by the score of the visuospatial index: score of the WPPSI-IV (Wechsler Preschool and Primary Scale of Intelligence). The secondary endpoints will allow to assess the executive functions, language and abilities, infant behavior, quality of life assessment, school performance and parental anxiety. DISCUSSION: This project's primary goal is to demonstrate the necessity of early visuospatial memory assessment within the vulnerable population of very preterm children, and to prove the feasibility and efficacy of computerized cognitive training using online software programs. A better global neuropsychological development improvement (visuospatial processing and other far transfer) can be expected with an improvement in learning and decreased behavioral problems. In the long term, these improvements might also reduce those global costs linked to the consequences of extreme prematurity. TRIAL REGISTRATION: NCT02757794 (registered on 2nd May 2016 at ClinicalTrial.gov).

Birthweight of IVF children is still a current issue and still related to maternal factors.

RESEARCH QUESTION: Does fresh embryo transfer after IVF with or without intracytoplasmic sperm injection (ICSI) increase the small for gestational age (SGA) rate, and frozen embryo transfer (FET) after IVF with or without ICSI increase the large for gestational age (LGA) rate versus natural conception? DESIGN: Retrospective comparison of an exposed historical group/cohort involving singletons conceived after fresh embryo transfer and after FET with an unexposed group/cohort involving singletons conceived after a natural conception. RESULTS: A total of 1961 fresh embryo transfer babies and 366 FET babies were compared with 6981 natural conception babies. The SGA rate in fresh embryo transfer babies was not significantly different to natural conception babies (6.9% versus 6.8%, P = 0.856). This outcome was not influenced by the fresh embryo transfer (adjusted odds ratio [aOR] 1.0; 95% confidence interval [CI] 0.8-1.3), but rather by a low rate of multiparity (aOR 0.5; 95% CI 0.3-0.7), advanced maternal age (aOR 1.1; 95% CI 1.0-1.2), maternal underweight (aOR 1.5; 95% CI 1.1-2.1), maternal smoking or cessation during pregnancy (aOR 1.8; 95% CI 1.4-2.3), pre-existing hypertension (aOR 2.3; 95% CI 1.3-4.1) and pregnancy-induced hypertension (aOR 2.5; 95% CI 1.7-3.7). The LGA rate in FET babies was significantly different from natural conception babies (6.6% versus 3.2%, P = 0.012). This outcome was influenced by the transfer of frozen embryos (aOR 2.2; 95% CI 1.3-3.8) and by a high maternal weight (aOR 1.9; 95% CI 1.1-3.6). CONCLUSIONS: Maternal background and obstetric parameters are more likely to influence the SGA rate than fresh embryo transfer conception. FET conception could be associated with an increase in LGA rate.

Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): study protocol for a multicentric French national observational cross-sectional study.

INTRODUCTION: Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life. METHODS AND ANALYSIS: We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag. ETHICS AND DISSEMINATION: The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public. TRIAL REGISTRATION NUMBER: NCT02866526; Pre-results.

No difference in congenital anomalies prevalence irrespective of insemination methods and freezing procedure: cohort study over fourteen years of an ART population in the south of France.

PURPOSE: A retrospective cohort study was conducted to evaluate and compare the prevalence of congenital anomalies in babies and fetuses conceived after four procedures of assisted reproduction technologies (ART). METHODS: The prevalence of congenital anomalies was compared retrospectively between 2750 babies and fetuses conceived between 2001 and 2014 in vitro fertilization with standard insemination (IVF), IVF with intracytoplasmic sperm injection (ICSI), IVF with frozen embryo transfer (FET-IVF), and ICSI with frozen embryo transfer (FET-ICSI). Congenital anomalies were described according to European Surveillance of Congenital Anomalies (EUROCAT) classification. The parental backgrounds, biologic parameters, obstetric parameters, and perinatal outcomes were compared between babies and fetuses with and without congenital anomalies. Data were analyzed by the generalized estimating equation. RESULTS: Between 2001 and 2014, a total of 2477 evolutionary pregnancies were notified. Among these pregnancies, 2379 were included in the analysis. One hundred thirty-four babies and fetuses had a congenital anomaly (4.9%). The major prevalences found among the recorded anomalies were congenital heart defects, chromosomal anomalies, and urinary defects. However, the risk of congenital anomalies in babies and fetuses conceived after FET was not increased compared with babies and fetuses conceived after fresh embryo transfer, even when adjusted for confounding factors (p = 0.40). CONCLUSIONS: There is no increased risk of congenital anomalies in babies and fetuses conceived by fresh versus frozen embryo transfer after in vitro fertilization with and without micromanipulation. Indeed, distribution of congenital anomalies found in our population is consistent with the high prevalence of congenital heart defects, chromosomal anomalies, and urinary defects that have been found by other authors in children conceived by infertile couples when compared to children conceived spontaneously.