Five-year outcomes for extremely preterm babies with active perinatal management: A clinical prediction model.

OBJECTIVE: To develop and validate a clinical prediction model for outcomes at 5 years of age for children born extremely preterm and receiving active perinatal management. DESIGN: The EPIPAGE-2 national prospective cohort. SETTING: France, 2011. POPULATION: Live-born neonates between 24+0 and 26+6 weeks of gestation who received active perinatal management (i.e. birth in a tertiary-level hospital, with antenatal steroids and resuscitation at birth). METHODS: A prediction model using logistic modelling, including gestational age, small-for gestational-age (SGA) status and sex, was developed. Model performance was assessed through calibration and discrimination, with bootstrap internal validation. MAIN OUTCOME MEASURES: Survival without moderate or severe neurodevelopmental disability (NDD) at 5 years. RESULTS: Among the 557 neonates included, 401 (72%) survived to 5 years, of which 59% survived without NDD (95% CI 54% to 63%). Predicted rates of survival without NDD ranged from 45% (95% CI 33% to 57%), to 56% (95% CI 49% to 64%) to 64% (95% CI 57% to 70%) for neonates born at 24, 25 and 26 weeks of gestation, respectively. Predicted rates of survival without NDD were 47% (95% CI 18% to 76%) and 62% (95% CI 49% to 76%) for SGA and non-SGA children, respectively. The model showed good calibration (calibration slope 0.85, 95% CI 0.54 to 1.16; calibration-in-the-large -0.0123, 95% CI -0.25 to 0.23) and modest discrimination (C-index 0.59, 95% CI 0.53 to 0.65). CONCLUSIONS: A simple prediction model using three factors easily known antenatally may help doctors and families in their decision-making for extremely preterm neonates receiving active perinatal management.

Intensity of perinatal care for extremely preterm babies and outcomes at a higher gestational age: evidence from the EPIPAGE-2 cohort study.

BACKGROUND: Perinatal decision-making affects outcomes for extremely preterm babies (22-26 weeks' gestational age (GA)): more active units have improved survival without increased morbidity. We hypothesised such units may gain skills and expertise meaning babies at higher gestational ages have better outcomes than if they were born elsewhere. We examined mortality and morbidity outcomes at age two for babies born at 27-28 weeks' GA in relation to the intensity of perinatal care provided to extremely preterm babies. METHODS: Fetuses from the 2011 French national prospective EPIPAGE-2 cohort, alive at maternal admission to a level 3 hospital and delivered at 27-28 weeks' GA, were included. Morbidity-free survival (survival without sensorimotor (blindness, deafness or cerebral palsy) disability) and overall survival at age two were examined. Sensorimotor disability and Ages and Stages Questionnaire (ASQ) result below threshold among survivors were secondary outcomes. Perinatal care intensity level was based on birth hospital, grouped using the ratio of 24-25 weeks' GA babies admitted to neonatal intensive care to fetuses of the same gestation alive at maternal admission. Sensitivity analyses used ratios based upon antenatal steroids, Caesarean section, and newborn resuscitation. Multiple imputation was used for missing data; hierarchical logistic regression accounted for births nested within centres. RESULTS: 633 of 747 fetuses (84.7%) born at 27-28 weeks' GA survived to age two. There were no differences in survival or morbidity-free survival: respectively, fully adjusted odds ratios were 0.96 (95% CI: 0.54 to 1.71) and 1.09 (95% CI: 0.59 to 2.01) in medium and 1.12 (95% CI: 0.63 to 2.00) and 1.16 (95% CI: 0.62 to 2.16) in high compared to low-intensity hospitals. Among survivors, there were no differences in sensorimotor disability or ASQ below threshold. Sensitivity analyses were consistent with the main results. CONCLUSIONS: No difference was seen in survival or morbidity-free survival at two years of age among fetuses alive at maternal hospital admission born at 27-28 weeks' GA, or in sensorimotor disability or presence of an ASQ below threshold among survivors. There is no evidence for an impact of intensity of perinatal care for extremely preterm babies on births at a higher gestational age.

Volume of Neonatal Care and Survival without Disability at 2 Years in Very Preterm Infants: Results of a French National Cohort Study.

OBJECTIVES: To investigate the relation between neonatal intensive care unit (NICU) volume and survival, and neuromotor and sensory disabilities at 2 years in very preterm infants. STUDY DESIGN: The EPIPAGE-2 (Etude Epidémiologique sur les Petits Âges Gestationnels-2) national prospective population-based cohort study was used to include 2447 babies born alive in 66 level III hospitals between 24 and 30 completed weeks of gestation in 2011. The outcome was survival without disabilities (levels 2-5 of the Gross Motor Function Classification System for cerebral palsy with or without unilateral or bilateral blindness or deafness). Units were grouped in quartiles according to volume, defined as the annual admissions of very preterm babies. Multivariate logistic regression analyses with population average models were used. RESULTS: Survival at discharge was lower in hospitals with lower volumes of neonatal activity (aOR 0.55, 95% CI 0.33-0.91). Survival without neuromotor and sensory disabilities at 2 years increased with hospital volume, from 75% to 80.7% in the highest volume units. After adjustment for gestational age, small for gestational age, sex, maternal age, infertility treatment, multiple pregnancy, principal cause of prematurity, parental socioeconomic status, and mother's country of birth, survival without neuromotor or sensory disabilities was significantly lower in hospitals with a lower volume of neonatal activity (aOR 0.60, 95% CI 0.38-0.95) than in the highest quartile hospitals. CONCLUSIONS: These results suggest that lower neonatal intensive care unit volume is associated with lower survival without an increase in disabilities at 2 years. These results could be useful to generate improvements of perinatal regionalization.

Assessing the risk of early unplanned rehospitalisation in preterm babies: EPIPAGE 2 study.

BACKGROUND: Gaining a better understanding of the probability, timing and prediction of rehospitalisation amongst preterm babies could help improve outcomes. There is limited research addressing these topics amongst extremely and very preterm babies. In this context, unplanned rehospitalisations constitute an important, potentially modifiable adverse event. We aimed to establish the probability, time-distribution and predictability of unplanned rehospitalisation within 30 days of discharge in a population of French preterm babies. METHODS: This study used data from EPIPAGE 2, a population-based prospective study of French preterm babies. Only those babies discharged home alive and whose parents responded to the one-year survey were eligible for inclusion in our study. For Kaplan-Meier analysis, the outcome was unplanned rehospitalisation censored at 30 days. For predictive modelling, the outcome was binary, recording unplanned rehospitalisation within 30 days of discharge. Predictors included routine clinical variables selected based on expert opinion. RESULTS: Of 3841 eligible babies, 350 (9.1, 95% CI 8.2-10.1) experienced an unplanned rehospitalisation within 30 days. The probability of rehospitalisation progressed at a consistent rate over the 30 days. There were significant differences in rehospitalisation probability by gestational age. The cross-validated performance of a ten predictor model demonstrated low discrimination and calibration. The area under the receiver operating characteristic curve was 0.62 (95% CI 0.59-0.65). CONCLUSIONS: Unplanned rehospitalisation within 30 days of discharge was infrequent and the probability of rehospitalisation progressed at a consistent rate. Lower gestational age increased the probability of rehospitalisation. Predictive models comprised of clinically important variables had limited predictive ability.

Neurodevelopment at age 5.5 years according to Ages & Stages Questionnaire at 2 years' corrected age in children born preterm: the EPIPAGE-2 cohort study.

OBJECTIVE: To report neurodevelopment at age 5.5 years according to developmental delay screening with the Ages & Stages Questionnaire (ASQ) in late infancy in preterm-born children. DESIGN: Population-based cohort study, EPIPAGE-2. SETTING: France, 2011-2017. PARTICIPANTS: 2504 children born at 24-26, 27-31 and 32-34 weeks, free of cerebral palsy, deafness or blindness at 2 years' corrected age. MAIN OUTCOME MEASURES: Moderate/severe, mild or no disability at age 5.5 years using gross and fine motor, sensory, cognitive and behavioural evaluations. Results of the ASQ completed between 22 and 26 months' corrected age described as positive screening or not. RESULTS: Among 2504 participants, 38.3% had ASQ positive screening. The probability of having moderate/severe or mild disability was higher for children with ASQ positive versus negative screening: 14.2% vs 7.0%, adjusted OR 2.5 (95% CI 1.8 to 3.4), and 37.6% vs 29.7%, adjusted OR 1.5 (1.2 to 1.9). For children with ASQ positive screening, the probability of having neurodevelopmental disabilities at age 5.5 years was associated with the number of domain scores below threshold, very low gestational age and severe neonatal morbidities. For children with ASQ negative screening, this probability was increased for boys and children born small-for-gestational age. For both groups, maternal level of education was strongly associated with outcomes. CONCLUSION: In preterm-born children, ASQ screening at 2 years' corrected age was associated with neurodevelopmental disabilities at age 5.5 years. However, other factors should be considered when interpreting the ASQ data to draw further follow-up. TRIAL REGISTRATION NUMBER: 2016-A00333-48.

Effects of the SARS-CoV-2 pandemic on perinatal activity in Yorkshire and the Humber region during 2020: an interrupted time series analysis.

OBJECTIVE: To assess the impact of public health measures taken during the COVID-19 pandemic on perinatal health indicators. DESIGN: Interrupted time series analysis comparing periods of the pandemic with the previous 5 years. SETTING: Yorkshire and the Humber region, England (2015-2020). MAIN OUTCOME MEASURES: Relative risk (RR) of stillbirth, extreme preterm (EPT, <27 weeks' gestational age) delivery, hypoxic ischaemic encephalopathy (HIE) and meconium aspiration syndrome (MAS), antenatal transfer for threatened EPT delivery and postnatal transfer for EPT birth, HIE or MAS. RESULTS: Stillbirths fell from 3.7/1000 deliveries prepandemic to 2.9/1000 afterwards; EPT births decreased from 2.5/1000 to 1.8/1000 live births. Following adjustment, during the first lockdown there were decreased antenatal transfers (RR 0.74, 95% CI 0.57 to 0.94) with non-statistically significant increased stillbirth (RR 1.08, 95% CI 0.78 to 1.51) and decreased EPT admissions (RR 0.88, 95% CI 0.60 to 1.29). Over the entire pandemic period, antenatal transfer (RR 0.64, 95% CI 0.55 to 0.76) and EPT birth (RR 0.73, 95% CI 0.56 to 0.94) decreased; stillbirths showed non-statistically significant increases overall (RR 1.21, 95% CI 0.98 to 1.49) but with increasing trend through the pandemic (RR 1.11, 95% CI 1.00 to 1.22). No changes were seen for HIE, MAS, postnatal transfers or in subgroup analyses by ethnicity. CONCLUSIONS: Lower rates of antenatal transfer and extreme preterm birth were identified, alongside an apparent increase in stillbirth over time. The findings provide evidence that effects on perinatal activity related to the pandemic changed over time.

Survival and neurodevelopmental impairment of outborn preterm infants at 5.5 years of age: an EPIPAGE-2 prospective, matched study using multiple imputation.

OBJECTIVE: To determine whether birth outside a level-3 centre (outborn) is associated with a difference in the combined outcome of mortality or moderate-to-severe neurological impairment at 5.5 years of age compared with birth in a level-3 centre (inborn) when antenatal steroids and gestational age (GA) are accounted for. DESIGN: Individual matched study nested within a prospective cohort. Each outborn infant was matched using GA and antenatal steroids with a maximum of four inborns. Conditional logistic regression was used to calculate ORs before being adjusted using maternal and birth characteristics. Analyses were carried out after multiple imputation for missing data. SETTING: EPIPAGE-2 French national prospective cohort including births up to 34 weeks GA inclusive. PATIENTS: Outborn and inborn control infants selected between 24 and 31 weeks GA were followed in the neonatal period and to 2 and 5.5 years. 3335 infants were eligible of whom all 498 outborns and 1235 inborn infants were included-equivalent to 2.5 inborns for each outborn. MAIN OUTCOME MEASURE: Survival without moderate-to-severe neurodevelopmental impairment at 5.5 years. RESULTS: Chorioamnionitis, pre-eclampsia, caesarian birth and small-for-dates were more frequent among inborns, and spontaneous labour and antepartum haemorrhage among outborns. There was no difference in the main outcome measure at 5.5 years of age (adjusted OR 1.09, 95% CI 0.82 to 1.44); sensitivity analyses suggested improved outcomes at lower GAs for inborns. CONCLUSION: In this GA and steroid matched cohort, there was no difference in survival without moderate-to-severe neurodevelopmental impairment to 5.5 years of age between inborn and outborn very preterm children. This suggests steroids might be important in determining outcomes.

Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study.

OBJECTIVES: To describe neurodevelopment at age 5 among children born preterm. DESIGN: Population based cohort study, EPIPAGE-2. SETTING: France, 2011. PARTICIPANTS: 4441 children aged 5½ born at 24-26, 27-31, and 32-34 weeks MAIN OUTCOME MEASURES: Severe/moderate neurodevelopmental disabilities, defined as severe/moderate cerebral palsy (Gross Motor Function Classification System (GMFCS) ≥2), or unilateral or bilateral blindness or deafness, or full scale intelligence quotient less than minus two standard deviations (Wechsler Preschool and Primary Scale of Intelligence, 4th edition). Mild neurodevelopmental disabilities, defined as mild cerebral palsy (GMFCS-1), or visual disability ≥3.2/10 and <5/10, or hearing loss <40 dB, or full scale intelligence quotient (minus two to minus one standard deviation) or developmental coordination disorders (Movement Assessment Battery for Children, 2nd edition, total score less than or equal to the fifth centile), or behavioural difficulties (strengths and difficulties questionnaire, total score greater than or equal to the 90th centile), school assistance (mainstream class with support or special school), complex developmental interventions, and parents' concerns about development. The distributions of the scores in contemporary term born children were used as reference. Results are given after multiple imputation as percentages of outcome measures with exact binomial 95% confidence intervals. RESULTS: Among 4441 participants, 3083 (69.4%) children were assessed. Rates of severe/moderate neurodevelopmental disabilities were 28% (95% confidence interval 23.4% to 32.2%), 19% (16.8% to 20.7%), and 12% (9.2% to 14.0%) and of mild disabilities were 38.5% (33.7% to 43.4%), 36% (33.4% to 38.1%), and 34% (30.2% to 37.4%) at 24-26, 27-31, and 32-34 weeks, respectively. Assistance at school was used by 27% (22.9% to 31.7%), 14% (12.1% to 15.9%), and 7% (4.4% to 9.0%) of children at 24-26, 27-31, and 32-34 weeks, respectively. About half of the children born at 24-26 weeks (52% (46.4% to 57.3%)) received at least one developmental intervention which decreased to 26% (21.8% to 29.4%) for those born at 32-34 weeks. Behaviour was the concern most commonly reported by parents. Rates of neurodevelopment disabilities increased as gestational age decreased and were higher in families with low socioeconomic status. CONCLUSIONS: In this large cohort of children born preterm, rates of severe/moderate neurodevelopmental disabilities remained high in each gestational age group. Proportions of children receiving school assistance or complex developmental interventions might have a significant impact on educational and health organisations. Parental concerns about behaviour warrant attention.

Health impact modelling of active travel visions for England and Wales using an Integrated Transport and Health Impact Modelling Tool (ITHIM).

BACKGROUND: Achieving health benefits while reducing greenhouse gas emissions from transport offers a potential policy win-win; the magnitude of potential benefits, however, is likely to vary. This study uses an Integrated Transport and Health Impact Modelling tool (ITHIM) to evaluate the health and environmental impacts of high walking and cycling transport scenarios for English and Welsh urban areas outside London. METHODS: Three scenarios with increased walking and cycling and lower car use were generated based upon the Visions 2030 Walking and Cycling project. Changes to carbon dioxide emissions were estimated by environmental modelling. Health impact assessment modelling was used to estimate changes in Disability Adjusted Life Years (DALYs) resulting from changes in exposure to air pollution, road traffic injury risk, and physical activity. We compare the findings of the model with results generated using the World Health Organization's Health Economic Assessment of Transport (HEAT) tools. RESULTS: This study found considerable reductions in disease burden under all three scenarios, with the largest health benefits attributed to reductions in ischemic heart disease. The pathways that produced the largest benefits were, in order, physical activity, road traffic injuries, and air pollution. The choice of dose response relationship for physical activity had a large impact on the size of the benefits. Modelling the impact on all-cause mortality rather than through individual diseases suggested larger benefits. Using the best available evidence we found fewer road traffic injuries for all scenarios compared with baseline but alternative assumptions suggested potential increases. CONCLUSIONS: Methods to estimate the health impacts from transport related physical activity and injury risk are in their infancy; this study has demonstrated an integration of transport and health impact modelling approaches. The findings add to the case for a move from car transport to walking and cycling, and have implications for empirical and modelling research.