Mortality and neurodevelopmental outcomes at 2 years' corrected age of very preterm infants with necrotising enterocolitis or spontaneous intestinal perforation: The EPIPAGE-2 cohort study.

PURPOSE: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). METHODS: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. RESULTS: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0-9.1) but not NEC as compared with controls. CONCLUSION: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA.

Trends in caesarean section rates in Europe from 2015 to 2019 using Robson's Ten Group Classification System: A Euro-Peristat study.

OBJECTIVE: To assess changes in caesarean section (CS) rates in Europe from 2015 to 2019 and utilise the Robson Ten Group Classification System (TGCS) to evaluate the contribution of different obstetric populations to overall CS rates and trends. DESIGN: Observational study utilising routine birth registry data. SETTING: A total of 28 European countries. POPULATION: Births at ≥22 weeks of gestation in 2015 and 2019. METHODS: Using a federated model, individual-level data from routine sources in each country were formatted to a common data model and transformed into anonymised, aggregated data. MAIN OUTCOME MEASURES: By country: overall CS rate. For TGCS groups (by country): CS rate, relative size, relative and absolute contribution to overall CS rate. RESULTS: Among the 28 European countries, both the CS rates (2015, 16.0%-55.9%; 2019, 16.0%-52.2%) and the trends varied (from -3.7% to +4.7%, with decreased rates in nine countries, maintained rates in seven countries (≤ ± 0.2) and with increasing rates in 12 countries). Using the TGCS (for 17 countries), in most countries labour induction increased (groups 2a and 4a), whereas multiple pregnancies (group 8) decreased. In countries with decreasing overall CS rates, CS tended to decrease across all TGCS groups, whereas in countries with increasing rates, CS tended to increase in most groups. In countries with the greatest increase in CS rates (>1%), the absolute contributions of groups 1 (nulliparous term cephalic singletons, spontaneous labour), 2a and 4a (induction of labour), 2b and 4b (prelabour CS) and 10 (preterm cephalic singletons) to the overall CS rate tended to increase. CONCLUSIONS: The TGCS shows varying CS trends and rates among countries of Europe. Comparisons between European countries, particularly those with differing trends, could provide insight into strategies to reduce CS without clinical indication.

Developing and testing a protocol using a common data model for federated collection and analysis of national perinatal health indicators in Europe.

Context: International comparisons of the health of mothers and babies provide essential benchmarks for guiding health practice and policy, but statistics are not routinely compiled in a comparable way. These data are especially critical during health emergencies, such as the coronavirus disease (COVID-19) pandemic. The Population Health Information Research Infrastructure (PHIRI) project aimed to promote the exchange of population data in Europe and included a Use Case on perinatal health. Objective: To develop and test a protocol for federated analysis of population birth data in Europe. Methods: The Euro-Peristat network with participants from 31 countries developed a Common Data Model (CDM) and R scripts to exchange and analyse aggregated data on perinatal indicators. Building on recommended Euro-Peristat indicators, complemented by a three-round consensus process, the network specified variables for a CDM and common outputs. The protocol was tested using routine birth data for 2015 to 2020; a survey was conducted assessing data provider experiences and opinions. Results: The CDM included 17 core data items for the testing phase and 18 for a future expanded phase. 28 countries and the four UK nations created individual person-level databases and ran R scripts to produce anonymous aggregate tables. Seven had all core items, 17 had 13-16, while eight had ≤12. Limitations were not having all items in the same database, required for this protocol. Infant death and mode of birth were most frequently missing. Countries took from under a day to several weeks to set up the CDM, after which the protocol was easy and quick to use. Conclusion: This open-source protocol enables rapid production and analysis of perinatal indicators and constitutes a roadmap for a sustainable European information system. It also provides minimum standards for improving national data systems and can be used in other countries to facilitate comparison of perinatal indicators.

Clarity and consistency in stillbirth reporting in Europe: why is it so hard to get this right?

BACKGROUND: Stillbirth is a major public health problem, but measurement remains a challenge even in high-income countries. We compared routine stillbirth statistics in Europe reported by Eurostat with data from the Euro-Peristat research network. METHODS: We used data on stillbirths in 2015 from both sources for 31 European countries. Stillbirth rates per 1000 total births were analyzed by gestational age (GA) and birthweight groups. Information on termination of pregnancy at ≥22 weeks' GA was analyzed separately. RESULTS: Routinely collected stillbirth rates were higher than those reported by the research network. For stillbirths with a birthweight ≥500 g, the difference between the mean rates of the countries for Eurostat and Euro-Peristat data was 22% [4.4/1000, versus 3.5/1000, mean difference 0.9 with 95% confidence interval (CI) 0.8-1.0]. When using a birthweight threshold of 1000 g, this difference was smaller, 12% (2.9/1000, versus 2.5/1000, mean difference 0.4 with 95% CI 0.3-0.5), but substantial differences remained for individual countries. In Euro-Peristat, missing data on birthweight ranged from 0% to 29% (average 5.0%) and were higher than missing data for GA (0-23%, average 1.8%). CONCLUSIONS: Routine stillbirth data for European countries in international databases are not comparable and should not be used for benchmarking or surveillance without careful verification with other sources. Recommendations for improvement include using a cut-off based on GA, excluding late terminations of pregnancy and linking multiple sources to improve the quality of national databases.

International versus national growth charts for identifying small and large-for-gestational age newborns: A population-based study in 15 European countries.

BACKGROUND: To inform the on-going debate about the use of universal prescriptive versus national intrauterine growth charts, we compared perinatal mortality for small and large-for-gestational-age (SGA/LGA) infants according to international and national charts in Europe. METHODS: We classified singleton births from 33 to 42 weeks of gestation in 2010 and 2014 from 15 countries (N = 1,475,457) as SGA (birthweight <10th percentile) and LGA (>90th percentile) using the international Intergrowth-21st newborn standards and national charts based on the customised charts methodology. We computed sex-adjusted odds ratios (aOR) for stillbirth, neonatal and extended perinatal mortality by this classification using multilevel models. FINDINGS: SGA and LGA prevalence using national charts were near 10% in all countries, but varied according to international charts with a north to south gradient (3.0% to 10.1% and 24.9% to 8.0%, respectively). Compared with appropriate for gestational age (AGA) infants by both charts, risk of perinatal mortality was increased for SGA by both charts (aOR[95% confidence interval (CI)]=6.1 [5.6-6.7]) and infants reclassified by international charts from SGA to AGA (2.7 [2.3-3.1]), but decreased for those reclassified from AGA to LGA (0.6 [0.4-0.7]). Results were similar for stillbirth and neonatal death. INTERPRETATION: Using international instead of national charts in Europe could lead to growth restricted infants being reclassified as having normal growth, while infants with low risks of mortality could be reclassified as having excessive growth. FUNDING: InfAct Joint Action, CHAFEA Grant n°801,553 and EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking ConcePTION grant n°821,520. AH received a PhD grant from EHESP.

Screening for Retinopathy of Prematurity in Very Preterm Children: The EPIPAGE-2 Cohort Study.

INTRODUCTION: Retinopathy of prematurity (ROP) is a blinding disease that requires screening by retinal examination. Screening practices are rarely evaluated. We aimed to determine the prevalence of ROP screening in very preterm infants and individual- and center-related factors associated with ROP screening. METHODS: Data were extracted from the EPIPAGE-2 cohort, a French prospective population-based study of premature births in 2011. Children born before 32 weeks' gestation (WG) without severe malformation and alive at the recommended time for ROP screening were included. Outcome measures were achievement of ROP screening and compliance with recommended screening timeline. Individual- and center-related factors associated with both measures were studied using mixed models. RESULTS: Among 3,077 eligible infants, 2,169 (70.5%) had a ROP screening, ranging from 96% at 24 WG to 50% at 31 WG. Large variability among units was observed. Individual characteristics associated with screening were low gestational age, low birth weight, severe bronchopulmonary dysplasia or neurological lesions, and transfer between neonatal units during the screening period. Odds of screening were higher in neonatal units using wide-angle imaging (odds ratio 2.65 [95% confidence interval 1.17-6.01]) but decreased in units without a local protocol for ROP screening (0.03 [0.01-0.09]). Among screened children, 1,641/2,169 (75.7%) were screened according to recommended timeline. Delayed screening was associated with low gestational age, severe bronchopulmonary dysplasia or necrotizing enterocolitis, and absence of local protocol for ROP screening. DISCUSSION/CONCLUSIONS: In this large cohort study of infants born very preterm, almost one-third were not screened for ROP. Children most at risk for ROP were the best screened but often with delay. The higher compliance of neonatal units using wide-angle imaging systems supports its use.

Variations in patterns of care across neonatal units and their associations with outcomes in very preterm infants: the French EPIPAGE-2 cohort study.

OBJECTIVES: To describe patterns of care for very preterm (VP) babies across neonatal intensive care units (NICUs) and associations with outcomes. DESIGN: Prospective cohort study, EPIPAGE-2. SETTING: France, 2011. PARTICIPANTS: 53 (NICUs); 2135 VP neonates born at 27 to 31 weeks. OUTCOME MEASURES: Clusters of units, defined by the association of practices in five neonatal care domains - respiratory, cardiovascular, nutrition, pain management and neurodevelopmental care. Mortality at 2 years corrected age (CA) or severe/moderate neuro-motor or sensory disabilities and proportion of children with scores below threshold on the neurodevelopmental Ages and Stages Questionnaire (ASQ). METHODS: Hierarchical cluster analysis to identify clusters of units. Comparison of outcomes between clusters, after adjustment for potential cofounders. RESULTS: Three clusters were identified: Cluster 1 with higher proportions of neonates free of mechanical ventilation at 24 hours of life, receiving early enteral feeding, and neurodevelopmental care practices (26 units; n=1118 babies); Cluster 2 with higher levels of patent ductus arteriosus and pain screening (11 units; n=398 babies); Cluster 3 with higher use of respiratory, cardiovascular and pain treatments (16 units; n=619 babies). No difference was observed between clusters for the baseline maternal and babies' characteristics. No differences in outcomes were observed between Clusters 1 and 3. Compared with Cluster 1, mortality at 2 years CA or severe/moderate neuro-motor or sensory disabilities was lower in Cluster 2 (adjusted OR 0.46, 95% CI 0.25 to 0.84) but with higher proportion of children with an ASQ below threshold (adjusted OR 1.49, 95% CI 1.07 to 2.08). CONCLUSION: In French NICUs, care practices for VP babies were non-randomly associated. Differences between clusters were poorly explained by unit or population differences, but were associated with mortality and development at 2 years. Better understanding these variations may help to improve outcomes for VPT babies, as it is likely that some of these discrepancies are unwarranted.

Perceived maternal information on premature infant's pain during hospitalization: the French EPIPAGE-2 national cohort study.

BACKGROUND: Parents of preterm neonates wish greater involvement in pain management; little is known about factors associated with this involvement. We aim to describe perceived maternal information on infants' pain during hospitalization (PMIP), to study associations between PMIP and mothers' attitudes during painful procedures, and to identify individual and contextual factors associated with PMIP. METHODS: Analyses of questionnaires from the French national cohort study of preterm neonates, EPIPAGE-2. PMIP was derived from mothers' answers to questions about information perceived on both pain assessment and management. RESULTS: Among 3056 eligible neonates born before 32 weeks, 1974, with available maternal reports, were included in the study. PMIP was classified as "sufficient," "little, not sufficient," or "insufficient, or none" for 22.7, 45.9, and 31.3% of neonates, respectively. Mothers reporting PMIP as "sufficient" were more frequently present and more likely comforting their child during painful procedures. Factors independently associated with "sufficient" PMIP were high maternal education, gestational age <29 weeks, daily maternal visits, perception of high team support, and implementation of the neonatal and individualized developmental care and assessment program. CONCLUSION: Perceived maternal information on premature infants' pain reported as sufficient increased maternal involvement during painful procedures and was associated with some units' policies.

The impact of neonatal unit policies on breast milk feeding at discharge of moderate preterm infants: The EPIPAGE-2 cohort study.

Facilitating factors and barriers to breast milk feeding (BMF) for preterm infants have been mainly studied in very preterm populations, but little is known about moderate preterm infants. We aimed to analyze hospital unit characteristics and BMF policies associated with BMF at discharge for infants born at 32 to 34 weeks' gestation. EPIPAGE-2, a French national cohort of preterm births, included 883 infants born at 32 to 34 weeks' gestation. We investigated kangaroo care in the first 24 hr, early involvement of parents in feeding support, volume of the unit, BMF information given to mothers hospitalized for threatened preterm delivery, protocols for BMF, presence of a professional trained in human lactation, unit training in neurodevelopmental care, and regional BMF initiation rates in the general population. Multilevel logistic regression analysis was used to investigate associations between unit policies and BMF at discharge, adjusted for individual characteristics and estimating odds ratios (ORs) and 95% confidence intervals (CIs). Overall, 59% (490/828) of infants received BMF at discharge (27% to 87% between units). Rates of BMF at discharge were higher with kangaroo care (adjusted OR 2.03 [95% CI 1.01, 4.10]), early involvement of parents in feeding support (1.94 [1.23, 3.04]), unit training in a neurodevelopmental care programme (2.57 [1.18, 5.60]), and in regions with a high level of BMF initiation in the general population (1.85 [1.05, 3.28]). Creating synergies by interventions at the unit and population level may reduce the variability in BMF rates at discharge for moderate preterm infants.

Unit policies and breast milk feeding at discharge of very preterm infants: The EPIPAGE-2 cohort study.

BACKGROUND: Facilitating factors and barriers to breast milk feeding (BMF) very preterm (VP) infants have been widely studied at the individual level. We aimed to describe and analyse factors associated with BMF at discharge for VP infants, with a special focus on unit policies aiming to support BMF. METHODS: We described BMF at discharge in 3108 VP infants enrolled in EPIPAGE-2, a French national cohort. Variables of interest were kangaroo care during the 1st week of life (KC); unit's policies supporting BMF initiation (BMF information systematically given to mothers hospitalised for threatened preterm delivery and breast milk expression proposed within 6 hours after birth) and BMF maintenance (availability of protocols for BMF and a special room for mothers to pump milk); the presence in units of a professional trained in human lactation and regional BMF initiation rates in the general population. Associations were investigated by multilevel logistic regression analysis, with adjustment on individual factors. RESULTS: In total, 47.2% of VP infants received BMF at discharge (range among units 21.1%-84.0%). Unit policies partly explained this variation, regardless of individual factors. BMF at discharge was associated with KC (adjusted odds ratio (aOR) 2.26 (95% confidence interval (CI) 1.40, 3.65)), with policies supporting BMF initiation (aOR 2.19 (95% CI 1.27, 3.77)) and maintenance (aOR 2.03 (95% CI 1.17, 3.55)), but not with BMF initiation rates in the general population. CONCLUSION: Adopting policies of higher performing units could be an effective strategy for increasing BMF rates at discharge among VP infants.

Quantifying the burden of stillbirths before 28 weeks of completed gestational age in high-income countries: a population-based study of 19 European countries.

BACKGROUND: International comparisons of stillbirth allow assessment of variations in clinical practice to reduce mortality. Currently, such comparisons include only stillbirths from 28 or more completed weeks of gestational age, which underestimates the true burden of stillbirth. With increased registration of early stillbirths in high-income countries, we assessed the reliability of including stillbirths before 28 completed weeks in such comparisons. METHODS: In this population-based study, we used national cohort data from 19 European countries participating in the Euro-Peristat project on livebirths and stillbirths from 22 completed weeks of gestation in 2004, 2010, and 2015. We excluded countries without national data for stillbirths by gestational age in these periods, or where data available were not comparable between 2004 and 2015. We also excluded those countries with fewer than 10 000 births per year because the proportion of stillbirths at 22 weeks to less than 28 weeks of gestation is small. We calculated pooled stillbirth rates using a random-effects model and changes in rates between 2004 and 2015 using risk ratios (RR) by gestational age and country. FINDINGS: Stillbirths at 22 weeks to less than 28 weeks of gestation accounted for 32% of all stillbirths in 2015. The pooled stillbirth rate at 24 weeks to less than 28 weeks declined from 0·97 to 0·70 per 1000 births from 2004 to 2015, a reduction of 25% (RR 0·75, 95% CI 0·65-0·85). The pooled stillbirth rate at 22 weeks to less than 24 weeks of gestation in 2015 was 0·53 per 1000 births and did not significantly changed over time (RR 0·97, 95% CI 0·80-1·16) although changes varied widely between countries (RRs 0·62-2·09). Wide variation in the percentage of all births occurring at 22 weeks to less than 24 weeks of gestation suggest international differences in ascertainment. INTERPRETATION: Present definitions used for international comparisons exclude a third of stillbirths. International consistency of reporting stillbirths at 24 weeks to less than 28 weeks suggests these deaths should be included in routinely reported comparisons. This addition would have a major impact, acknowledging the burden of perinatal death to families, and making international assessments more informative for clinical practice and policy. Ascertainment of fetal deaths at 22 weeks to less than 24 weeks should be stabilised so that all stillbirths from 22 completed weeks of gestation onwards can be reliably compared. FUNDING: EU Union under the framework of the Health Programme and the Bridge Health Project.

Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants.

Background: The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood.Objective: We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC.Design: We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidémiologique sur les Petits Ages Gestationnels), including preterm infants born at <32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensity-matched case-control study, EPIFLORE (Etude Epidémiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing.Results: Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; P = 0.01) and 2.0 (95% CI: 1.1, 3.5; P = 0.02), respectively. Less favorable and intermediate direct-breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; P = 0.03) and 2.3 (95% CI: 1.1, 4.8; P = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between Clostridium neonatale and Staphylococcus aureus with NEC (P = 0.001 and P = 0.002).Conclusions: A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by C. neonatale and/or S. aureus is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698.

Leading causes of preterm delivery as risk factors for intraventricular hemorrhage in very preterm infants: results of the EPIPAGE 2 cohort study.

BACKGROUND: Intraventricular hemorrhage is a major risk factor for neurodevelopmental disabilities in preterm infants. However, few studies have investigated how pregnancy complications responsible for preterm delivery are related to intraventricular hemorrhage. OBJECTIVE: We sought to investigate the association between the main causes of preterm delivery and intraventricular hemorrhage in very preterm infants born in France during 2011 between 22-31 weeks of gestation. STUDY DESIGN: The study included 3495 preterm infants from the national EPIPAGE 2 cohort study who were admitted to neonatal intensive care units and had at least 1 cranial ultrasound assessment. The primary outcome was grade I-IV intraventricular hemorrhage according to the Papile classification. Multinomial logistic regression models were used to study the relationship between risk of intraventricular hemorrhage and the leading causes of preterm delivery: vascular placental diseases, isolated intrauterine growth retardation, placental abruption, preterm labor, and premature rupture of membranes, with or without associated maternal inflammatory syndrome. RESULTS: The overall frequency of grade IV, III, II, and I intraventricular hemorrhage was 3.8% (95% confidence interval, 3.2-4.5), 3.3% (95% confidence interval, 2.7-3.9), 12.1% (95% confidence interval, 11.0-13.3), and 17.0% (95% confidence interval, 15.7-18.4), respectively. After adjustment for gestational age, antenatal magnesium sulfate therapy, level of care in the maternity unit, antenatal corticosteroids, and chest compressions, infants born after placental abruption had a higher risk of grade IV and III intraventricular hemorrhage compared to those born under placental vascular disease conditions, with adjusted odds ratios of 4.3 (95% confidence interval, 1.1-17.0) and 4.4 (95% confidence interval, 1.1-17.6), respectively. Similarly, preterm labor with concurrent inflammatory syndrome was associated with an increased risk of grade IV intraventricular hemorrhage (adjusted odds ratio, 3.4; 95% confidence interval, 1.1-10.2]). Premature rupture of membranes did not significantly increase the risk. CONCLUSION: Relationships between the causes of preterm birth and intraventricular hemorrhage were limited to specific and rare cases involving acute hypoxia-ischemia and/or inflammation. While the emergent nature of placental abruption would challenge any attempts to optimize management, the prenatal care offered during preterm labor could be improved.

Translating Neurodevelopmental Care Policies Into Practice: The Experience of Neonatal ICUs in France-The EPIPAGE-2 Cohort Study.

OBJECTIVES: To describe the implementation of neurodevelopmental care for newborn preterm infants in neonatal ICUs in France in 2011, analyze changes since 2004, and investigate factors associated with practice. DESIGN: Prospective national cohort study of all births before 32 weeks of gestation. SETTING: Twenty-five French regions. PARTICIPANTS: All neonatal ICUs (n = 66); neonates surviving at discharge (n = 3,005). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Neurodevelopmental care policies and practices were assessed by structured questionnaires. Proportions of neonates initiating kangaroo care during the first week of life and those whose mothers expressed breast milk were measured as neurodevelopmental care practices. Multilevel logistic regression analyses were used to investigate relationships between kangaroo care or breast-feeding practices and unit policies, taking into account potential confounders. Free visiting policies, bed availability for parents, and kangaroo care encouragement significantly improved between 2004 and 2011 but with large variabilities between units. Kangaroo care initiation varied from 39% for neonates in the most restrictive units to 68% in less restrictive ones (p < 0.001). Individual factors associated with kangaroo care initiation were gestational age (odds ratio, 5.79; 95% CI, 4.49-7.48 for babies born at 27-31 wk compared with babies born at 23-26 wk) and, to a lesser extent, single pregnancy, birthweight above the 10th centile, and mother's employment before pregnancy. At unit level, policies and training in neurodevelopmental care significantly influenced kangaroo care initiation (odds ratio, 3.5; 95% CI, 1.8-7.0 for Newborn Individualized Developmental Care and Assessment Program implementation compared with no training). Breast milk expression by mothers was greater in units with full-time availability professionals trained for breast-feeding support (60% vs 73%; p < 0.0001). CONCLUSIONS: Dissemination of neurodevelopmental practices occurred between 2004 and 2011, but large variabilities between units persist. Practices increased in units with supportive policies. Specific neurodevelopmental care training with multifaceted interventions strengthened the implementation of policies.

Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants.

IMPORTANCE: There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. OBJECTIVE: To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS: Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. EXPOSURES: Early screening echocardiography before day 3 of life. MAIN OUTCOMES AND MEASURES: The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). RESULTS: Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. CONCLUSIONS AND RELEVANCE: In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity.