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.

Heterogeneity of design features in studies included in systematic reviews with meta-analysis of cognitive outcomes in children born very preterm.

BACKGROUND: Meta-analyses of the voluminous scientific literature on the impact of very preterm (VPT, <32 weeks' gestation) birth on cognition find a marked deficit in intelligence quotient (IQ) among children born VPT relative to term-born peers, but with unexplained between-study heterogeneity in effect size. OBJECTIVES: To conduct an umbrella review to describe the design and methodology of primary studies and to assess whether methodological heterogeneity affects the results of meta-analyses. DATA SOURCES: Primary studies from five systematic reviews with meta-analysis on VPT birth and childhood IQ. STUDY SELECTION AND DATA EXTRACTION: Information on study design, sample characteristics and results was extracted from studies. Study features covered study type, sample size, follow-up rates, adjustment for social context, management of severe impairments and test type. SYNTHESIS: We used random-effects subgroup meta-analyses and meta-regressions to investigate the contribution of study features to between-study variance in standardised mean differences (SMD) in IQ between groups. RESULTS: In 58 cohorts (56%), children with severe impairments were excluded, while 23 (22%) cohorts accounted for social factors. The least reported feature was the follow-up rate (missing in 38 cohorts). The largest difference in SMDs was between studies using full scale IQ tests (61 cohorts, SMD -0.89, 95% CI -0.96, -0.82) versus short-form tests (27 cohorts, SMD -0.68, 95% CI -0.79, -0.57). The proportion of between-study variance explained by the type of test was 14%; the other features explained less than 1% of the variance. CONCLUSIONS: Study design and methodology varied across studies, but most of them did not affect the variance in effect size, except the type of cognitive test. Key features, such as the follow-up rate, were not consistently reported limiting the evaluation of their potential contribution. Incomplete reporting limited the evaluation of the full impact of this methodological diversity.

Circumstances, causes and timing of death in extremely preterm infants admitted to NICU: The EPIPAGE-2 study.

AIM: To describe the circumstances, causes and timing of death in extremely preterm infants. METHODS: We included from the EPIPAGE-2 study infants born at 24-26 weeks in 2011 admitted to neonatal intensive care units (NICU). Vital status and circumstances of death were used to define three groups of infants: alive at discharge, death with or without withholding or withdrawing life-sustaining treatment (WWLST). The main cause of death was classified as respiratory disease, necrotizing enterocolitis, infection, central nervous system (CNS) injury, other or unknown. RESULTS: Among 768 infants admitted to NICU, 224 died among which 89 died without WWLST and 135 with WWLST. The main causes of death were respiratory disease (38%), CNS injury (30%) and infection (12%). Among the infants who died with WWLST, CNS injury was the main cause of death (47%), whereas respiratory disease (56%) and infection (20%) were the main causes in case of death without WWLST. Half (51%) of all deaths occurred within the first 7 days of life, and 35% occurred within 8 and 28 days. CONCLUSION: The death of extremely preterm infants in NICU is a complex phenomenon in which the circumstances and causes of death are intertwined.

Neurodevelopment at 5 years of age for preterm-born children according to mode of conception: a cohort study.

BACKGROUND: Preterm delivery is a risk factor for suboptimal neurodevelopment. Pregnancies conceived after medically assisted reproduction-which includes in vitro fertilization, with or without intracytoplasmic insemination, and induction of ovulation followed by intrauterine insemination or timed intercourse-have a higher risk of preterm delivery. Few studies have evaluated the outcome at >2 years of age of such preterm-born children. OBJECTIVE: To evaluate neurodevelopmental outcome at 5½ years of age of children born preterm according to the mode of conception (spontaneous vs medically assisted reproduction). STUDY DESIGN: A total of 4349 children born between 24 and 34 weeks of gestation who survived to 5½ years of age in the 2011 French prospective national cohort study "EPIPAGE-2" were included: 814 in the medically assisted reproduction group (433 by in vitro fertilization, with or without intracytoplasmic insemination, and 381 by induction of ovulation) and 3535 in the spontaneously conceived group. The studied neurodevelopmental outcomes were sensory (hearing and vision) impairments, cerebral palsy, cognition, and developmental coordination disorders. Multivariate analyses were performed with generalized estimating equation models adjusted for gestational age, antenatal steroids, and social characteristics. All analyses were performed following multiple imputation. Sensitivity analyses were performed with the populations of singletons and cases with complete data. RESULTS: No differences in cerebral palsy (adjusted odds ratio, 1.00; 95% confidence interval, 0.67-1.49), neurodevelopmental impairment (adjusted odds ratio, 1.09; 95% confidence interval, 0.82-1.45), or developmental coordination disorders (adjusted odds ratio, 0.75; 95% confidence interval, 0.50-1.12) were found between children born following medically assisted reproduction and children born following spontaneous conception after adjustment for sociodemographic factors. For proportions of children with an intelligence quotient below 1 and 2 standard deviations, there were no differences between those born after medically assisted reproduction and those born after spontaneous pregnancy (respectively, adjusted odds ratio, 0.99; 95% confidence interval, 0.80-1.23 and adjusted odds ratio, 1.14; 95% confidence interval, 0.83-1.56). In subgroup analyses, no differences were observed between children born following induction of ovulation or in vitro fertilization and those conceived spontaneously. Sensitivity analyses were consistent with the main results. CONCLUSION: In this cohort of preterm-born children, there was no evidence of an impact of the mode of conception on neurodevelopmental outcomes at 5½ years of age.

The challenges of heterogeneity in gestational age and birthweight inclusion criteria for research synthesis on very preterm birth and childhood cognition: An umbrella review and meta-regression analysis.

BACKGROUND: Meta-analyses of studies on very preterm (VPT) birth and childhood cognition select primary studies using gestational age inclusion criteria only, while others also include birthweight criteria. The consequences of this choice are unknown. OBJECTIVE: The objective of this study was to describe the gestational age (GA) and birthweight (BW) criteria used in studies of VPT birth and cognition and to investigate whether meta-analysis results differ based on these criteria. DATA SOURCES: Five systematic reviews on VPT birth and childhood IQ. STUDY SELECTION AND DATA EXTRACTION: Country, birth years, GA-BW selection criteria and participant IQ were extracted from 156 studies representing 103 birth cohorts. SYNTHESIS: Pooled standardised mean differences (SMD) in IQ between children born VPT and term-born controls were estimated by sub-group based on GA-BW criteria (GA, BW and GA-BW combined) and degree of preterm birth-low birthweight combinations: extremely preterm (EPT, <28 weeks) and extremely low BW (ELBW, <1000 g); VPT (<32 weeks) and very low BW (VLBW, <1500 g); and moderately MPT (<34 weeks) and moderately low BW (MLBW, <1800 g). RESULTS: Cohorts used 27 distinct GA-BW inclusion criteria. Most common criteria were BW <1500 g (24 cohorts), BW <1000 g (12), GA <32 weeks (12) and GA <33 weeks (12); 23 studies used GA-BW combinations. BW-only criteria were more frequent in North America than Europe (63% versus 24%) and for cohorts before than after 1990 (67% vs 26%). Pooled SMD in IQ varied: SMDEPT/ELBW -0.94, 95% confidence interval [CI] -1.07, -0.82; SMDVPT/VLBW -0.78, 95% CI -0.85, -0.71; SMDMPT/MLBW -0.68, 95% CI -0.79, -0.57; however, there was no difference in SMD across cohorts using BW compared to GA criteria after adjustment on risk group. CONCLUSIONS: These findings support the inclusion of studies using GA and/or BW criteria in meta-analyses on VPT birth and cognition to increase the geographical and temporal generalisability of the results and to allow investigation of the impact of the heterogeneous inclusion criteria in this literature on outcomes.

Birth outcomes between 22 and 26 weeks' gestation in national population-based cohorts from Sweden, England and France.

AIM: We investigated the timing of survival differences and effects on morbidity for foetuses alive at maternal admission to hospital delivered at 22 to 26 weeks' gestational age (GA). METHODS: Data from the EXPRESS (Sweden, 2004-07), EPICure-2 (England, 2006) and EPIPAGE-2 (France, 2011) cohorts were harmonised. Survival, stratified by GA, was analysed to 112 days using Kaplan-Meier analyses and Cox regression adjusted for population and pregnancy characteristics; neonatal morbidities, survival to discharge and follow-up and outcomes at 2-3 years of age were compared. RESULTS: Among 769 EXPRESS, 2310 EPICure-2 and 1359 EPIPAGE-2 foetuses, 112-day survival was, respectively, 28.2%, 10.8% and 0.5% at 22-23 weeks' GA; 68.5%, 40.0% and 23.6% at 24 weeks; 80.5%, 64.8% and 56.9% at 25 weeks; and 86.6%, 77.1% and 74.4% at 26 weeks. Deaths were most marked in EPIPAGE-2 before 1 day at 22-23 and 24 weeks GA. At 25 weeks, survival varied before 28 days; differences at 26 weeks were minimal. Cox analyses were consistent with the Kaplan-Meier analyses. Variations in morbidities were not clearly associated with survival. CONCLUSION: Differences in survival and morbidity outcomes for extremely preterm births are evident despite adjustment for background characteristics. No clear relationship was identified between early mortality and later patterns of morbidity.

Cause of preterm birth and late-onset sepsis in very preterm infants: the EPIPAGE-2 cohort study.

BACKGROUND: The pathogenesis of late-onset sepsis (LOS) in preterm infants is poorly understood and knowledge about risk factors, especially prenatal risk factors, is limited. This study aimed to assess the association between the cause of preterm birth and LOS in very preterm infants. METHODS: 2052 very preterm singletons from a national population-based cohort study alive at 72 h of life were included. Survival without LOS was compared by cause of preterm birth using survival analysis and Cox regression models. RESULTS: 437 (20.1%) had at least one episode of LOS. The frequency of LOS varied by cause of preterm birth: 17.1% for infants born after preterm labor, 17.9% after preterm premature rupture of membranes, 20.3% after a placental abruption, 20.3% after isolated hypertensive disorders, 27.5% after hypertensive disorders with fetal growth restriction (FGR), and 29.4% after isolated FGR. In multivariate analysis, when compared to infants born after preterm labor, the risk remained higher for infants born after hypertensive disorders (hazard ratio HR = 1.7, 95% CI = 1.2-2.5), hypertensive disorders with FGR (HR = 2.6, 95% CI = 1.9-3.6) and isolated FGR (HR = 2.9, 95% CI = 1.9-4.4). CONCLUSION: Very preterm infants born after hypertensive disorders or born after FGR had an increased risk of LOS compared to those born after preterm labor. IMPACT: Late-onset sepsis risk differs according to the cause of preterm birth. Compared with those born after preterm labor, infants born very preterm because of hypertensive disorders of pregnancy and/or fetal growth restriction display an increased risk for late-onset sepsis. Antenatal factors, in particular the full spectrum of causes leading to preterm birth, should be taken into consideration to better prevent and manage neonatal infectious morbidity and inform the parents.

Early postnatal growth and subsequent neurodevelopment in children delivered at term: The ELFE cohort study.

BACKGROUND: Despite the limited evidence, accelerated early postnatal growth (EPG) is commonly believed to benefit neurodevelopment for term-born infants, especially those small for gestational age. OBJECTIVES: To investigate the existence of critical time windows in the association of EPG with neurodevelopment, considering birth size groups. STUDY DESIGN: In the French ELFE birth cohort, 12,854 term-born neonates were classified as small, appropriate or large for gestational age (SGA, AGA, LGA, respectively). Parents reported their child's development by using the Child Development Inventory (CDI-score) at age 12 months and the MacArthur-Bates Development Inventory (MAB-score; 100 score units) assessing language ability at age 24 months. Predictions of individual weight, body mass index (BMI), length, and head circumference (HC) from birth to age 24 months were obtained from repeated measurements fitted with the Jenss-Bayley mixed-effects model. For each infant, conditional gains (CG) in these growth parameters were generated at four-time points (3, 6, 12 and 24 months) representing specific variations in growth parameters during 0-3, 3-6, 6-12, 12-24 months, independent of previous measures. Using multivariable linear regression models, we provided the estimate differences of the neurodevelopmental scores according to variation of each growth parameter CG, by birth size group. RESULTS: For SGA infants, the MAB-score differed by 5.8 (95% confidence interval [CI] -0.2, 11.8), 6.7 (95% CI -0.1, 13.3), and 9.7 (95% CI 1.9, 17.5) score units when CG in BMI, weight, and HC at 3 months varied from -2 to 1 standard deviation, respectively. For all infants, MAB-score was linearly and positively associated with length conditional gains at 12 months, with stronger magnitude for SGA infants. Results for the CDI-score were overall consistent with those for MAB-score. CONCLUSIONS: For term-born SGA infants, moderate catch-up in HC, BMI and weight within the first 3 months of life may benefit later neurodevelopment, which could guide clinicians to monitor EPG.

Risk factors for very preterm delivery out of a level III maternity unit: The EPIPAGE-2 cohort study.

BACKGROUND: Regionalisation programmes aim to ensure that very preterm infants are born in level III units (inborn) through antenatal referral or transfer. Despite widespread knowledge about better survival without disability for inborn babies, 10%-30% of women deliver outside these units (outborn). OBJECTIVE: To investigate risk factors associated with outborn deliveries and to estimate the proportion that were probably or possibly avoidable. METHODS: We used a national French population-based cohort including 2205 women who delivered between 24 and 30+6  weeks in 2011. We examined risk factors for outborn delivery related to medical complications, antenatal care, sociodemographic characteristics and living far from a level III unit using multivariable binomial regression. Avoidable outborn deliveries were defined by pregnancy risk (obstetric history, antenatal hospitalisation) and time available for transfer. RESULTS: 25.0% of women were initially booked in level III, 9.1% were referred, 49.8% were transferred, and 16.1% had outborn delivery. Risk factors for outborn delivery were gestational age <26 weeks (adjusted relative risk (aRR) 1.37, 95% confidence interval (CI) 1.13, 1.66), inadequate antenatal care (aRR 1.39, 95% CI 1.10, 1.81), placental abruption (aRR 1.66, 95% CI 1.27, 2.17), and increased distance to the closest level III unit ((aRR 2.79, 95% CI 2.00, 3.92) in the 4th versus 1st distance quartile). Among outborn deliveries, 16.7% were probably avoidable, and 25.6% possibly avoidable, which could increase the proportion of inborn deliveries between 85.9% and 92.9%. Avoidable outborn deliveries were mainly associated with gestational age, intrauterine growth restriction, preterm premature rupture of membranes, and haemorrhage, but not distance. CONCLUSIONS: Our study identified some modifiable risk factors for outborn delivery; however, when regionalised care relies heavily on antenatal transfer, as it does in France, only some outborn deliveries may be prevented. Earlier referral of high-risk women will be needed to achieve full access to tertiary care.

Impact of antenatal corticosteroids on head circumference of full-term newborns: A French multicenter cohort study.

INTRODUCTION: Our main objective was to evaluate whether antenatal corticosteroids increase the risk of small head circumference in children born at term. Secondary objectives were to evaluate whether they increase the risk of small birthweight and birth length among those children. MATERIAL AND METHODS: A historical cohort included 275 270 live term born children between 2000 and 2013 in 175 French maternity units. The rate of head circumference below the 5th percentile among children born at term and exposed to antenatal corticosteroids was compared with that of two unexposed groups: those children born at term whose mothers had an episode of threatened preterm labor without corticosteroids and those whose mothers had neither threatened preterm labor nor corticosteroids. The association between this treatment and head circumference was evaluated by calculating adjusted risk ratios (aRRs) and their 95% confidence intervals (CIs). The main outcome measure was a head circumference below the 5th percentile at birth, adjusted for sex, and gestational age according to the Pediatric, Obstetrics, and Gynecology Electronic Records Users Association (AUDIPOG) curves. Secondary outcomes were birthweight and birth length below the 5th percentile. RESULTS: The rate of head circumference below the 5th percentile was 5.8% (n = 3388) among children exposed to antenatal corticosteroids and 4.3% (n = 7077) and 4.6% (n = 198 462), respectively, for the two unexposed groups. After adjustment, the risk of having a head circumference below the 5th percentile did not differ between the exposed group and the two control groups (aRR 1.28, 95% confidence interval [CI] 0.97-1.69] and aRR 0.91, 95% CI 0.74-1.13). We did not find an association between antenatal corticosteroids and the rate of birthweight below the 5th percentile. Children exposed to antenatal corticosteroids had a higher risk of a birth length below the 5th percentile when compared with those not exposed to threatened preterm labor or corticosteroids. CONCLUSIONS: We found no association between antenatal corticosteroids and increased risk of head circumference below the 5th percentile in children born at term.

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.

Intensity of perinatal care, extreme prematurity and sensorimotor outcome at 2 years corrected age: evidence from the EPIPAGE-2 cohort study.

BACKGROUND: Emerging evidence suggests intensity of perinatal care influences survival for extremely preterm babies. We evaluated the effect of differences in perinatal care intensity between centres on sensorimotor morbidity at 2 years of age. We hypothesised that hospitals with a higher intensity of perinatal care would have improved survival without increased disability. METHODS: Foetuses alive at maternal admission to a level 3 hospital in France in 2011, subsequently delivered between 22 and 26 weeks gestational age (GA) and included in the EPIPAGE-2 national prospective observational cohort study formed the baseline population. Level of intensity of perinatal care was assigned according to hospital of birth, categorised into three groups using 'perinatal intensity' ratios (ratio of 24-25 weeks GA babies admitted to neonatal intensive care to foetuses of the same GA alive at maternal admission to hospital). Multiple imputation was used to account for missing data; hierarchical logistic regression accounting for births nested within centres was then performed. RESULTS: One thousand one hundred twelve foetuses were included; 473 survived to 2 years of age (126 of 358 in low-intensity, 140 of 380 in medium-intensity and 207 of 374 in high-intensity hospitals). There were no differences in disability (adjusted odds ratios 0.93 (95% CI 0.28 to 3.04) and 1.04 (95% CI 0.34 to 3.14) in medium- and high- compared to low-intensity hospitals, respectively). Compared to low-intensity hospitals, survival without sensorimotor disability was increased in the population of foetuses alive at maternal admission to hospital and in live-born babies, but there were no differences when considering only babies admitted to NICU or survivors. CONCLUSIONS: No difference in sensorimotor outcome for survivors of extremely preterm birth at 2 years of age was found according to the intensity of perinatal care provision. Active management of periviable births was associated with increased survival without sensorimotor disability.

Neonatal Outcomes in Extremely Preterm Newborns Admitted to Intensive Care after No Active Antenatal Management: A Population-Based Cohort Study.

OBJECTIVE: To evaluate the association between active antenatal management and neonatal outcomes in extremely preterm newborns admitted to a neonatal intensive care unit (NICU). STUDY DESIGN: This population-based cohort study was conducted in 25 regions of France. Infants born in 2011 between 220/7 and 266/7 weeks of gestation and admitted to a NICU were included. Infants with lethal congenital malformations or death in the delivery room were excluded. A multilevel multivariable analysis was performed, accounting for clustering by mother (multiple pregnancies) and hospital plus individual characteristics, to estimate the association between the main exposure of no active antenatal management (not receiving antenatal corticosteroids, magnesium sulfate, or cesarean delivery for fetal indications) and a composite outcome of death or severe neonatal morbidity (including severe forms of brain or lung injury, retinopathy of prematurity, and necrotizing enterocolitis). RESULTS: Among 3046 extremely preterm births, 783 infants were admitted to a NICU. Of these, 138 (18%) did not receive active antenatal management. The risk of death or severe morbidity was significantly higher for infants without active antenatal management (crude OR, 2.60; 95% CI, 1.44-4.66). This finding persisted after adjustment for gestational age (OR, 2.08; 95% CI, 1.19-3.62) and all confounding factors (OR, 1.86; 95% CI, 1.09-3.20). CONCLUSIONS: The increased risk of severe neonatal outcomes for extremely preterm babies admitted to a NICU without optimal antenatal management should be considered in individual-level decision making and in the development of professional guidelines for the management of extremely preterm births.

Investigating increased admissions to neonatal intensive care in England between 1995 and 2006: data linkage study using Hospital Episode Statistics.

BACKGROUND: A 44 % increase was observed in admissions to neonatal intensive care of babies born ≤26 weeks completed gestational age in England between 1995 and 2006. Hospital Episode Statistics (HES) may provide supplementary information to investigate this. The methods and results of a probabilistic data linkage exercise are reported. METHODS: Two data sets were linked for each year (1995 and 2006) using 3 different algorithms (Fellegi and Sunter, Contiero and estimation-maximisation). RESULTS: In 1995, linkage was performed between 668 EPICure and 486,705 HES records; 1,820 linked pairs were identified of which 422 (63.17 %) were confirmed. In 2006, from 2,750 EPICure and 631,401 HES records, 8,913 linked pairs were identified with 1,662 (60.40 %) confirmed as true. Reported births in HES at <26 weeks gestation increased 37.0 % from 867 to 1188. CONCLUSIONS: Results support the EPICure findings that there was an increase in the birth rate for extremely premature babies between 1995 and 2006. There were insufficient data available for detailed investigation. Routine data sources may not be suitable for investigations at the margins of viability.

Impact of obstetric interventions on condition at birth in extremely preterm babies: evidence from a national cohort study.

BACKGROUND: To investigate perinatal decision-making and the use of obstetric interventions, we examined the effects of antenatal steroids, tocolysis, and delivery mode on birth in a good condition (defined as presence of an infant heart rate >100 at five minutes of age) and delivery-room (DR) death in extremely preterm deliveries. METHODS: Prospective cohort of all singleton births in England in 2006 at 22-26 weeks of gestation where the fetus was alive at the start of labour monitoring or decision to perform caesarean section. Odds ratios adjusted for potential confounders (aOR) were calculated using logistic regression. RESULTS: One thousand seven hundred twenty two singleton pregnancies were included. 1231 women received antenatal steroids, 437 tocolysis and 356 delivered by Caesarean section. In babies born vaginally, aOR between a partial course of steroids and improved condition at birth was 1.84, 95% CI: 1.20 to 2.82 and, for a complete course, 1.63, 95% CI: 1.08 to 2.47; for DR death, aORs were 0.34 (0.21 to 0.55) and 0.41 (0.26 to 0.64) for partial and complete courses of steroids. No association was seen for steroid use in babies delivered by Caesarean section. Tocolysis was associated with improved condition at birth (aOR 1.45, 95% CI: 1.05 to 2.0) and lower odds of death (aOR 0.48, 95% CI: 0.32 to 0.73). In women without spontaneous labour, Caesarean delivery at ≤24 and 25 weeks was associated with improved condition at birth ((aORs 12.67 (2.79 to 57.60) and 4.94 (1.44 to 16.90), respectively) and lower odds of DR death (aORs 0.03 (0.01 to 0.21) and 0.13 (0.03 to 0.55)). There were no differences at 26 weeks gestation or in women with spontaneous labour. CONCLUSIONS: Antenatal steroids are strongly associated with improved outcomes in babies born vaginally. Tocolysis was associated with improvements in all analyses. Effects persisted after adjustment for perinatal decision-making. However, associations between delivery mode and birth outcomes may be attributable to case selection.

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.

Risk Factors for High-Arched Palate and Posterior Crossbite at the Age of 5 in Children Born Very Preterm: EPIPAGE-2 Cohort Study.

Introduction: Children born very preterm have an immature sucking reflex at birth and are exposed to neonatal care that can impede proper palate growth. Objectives: We aimed to describe the frequency of high-arched palate and posterior crossbite at the age of 5 in children born very preterm and to identify their respective risk factors. Methods: Our study was based on the data from EPIPAGE-2, a French national prospective cohort study, and included 2,594 children born between 24- and 31-week gestation. Outcomes were high-arched palate and posterior crossbite. Multivariable models estimated by generalized estimation equations with multiple imputation were used to study the association between the potential risk factors studied and each outcome. Results: Overall, 8% of children born very preterm had a high-arched palate and 15% posterior crossbite. The odds of high-arched palate were increased for children with low gestational age (24-29 vs. 30-31 weeks of gestation) [adjusted odds ratio (aOR) 1.76, 95% confidence interval (CI) 1.17, 2.66], thumb-sucking habits at the age of 2 (aOR 1.53, 95% CI 1.03, 2.28), and cerebral palsy (aOR 2.18, 95% CI 1.28, 3.69). The odds of posterior crossbite were increased for children with pacifier-sucking habits at the age of 2 (aOR 1.75, 95% CI 1.30, 2.36). Conclusions: Among very preterm children, low gestational age and cerebral palsy are the specific risk factors for a high-arched palate. High-arched palate and posterior crossbite share non-nutritive sucking habits as a common risk factor. The oro-facial growth of these children should be monitored.