Recommendations for data collection in cohort studies of preterm born individuals - The RECAP Preterm Core Dataset.

BACKGROUND: Preterm birth (before 37 completed weeks of gestation) is associated with an increased risk of adverse health and developmental outcomes relative to birth at term. Existing guidelines for data collection in cohort studies of individuals born preterm are either limited in scope, have not been developed using formal consensus methodology, or did not involve a range of stakeholders in their development. Recommendations meeting these criteria would facilitate data pooling and harmonisation across studies. OBJECTIVES: To develop a Core Dataset for use in longitudinal cohort studies of individuals born preterm. METHODS: This work was carried out as part of the RECAP Preterm project. A systematic review of variables included in existing core outcome sets was combined with a scoping exercise conducted with experts on preterm birth. The results were used to generate a draft core dataset. A modified Delphi process was implemented using two stages with three rounds each. Three stakeholder groups participated: RECAP Preterm project partners; external experts in the field; people with lived experience of preterm birth. The Delphi used a 9-point Likert scale. Higher values indicated greater importance for inclusion. Participants also suggested additional variables they considered important for inclusion which were voted on in later rounds. RESULTS: An initial list of 140 data items was generated. Ninety-six participants across 22 countries participated in the Delphi, of which 29% were individuals with lived experience of preterm birth. Consensus was reached on 160 data items covering Antenatal and Birth Information, Neonatal Care, Mortality, Administrative Information, Organisational Level Information, Socio-economic and Demographic information, Physical Health, Education and Learning, Neurodevelopmental Outcomes, Social, Lifestyle and Leisure, Healthcare Utilisation and Quality of Life. CONCLUSIONS: This core dataset includes 160 data items covering antenatal care through outcomes in adulthood. Its use will guide data collection in new studies and facilitate pooling and harmonisation of existing data internationally.

Variation in follow-up for children born very preterm in Europe.

BACKGROUND: Children born very preterm (<32 weeks of gestation) face high risks of neurodevelopmental and health difficulties compared with children born at term. Follow-up after discharge from the neonatal intensive care unit is essential to ensure early detection and intervention, but data on policy approaches are sparse. METHODS: We investigated the characteristics of follow-up policy and programmes in 11 European countries from 2011 to 2022 using healthcare informant questionnaires and the published/grey literature. We further explored how one aspect of follow-up, its recommended duration, may be reflected in the percent of parents reporting that their children are receiving follow-up services at 5 years of age in these countries using data from an area-based cohort of very preterm births in 2011/12 (N = 3635). RESULTS: Between 2011/12 and 22, the number of countries with follow-up policies or programmes increased from 6 to 11. The policies and programmes were heterogeneous in eligibility criteria, duration and content. In countries that recommended longer follow-up, parent-reported follow-up rates at 5 years of age were higher, especially among the highest risk children, born <28 weeks' gestation or with birthweight <1000 g: between 42.1% and 70.1%, vs. <20% in most countries without recommendations. CONCLUSIONS: Large variations exist in follow-up policies and programmes for children born very preterm in Europe; differences in recommended duration translate into cross-country disparities in reported follow-up at 5 years of age.

Treating very preterm European infants with inhaled nitric oxide increased in-hospital mortality but did not affect neurodevelopment at 5 years of age.

AIM: We examined the outcomes of using inhaled nitric oxide (iNO) to treat very preterm born (VPT) infants across Europe. METHODS: This was a sub-study of the Screening to Improve Health in Very Preterm Infants in Europe research. It focused on all infants born between 22 + 0 and 31 + 6 weeks/days of gestation from 2011 to 2012, in 19 regions in 11 European countries. We studied 7268 infants admitted to neonatal care and 5 years later, we followed up the outcomes of 103 who had received iNO treatment. They were compared with 3502 propensity score-matched controls of the same age who did not receive treatment. RESULTS: All countries used iNO and 292/7268 (4.0%) infants received this treatment, ranging from 1.2% in the UK to 10.5% in France. There were also large regional variations within some countries. Infants treated with iNO faced higher in-hospital mortality than matched controls (odds ratio 2.03, 95% confidence interval 1.33-3.09). The 5-year follow-up analysis of 103 survivors showed no increased risk of neurodevelopmental impairment after iNO treatment. CONCLUSION: iNO was used for VPT patients in all 11 countries. In-hospital mortality was increased in infants treated with iNO, but long-term neurodevelopmental outcomes were not affected in 103 5-year-old survivors.

Developmental motor problems and health-related quality of life in 5-year-old children born extremely preterm: A European cohort study.

AIM: To measure the association between cerebral palsy (CP) and non-CP-related movement difficulties and health-related quality of life (HRQoL) among 5-year-old children born extremely preterm (<28 weeks gestational age). METHOD: We included 5-year-old children from a multi-country, population-based cohort of children born extremely preterm in 2011 to 2012 in 11 European countries (n = 1021). Children without CP were classified using the Movement Assessment Battery for Children, Second Edition as having significant movement difficulties (≤5th centile of standardized norms) or being at risk of movement difficulties (6th-15th centile). Parents reported on a clinical CP diagnosis and HRQoL using the Pediatric Quality of Life Inventory. Associations were assessed using linear and quantile regressions. RESULTS: Compared to children without movement difficulties, children at risk of movement difficulties, with significant movement difficulties, and CP had lower adjusted HRQoL total scores (ß [95% confidence interval] = -5.0 [-7.7 to -2.3], -9.1 [-12.0 to -6.1], and - 26.1 [-31.0 to -21.2]). Quantile regression analyses showed similar decreases in HRQoL for all children with CP, whereas for children with non-CP-related movement difficulties, reductions in HRQoL were more pronounced at lower centiles. INTERPRETATION: CP and non-CP-related movement difficulties were associated with lower HRQoL, even for children with less severe difficulties. Heterogeneous associations for non-CP-related movement difficulties raise questions for research about mitigating and protective factors.

The impact of perinatal brain injury on retinal nerve fiber layer thickness and optic nerve head parameters of premature children.

PURPOSE: This study aims to evaluate the impact of birth weight (BW), gestational age (GA), retinopathy of prematurity (ROP), and perinatal brain injury (PBI) on optic nerve head (ONH) parameters and nerve fiber layer thickness (RNFLT) in preterm children. METHODS: ONH parameters and RNFLT were examined prospectively in 5-15-year-old preterm and full-term children with RTVue-100 OCT (Optovue, USA). The parameters of the two groups were compared and possible influences of BW, GA, ROP, and PBI analyzed in preterm children. RESULTS: In total, 51 full-term and 55 preterm children were included. The mean age was 9.98 ± 3.4 years in full-term and 10.0 ± 2.5 years in preterm children. The mean GA in preterm children was 29.6 ± 3.8 weeks with a BW of 1523 ± 732 g. RNFLT was significantly lower in preterm than in full-term children in all but temporal quadrants. Cup area, volume, cup/disc area ratio, and horizontal cup/disc ratio (CDR) were significantly larger and rim area significantly thinner in preterm children. GA was positively correlated with superior, nasal, and overall RNFLT and negatively correlated with cup area, volume, and horizontal CDR. ROP stage correlated negatively with superior and nasal RNFLT. PBI was the only significant predicting factor for RNFL thinning in all but temporal quadrant in multiple regression analysis. Preterm children with PBI had a significantly larger optic cup (CDR 0.70 ± 0.33 vs. 0.37 ± 0.27) and thinner optic rim. CONCLUSION: PBI correlated strongest with RNFL thinning, a thinner optic rim, and a larger optic cup in preterm children and should be evaluated in each patient to prevent incorrect diagnosis like glaucoma.

International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

High Healthcare Use at Age 5 Years in a European Cohort of Children Born Very Preterm.

OBJECTIVES: To describe parent-reported healthcare service use at age 5 years in children born very preterm and investigate whether perinatal and social factors and the use of very preterm follow-up services are associated with high service use. STUDY DESIGN: We used data from an area-based cohort of births at <32 weeks of gestation from 11 European countries, collected from birth records and parental questionnaires at 5 years of age. Using the published literature, we defined high use of outpatient/inpatient care (≥4 sick visits to general practitioners, pediatricians, or nurses, ≥3 emergency room visits, or ≥1 overnight hospitalization) and specialist care (≥2 different specialists or ≥3 visits). We also categorized countries as having either a high or a low rate of children using very preterm follow-up services at age 5 years. RESULTS: Overall, 43% of children had high outpatient/inpatient care use and 48% had high specialist care use during the previous year. Perinatal factors were associated with high outpatient/inpatient and specialist care use, with a more significant association with specialist services. Associations with intermediate parental educational level and unemployment were stronger for outpatient/inpatient services. Living in a country with higher rates of very preterm follow-up service use was associated with lower use of outpatient/inpatient services. CONCLUSIONS: Children born very preterm had high healthcare service use at age 5 years, with different patterns for outpatient/inpatient and specialist care by perinatal and social factors. Longer follow-up of children born very preterm may improve care coordination and help avoid undesirable health service use.

What drives change in neonatal intensive care units? A qualitative study with physicians and nurses in six European countries.

BACKGROUND: Innovation is important to improve patient care, but few studies have explored the factors that initiate change in healthcare organizations. METHODS: As part of the European project EPICE on evidence-based perinatal care, we carried out semi-structured interviews (N = 44) with medical and nursing staff from 11 randomly selected neonatal intensive care units in 6 countries. The interviews focused on the most recent clinical or organizational change in the unit relevant to the care of very preterm infants. Thematic analysis was performed using verbatim transcripts of recorded interviews. RESULTS: Reported changes concerned ventilation, feeding and nutrition, neonatal sepsis, infant care, pain management and care of parents. Six categories of drivers to change were identified: availability of new knowledge or technology; guidelines or regulations from outside the unit; need to standardize practices; participation in research; occurrence of adverse events; and wish to improve care. Innovations originating within the unit, linked to the availability of new technology and seen to provide clear benefit for patients were more likely to achieve consensus and rapid implementation. CONCLUSIONS: Innovation can be initiated by several drivers that can impact on the success and sustainability of change.

Survey on clinical use and non-use of recombinant human erythropoietin in European neonatal units.

Objectives Recombinant human erythropoietin (rhEPO) has been shown to effectively and safely prevent the anemia of prematurity and to reduce the transfusion need in very low birth weight (VLBW) infants and has been licensed for this indication in Europe in 1997. The objective of the study was to obtain information on the use or non-use of rhEPO in neonatal units in Germany and other European countries. Methods Anonymized 14-questions web-based questionnaire. Results Seventy-nine questionnaires from Germany and 63 questionnaires from other 15 European countries were completed. Of the responders, 39% indicated to use rhEPO routinely or occasionally in VLBW infants, whereas 61% responded to never use rhEPO in this population. The major reasons given for non-use were lack of recommendation in national guidelines (69%) and/or doubt about efficacy of rhEPO to reduce transfusion need (53%). Twenty-seven percent of the responders indicated to use rhEPO for neonates with birth weights above 1,500 g. Neuroprotection in VLBW infants (26%) and hypoxic ischemic encephalopathy in term neonates (27%) were given as indications for off label use of rhEPO. Conclusions This survey indicates that rhEPO is used for the anemia of prematurity as licensed in less than half of neonatal units in Germany and other European countries. On the other hand it seems to be used off label in neonates for neuroprotection in a considerable number of units although there is no final evidence on its neuroprotective effects.

Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial.

Importance: Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds. Objective: To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability. Design, Setting, and Participants: Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018. Interventions: Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state. Main Outcome and Measures: The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth. Results: Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups. Conclusions and Relevance: Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age. Trial Registration: ClinicalTrials.gov Identifier: NCT01393496.

[What is the Optimal Minimum Provider Volume in the Provision of Care for Preterm Infants with a Birth Weight below 1250 g in Germany?] / Wie hoch ist die optimale Mindestmenge für die Behandlung Frühgeborener mit einem Geburtsgewicht unter 1250 g in Deutschland?

INTRODUCTION: Numerous studies have investigated volume-outcome relationships in the treatment of very low birth weight infants. However, studies addressing the identification of optimal thresholds when introducing minimum provider volumes for treatment of these infants do not exist. METHODS: Publicly available data (www.perinatalzentren.org) of more than 56,000 infants weighing less than 1250 g at birth (NB<1250) and treated in level-1 perinatal centers (highest level in Germany) between 2010 and 2018 was used for statistical analysis. Potentially avoidable deaths after the introduction of minimum provider volumes were calculated by deducting observed deaths from estimated deaths based on logistic regression models for every existing empirical provider volume. Various smoothing functions were used to ascertain optimal thresholds for minimum provider volumes. RESULTS: Independent of the observation period or smoothing technique, the highest number of potentially avoidable deaths was observed for minimum provider volumes of 50-60 NB<1250 per year. Introducing a minimum provider volume of 50 without a transition period would reduce the number of level-1 perinatal centers to a quarter of the current number in Germany. Approximately 60% of NB<1250 would have to be reallocated. CONCLUSION: Analyses of resulting geographical distances are needed in the preparation of minimum provider volumes for treatment of NB<1250 in Germany. Such analyses should include perinatal centers expected to reach minimum provider volumes after subsequent reallocation in the future.

Specialist health care services use in a European cohort of infants born very preterm.

AIM: Children born very preterm require additional specialist care because of the health and developmental risks associated with preterm birth, but information on their health service use is sparse. We sought to describe the use of specialist services by children born very preterm in Europe. METHOD: We analysed data from the multi-regional, population-based Effective Perinatal Intensive Care in Europe (EPICE) cohort of births before 32 weeks' gestation in 11 European countries. Perinatal data were abstracted from medical records and parents completed a questionnaire at 2 years corrected age (4322 children; 2026 females, 2296 males; median gestational age 29wks, interquartile range [IQR] 27-31wks; median birthweight 1230g, IQR 970-1511g). We compared parent-reported use of specialist services by country, perinatal risk (based on gestational age, small for gestational age, and neonatal morbidities), maternal education, and birthplace. RESULTS: Seventy-six per cent of the children had consulted at least one specialist, ranging across countries from 53.7% to 100%. Ophthalmologists (53.4%) and physiotherapists (48.0%) were most frequently consulted, but individual specialists varied greatly by country. Perinatal risk was associated with specialist use, but the gradient differed across countries. Children with more educated mothers had higher proportions of specialist use in three countries. INTERPRETATION: Large variations in the use of specialist services across Europe were not explained by perinatal risk and raise questions about the strengths and limits of existing models of care. WHAT THIS PAPER ADDS: Use of specialist services by children born very preterm varied across Europe. This variation was observed for types and number of specialists consulted. Perinatal risk was associated with specialist care, but did not explain country-level differences. In some countries, mothers' educational level affected use of specialist services.

UTILIZACIÓN DE SERVICIOS DE SALUD ESPECIALIZADOS EN UN ESTUDIO DE COHORTE EUROPEO DE NIÑOS NACIDOS MUY PREMATUROS: OBJETIVO: Niños nacidos muy prematuramente requieren cuidados especializados adicionales debido a su salud y a los riesgos asociados con la prematuros, sin embargo la información sobre el uso de servicios de salud es escasa. Buscamos describir la utilización de servicios especializados por niños nacidos muy prematuramente, en Europa. MÉTODO: Analizamos datos de una cohorte de nacimientos ocurridos antes de las 32 semanas de gestación tomados del Effective Perinatal Intensive Care in Europe (EPICE), basado en la población y multirregional, en 11 países europeos. Los datos perinatales fueron extraídos de las historias clínicas y los padres completaron un cuestionario a los 2 años de edad corregida (4.322 niños; 2026 sexo femenino, 2.296 masculino; edad gestacional mediana 29 semanas, rango intercuartílico (IQR) 27-31 semanas; mediana de peso de nacimiento 1.230 gr, IQR 970-1.511 gr). Comparamos el uso de servicios especializados (según informe de los padres) por país, riesgo perinatal (basado en edad gestacional, bajo peso para edad gestacional y morbilidades neonatales), educación materna y lugar de nacimiento. RESULTADOS: En total 65% de los niños habían consultado por lo menos a un especialista, con un rango entre países de 53,7% a 100%. Los especialistas más frecuentemente consultados fueron Oftalmólogos (53,4%) y Fisioterapeutas (48%) pero los especialistas consultados por cada individuo variaron mucho según el país. El riesgo perinatal se asoció al uso de especialista, pero el gradiente varió entre los países. Niños de madres con mayor nivel educativo tuvieron mayor proporción de uso de especialistas en tres países. INTERPRETACIÓN: Las grandes variaciones en el uso de servicios especializados en Europa no fueron explicadas por el riesgo perinatal y arrojan cuestionamientos sobre las fortalezas y limitaciones de los modelos de cuidados existentes.

USO DE SERVIÇOS DE SAÚDE ESPECIALIZADOS EM UMA COORTE EUROPÉIA DE LACTENTES NASCIDOS MUITO PREMATUROS: OBJETIVO: Crianças nascidas muito prematuras requerem cuidado especializado adicional por causa dos riscos à saúde e ao desenvolvimento associados ao nascimento premature, mas informações sobreo uso de serviços de saúde são escassas. Procuramos descrever o uso de serviços especializados por crianças nascidas muito prematuras na Europa. MÉTODO: Analisamos dados de uma coorte populacional multi-regional, do Cuidado Intensivo Neonatal Efetivo na Europa (EPICE), com lactentes nascidos antes de 32 semanas de gestação em 11 países europeus. Dados perinatais foram extraídos dos registros médicos, e os pais completaram um questionário com 2 anos de idade corrigida (4.322 crianças; 2.026 do sexo feminino, 2.296 do sexo masculino; idade gestacional mediana 29semanas, intervalo interquartile [IIQ] 27-31sem; peso ao nascimento mediano 1,230g, IIQ 970-1511g). Comparamos o uso de serviços especializados reportados pelos pais por país, risco perinatal (com base na idade gestacional, pequeno para a idade gestacional e morbidades neonatais), educação materna e local de nascimento. RESULTADOS: Setenta e seis por cento das crianças consultou pelo menos um especialista, variando entre países de 53,7 a 100%. Oftalmologistas (53,4%) e fisioterapeutas (48,0%) foram os mais frequentemente consultados, mas os especialistas individuais variaram bastante por país. O risco perinatal se associou com uso de serviços especializados, mas o gradient diferiu entre países. Crianças com mães mais educadas tinham maior proporção de uso de especialistas em três países. INTERPRETAÇÃO: Grandes variações no uso de serviços especializados na Europa não foram explicadas pelo risco perinatal, e levantam questões sobre as forças e limitações dos modelos de cuidado existentes.

Unlike in Children with Allergic Asthma, IgE Transcripts from Preschool Children with Atopic Dermatitis Display Signs of Superantigen-Driven Activation.

The IgE repertoire in children with asthma reflects an adaptive B cell response, indicative of Ag-driven selection. However, the same might not apply to atopic dermatitis, which is often the first manifestation of atopy. The objective of our present study was to characterize the IgE repertoire of preschool children with atopic dermatitis with regard to signs of superantigen-like activation, clonal relationship, and indications of Ag selection. Total RNA was isolated from PBMCs of five children with atopic dermatitis. IgE transcripts were amplified, cloned, and sequenced using RT-PCR. We obtained 200 functional IgE sequences, which were compared with 1140 sequences from 11 children with asthma. Whereas variable gene segment of the H Ig chain (VH) gene usage in asthma reflected germline distribution, IgE transcripts from children with atopic dermatitis displayed a dominance of the otherwise scarcely expressed VH2 and VH4 family. Whereas IgE transcripts from children with asthma were highly mutated (7.2%), somatic mutation rate in atopic dermatitis was less than half as high (3.4%). Moreover, the proportion of transcripts that were indicative of Ag selection was reduced to 11% in atopic dermatitis (24% in asthma). In summary, IgE repertoires vary significantly between children with different atopic diseases. Compared with children with asthma, IgE transcripts from preschool children with atopic dermatitis are significantly less mutated, clonally less focused, and less indicative of Ag selection. We consider our data reconcilable with the hypothesis that a superantigen-like activation contributes to the maturation and selection of the IgE repertoire in atopic dermatitis.

Duration and Time Trends in Hospital Stay for Very Preterm Infants Differ Across European Regions.

OBJECTIVES: To compare duration and changes over time in length of hospital stay for very preterm and extremely preterm infants in 10 European regions. DESIGN: Two area-based cohort studies from the same regions in 2003 and 2011/2012. SETTING: Ten regions from nine European countries. PATIENTS: Infants born between 22 + 0 and 31 + 6 weeks of gestational age and surviving to discharge (Models of Organising Access to Intensive Care for Very Preterm Births cohort in 2003, n = 4,011 and Effective Perinatal Intensive Care in Europe cohort in 2011/2012, n = 4,336). INTERVENTIONS: Observational study, no intervention. MEASUREMENTS AND MAIN RESULTS: Maternal and infant characteristics were abstracted from medical records using a common protocol and length of stay until discharge was adjusted for case-mix using negative binomial regression. Mean length of stay was 63.6 days in 2003 and varied from 52.4 to 76.5 days across regions. In 2011/2012, mean length of stay was 63.1 days, with a narrower regional range (54.0-70.1). Low gestational age, small for gestational age, low 5-minute Apgar score, surfactant administration, any surgery, and severe neonatal morbidities increased length of stay. Infant characteristics explained some of the differences between regions and over time, but large variations remained after adjustment. In 2011/2012, mean adjusted length of stay ranged from less than 54 days in the Northern region of the United Kingdom and Wielkopolska, Poland to over 67 days in the Ile-de-France region of France and the Eastern region of the Netherlands. No systematic decrease in very preterm length of stay was observed over time after adjustment for patient case-mix. CONCLUSIONS: A better understanding of the discharge criteria and care practices that contribute to the wide differences in very preterm length of stay across European regions could inform policies to optimize discharge decisions in terms of infant outcomes and health system costs.

Cohort study from 11 European countries highlighted differences in the use and efficacy of hypothermia prevention strategies after very preterm birth.

AIM: This study investigated the different strategies used in 11 European countries to prevent hypothermia, which continues to affect a large proportion of preterm births in the region. METHODS: We examined the association between the reported use of hypothermia prevention strategies in delivery rooms and body temperatures on admission to neonatal intensive care units (NICUs) in 5861 infants born at 22 + 0 to 31 +6 weeks of gestation. The use of plastic bags, wraps, caps, exothermic heat and mattresses was investigated. RESULTS: The proportion of infants born in units that systematically used one or more hypothermia prevention strategies was 88.2% and 50.9% of those infants were hypothermic on admission to NICUs. Of the 9.6% born in units without systematic hypothermia prevention, 73.2% were hypothermic. Only 2.2% of infants were born in units with no reported prevention strategies. Lower gestational age increased the probability of hypothermia. No significant differences were found between the various hypothermia prevention strategies. Hyperthermia was seen in 4.8% of all admitted infants. CONCLUSION: Very preterm infants had lower risks of hypothermia on NICU admission if the unit used systematic prevention strategies. All the strategies had similar effects, possibly due to implementation rather than a strategy's specific efficacy.

Variation in term birthweight across European countries affects the prevalence of small for gestational age among very preterm infants.

AIM: This study assessed the prevalence of small for gestational age (SGA) among very preterm (VPT) infants using national and European intrauterine references. METHODS: We generated country-specific and common European intrauterine growth references for 11 European countries, according to Gardosi's approach and Hadlock's foetal growth model, using national data on birthweights by sex. These references were applied to the Effective Perinatal Intensive Care in Europe (EPICE) cohort, which comprised 7766 live VPT births without severe congenital anomalies under 32 weeks of gestation in 2011-2012, to estimate the prevalence of infants with SGA birthweights, namely those below the 10th percentile. RESULTS: The SGA prevalence was 31.8% with country-specific references and 34.0% with common European references. The European references yielded a 10-point difference in the SGA prevalence between countries with lower term birthweights (39.9%) - Portugal, Italy and France - and higher term birthweights, namely Denmark, the Netherlands, Sweden (28.9%; p < 0.001). This was not observed with country-specific references, where the respective figures were 32.4% and 33.9% (p = 0.34), respectively. CONCLUSION: One-third of VPT infants were SGA according to intrauterine references. Common European references showed significant differences in SGA prevalence between countries with high and low-term birthweights.

Admission Hypothermia in Very Preterm Infants and Neonatal Mortality and Morbidity.

OBJECTIVE: To investigate the association between body temperature at admission to neonatal intensive care and in-hospital mortality in very preterm infants, stratified by postnatal age of death. Moreover, we assessed the association between admission temperature and neonatal morbidity. STUDY DESIGN: In this cohort study from 19 regions in 11 European countries, we measured body temperature at admission for infants admitted for neonatal care after very preterm birth (<32 weeks of gestation; n = 5697) who were followed to discharge or death. Associations between body temperature at admission and in-hospital mortality and neonatal morbidity were analyzed by the use of mixed effects generalized linear models. The final model adjusted for pregnancy complications, singleton or multiple pregnancy, antenatal corticosteroids, mode of delivery, gestational age, infant size and sex, and Apgar score <7 at 5 minutes. RESULTS: A total of 53.4% of the cohort had a body temperature at admission less than 36.5°C, and 12.9% below 35.5°C. In the adjusted model, an admission temperature <35.5°C was associated with increased mortality at postnatal ages 1-6 days, (risk ratio 2.41; 95% CI 1.45-4.00), and 7-28 days (risk ratio 1.79; 1.15-2.78) but not after 28 days of age. We found no associations between admission temperature and neonatal morbidity. CONCLUSION: Admission hypothermia after very preterm birth is a significant problem in Europe, associated with an increased risk of early and late neonatal death.

IgG4 and IgE transcripts in childhood allergic asthma reflect divergent antigen-driven selection.

The physiologic function of the "odd" Ab IgG4 remains enigmatic. IgG4 mediates immunotolerance, as, for example, during specific immunotherapy of allergies, but it mediates tissue damage in autoimmune pemphigus vulgaris and "IgG4-related disease." Approximately half of the circulating IgG4 molecules are bispecific owing to their unique ability to exchange half-molecules. Better understanding of the interrelation between IgG4 and IgE repertoires may yield insight into the pathogenesis of allergies and into potential novel therapies that modulate IgG4 responses. We aimed to compare the selective forces that forge the IgG4 and IgE repertoires in allergic asthma. Using an IgG4-specific RT-PCR, we amplified, cloned, and sequenced IgG4 H chain transcripts of PBMCs from 10 children with allergic asthma. We obtained 558 functional IgG4 sequences, of which 286 were unique. Compared with previously published unique IgE transcripts from the same blood samples, the somatic mutation rate was significantly enhanced in IgG4 transcripts (62 versus 83%; p < 0.001), whereas fewer IgG4 sequences displayed statistical evidence of Ag-driven selection (p < 0.001). On average, the hypervariable CDRH3 region was four nucleotides shorter in IgG4 than in IgE transcripts (p < 0.001). IgG4 transcripts in the circulation of children with allergic asthma reflect some characteristics of classical Ag-driven B2 immune responses but display less indication of Ag selection than do IgE transcripts. Although allergen-specific IgG4 can block IgE-mediated allergen presentation and degranulation of mast cells, key factors that influence the Ag-binding properties of the Ab differ between the overall repertoires of circulating IgG4- and IgE-expressing cells.