Clinical Chorioamnionitis and Neurodevelopment at 5 Years of Age in Children Born Preterm: The EPIPAGE-2 Cohort Study.

OBJECTIVE: To assess the association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born preterm. STUDY DESIGN: EPIPAGE 2 is a national, population-based cohort study of children born before 35 weeks of gestation in France in 2011. We included infants born alive between 240/7 and 346/7 weeks after preterm labor or preterm premature rupture of membranes. Clinical chorioamnionitis was defined as maternal fever before labor (>37.8°C) with ≥2 of the following criteria: maternal tachycardia, hyperleukocytosis, uterine contractions, purulent amniotic fluid, or fetal tachycardia. The primary outcome was a composite, including cerebral palsy, coordination disorders, cognitive disorders, sensory disorders, or behavioral disorders. We also analyzed each of these disorders separately as secondary outcomes. We performed a multivariable analysis using logistic regression models. We accounted for the nonindependence of twins and missing data by generalized estimating equation models and multiple imputations, respectively. RESULTS: Among 2927 children alive at 5 years of age, 124 (3%) were born in a context of clinical chorioamnionitis. Overall, 8.2% and 9.6% of children exposed and unexposed, respectively, to clinical chorioamnionitis had moderate-to-severe neurodevelopmental disorders. After multiple imputations and multivariable analysis, clinical chorioamnionitis was not associated with the occurrence of moderate-to-severe neurodevelopmental disorders (aOR, 0.9; 95% CI, 0.5-1.8). CONCLUSIONS: We did not find any association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born at <35 weeks of gestation after preterm labor or preterm premature rupture of membrane.

Screening preterm-born infants for autistic traits may help to identify social communication difficulties at five years of age.

AIM: This study compared neurodevelopmental screening questionnaires completed when preterm-born children reached 2 years of corrected age with social communication skills at 5.5 years of age. METHODS: Eligible subjects were born in 2011 at 24-34 weeks of gestation, participated in a French population-based epidemiological study and were free of motor and sensory impairment at 2 years of corrected age. The Ages and Stages Questionnaire (ASQ) and the Modified Checklist for Autism in Toddlers (M-CHAT) were used at 2 years and the Social Communication Questionnaire (SCQ) at 5.5 years of age. RESULTS: We focused on 2119 children. At 2 years of corrected age, the M-CHAT showed autistic traits in 20.7%, 18.5% and 18.2% of the children born at 24-26, 27-31 and 32-34 weeks of gestation, respectively (p = 0.7). At 5.5 years of age, 12.6%, 12.7% and 9.6% risked social communication difficulties, with an SCQ score ≥90th percentile (p = 0.2). A positive M-CHAT score at 2 years was associated with higher risks of social communication difficulties at 5.5 years of age (odds ratio 3.46, 95% confidence interval 2.04-5.86, p < 0.001). Stratifying ASQ scores produced similar results. CONCLUSION: Using parental neurodevelopmental screening questionnaires for preterm-born children helped to identify the risk of later social communication difficulties.

Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study.

BACKGROUND: The administration of tocolytics after preterm prelabor rupture of membranes remains a controversial practice. In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, thereby reducing the risks for prematurity and adverse consequences over the life course. However, tocolysis may be associated with neonatal death or long-term adverse neurodevelopmental outcomes, mainly related to prolonged fetal exposure to intrauterine infection or inflammation. In a previous study, we showed that tocolysis administration was not associated with short-term benefits. There are currently no data available to evaluate the impact of tocolysis on neurodevelopmental outcomes in school-aged children born prematurely in this clinical setting. OBJECTIVE: This study aimed to investigate whether tocolysis administered after preterm prelabor rupture of membranes is associated with neurodevelopmental outcomes at 5.5 years of age. STUDY DESIGN: We used data from a prospective, population-based cohort study of preterm births recruited in 2011 (referred to as the EPIPAGE-2 study) and for whom the results of a comprehensive medical and neurodevelopmental assessment of the infant at age 5.5 years were available. We included pregnant individuals with preterm prelabor rupture of membranes at 24 to 32 weeks' gestation in singleton pregnancies with a live fetus at the time of rupture, birth at 24 to 34 weeks' gestation, and participation of the infant in an assessment at 5.5 years of age. Exposure was the administration of any tocolytic treatment after preterm prelabor rupture of membranes. The main outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years of age. Secondary outcomes included survival without any neurodevelopmental disabilities, cerebral palsy, full-scale intelligence quotient, developmental coordination disorders, and behavioral difficulties. A propensity-score analysis was used to minimize the indication bias in the estimation of the treatment effect on outcomes. RESULTS: Overall, 596 of 803 pregnant individuals (73.4%) received tocolytics after preterm prelabor rupture of membranes. At the 5.5-year follow-up, 82.7% and 82.5% of the children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1%, respectively, were alive without any neurodevelopmental disabilities. After applying multiple imputations and inverse probability of treatment weighting, we found no association between the exposure to tocolytics and survival without moderate to severe neurodevelopmental disabilities (odds ratio, 0.93; 95% confidence interval, 0.55-1.60), survival without any neurodevelopmental disabilities (odds ratio, 1.02; 95% confidence interval, 0.65-1.61), or any of the other outcomes. CONCLUSION: There was no difference in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolysis after preterm prelabor rupture of membranes. To date, the health benefits of tocolytics remain unproven, both in the short- and long-term.

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.

Early Antibiotic Exposure and Adverse Outcomes in Very Preterm Infants at Low Risk of Early-Onset Sepsis: The EPIPAGE-2 Cohort Study.

OBJECTIVE: To assess the association between early empirical antibiotics and neonatal adverse outcomes in very preterm infants without risk factors for early-onset sepsis (EOS). STUDY DESIGN: This is a secondary analysis of the EPIPAGE-2 study, a prospective national population-based cohort that included all liveborn infants at 22-31 completed weeks of gestation in France in 2011. Infants at high risk of EOS (ie, born after preterm labor or preterm premature rupture of membranes or from a mother who had clinical chorioamnionitis or had received antibiotics during the last 72 hours) were excluded. Early antibiotic exposure was defined as antibiotic therapy started at day 0 or day 1 of life, irrespective of the duration and type of antibiotics. We compared treated and untreated patients using inverse probability of treatment weighting based on estimated propensity scores. RESULTS: Among 648 very preterm infants at low risk of EOS, 173 (26.2%) had received early antibiotic treatment. Early antibiotic exposure was not associated with death or late-onset sepsis or necrotizing enterocolitis (OR, 1.04; 95% CI, 0.72-1.50); however, it was associated with higher odds of severe cerebral lesions (OR, 2.71; 95% CI, 1.25-5.86) and moderate-severe bronchopulmonary dysplasia (BPD) (OR, 2.30; 95% CI, 1.21-4.38). CONCLUSIONS: Early empirical antibiotic therapy administrated in very preterm infants at low risk of EOS was associated with a higher risk of severe cerebral lesions and moderate-severe BPD.

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.

Antibiotic prophylaxis in preterm premature rupture of membranes at 24-31 weeks' gestation: Perinatal and 2-year outcomes in the EPIPAGE-2 cohort.

OBJECTIVE: To compare different antibiotic prophylaxis administered after preterm premature rupture of membranes to determine whether any were associated with differences in obstetric and/or neonatal outcomes and/or neurodevelopmental outcomes at 2 years of corrected age. DESIGN: Prospective, nationwide, population-based EPIPAGE-2 cohort study of preterm infants. SETTING: France, 2011. SAMPLE: We included 492 women with a singleton pregnancy and a diagnosis of preterm premature rupture of membranes at 24-31 weeks. Exclusion criteria were contraindication to expectant management or indication for antibiotic therapy other than preterm premature rupture of membranes. Antibiotic prophylaxis was categorised as amoxicillin (n = 345), macrolide (n = 30), third-generation cephalosporin (n = 45) or any combinations covering Streptococcus agalactiae and >90% of Escherichia coli (n = 72), initiated within 24 hours after preterm premature rupture of membranes. METHODS: Population-averaged robust Poisson models. MAIN OUTCOME MEASURES: Survival at discharge without severe neonatal morbidity, 2-year neurodevelopment. RESULTS: With amoxicillin, macrolide, third-generation cephalosporin and combinations, 78.5%, 83.9%, 93.6% and 86.0% of neonates were discharged alive without severe morbidity. The administration of third-generation cephalosporin or any E. coli-targeting combinations was associated with improved survival without severe morbidity (adjusted risk ratio 1.25 [95% confidence interval 1.08-1.45] and 1.10 [95 % confidence interval 1.01-1.20], respectively) compared with amoxicillin. We evidenced no increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen. CONCLUSION: In preterm premature rupture of membranes at 24-31 weeks, antibiotic prophylaxis based on third-generation cephalosporin may be associated with improved survival without severe neonatal morbidity when compared with amoxicillin, with no evidence of increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen. TWEETABLE ABSTRACT: Antibiotic prophylaxis after PPROM at 24-31 weeks: 3rd-generation cephalosporins associated with improved neonatal 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.

Association of Continuous Opioids and/or Midazolam During Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort.

OBJECTIVE: To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2 years in very premature infants who were ventilated. STUDY DESIGN: This national observational study included premature infants born before 32 weeks of gestation intubated within 1 hour after birth and still intubated at 24 hours from the French EPIPAGE 2 cohort. Infants only treated with bolus were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7 days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n = 450) vs naive (n = 472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age 2 years. RESULTS: Survival at age 2 years was significantly higher in the treated group (92.5% vs 87.9%, risk difference, 4.7%; 95% CI, 0.3-9.1; P = .037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%; risk difference, 5.3%; 95% CI -0.3 to 11.0; P = .063). These results were confirmed by sensitivity analyses using 5 alternative models. CONCLUSIONS: Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24 hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2 years.

Factors associated with non-nutritive sucking habits at 2 years of age among very preterm children: EPIPAGE-2 cohort study.

BACKGROUND: The association between prolonged non-nutritive sucking habits (NNSHs, ie, sucking pacifiers or fingers) and maxillofacial growth anomalies in the general population has been widely described. Because maturation of sucking abilities is not fully achieved in very preterm infants (<32 weeks' gestation), neonatal services worldwide rely on the use of pacifiers to promote the development of adequate sucking reflexes, possibly prolonging NNSHs during infancy. OBJECTIVE: We aimed to describe the frequency and to identify factors associated with NNSHs at age 2 years in very preterm children. METHODS: The study was based on data from EPIPAGE-2, a French national prospective cohort study of preterm births during 2011 that included 2593 children born between 24 and 31 weeks' gestation. The primary outcome was NNSHs at 2 years. Multivariable log-linear regression models with generalized estimation equations were used to study the association between the characteristics studied and NNSHs. Multiple imputations were used to take into account missing data. RESULTS: The frequency of NNSHs was 69% in the overall sample but higher among girls (adjusted risk ratio [RR] 1.12, 95% confidence interval [CI] 1.05, 1.17), children born from multiple pregnancies (eg, twins/triplets) (RR 1.07, 95% CI 1.00, 1.11), children who were fed by nasogastric tube (RR 1.07, 95% CI 1.01, 1.13), or those who benefitted from developmental care programmes (RR 1.10, 95% CI 1.02, 1.19). The NNSHs frequency was lower if mothers were not born in France (RR 0.70, 95% CI 0.64, 0.77), children had 2 or more older siblings (RR 0.88, 95% CI 0.82, 0.96), or children were breast-fed at discharge (RR 0.90, 95% CI 0.85, 0.95). CONCLUSIONS: NNSHs at 2 years seemed associated with cultural background, development care programmes, and breast feeding. Whether NNSHs at 2 years among very preterm children are associated with future maxillofacial growth anomalies deserves further attention.

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.

Association of Language Skills with Other Developmental Domains in Extremely, Very, and Moderately Preterm Children: EPIPAGE 2 Cohort Study.

OBJECTIVE: To analyze language skills in children born at 24-34 weeks of gestation at 2 years of corrected age and the association between language and other developmental domains. STUDY DESIGN: We included 2424 children (64% of the eligible population) from the French population-based EPIPAGE 2 cohort study. At 2 years' corrected age, children were screened with the French short version of the MacArthur-Bates Communication Developmental Inventories and the Ages and Stages Questionnaire completed by parents. RESULTS: Small lexicon size, <10th percentile of the calibration sample (ie, 28 words in a list of 100) was observed in 135 of 300 children (45%) born at 23-26 weeks, 484 of 1513 (32%) born at 27-31 weeks, and 165 of 611 (27%) born at 32-34 weeks of gestation. Small lexicon size was associated with 2 other language measures: word combination use and the Ages and Stages Questionnaire communication domain score. It was also significantly associated with the Ages and Stages Questionnaire score below the threshold in the other developmental domains (gross motor function, fine motor function, problem solving skills, and personal social skills) for all gestational age groups, after adjustment for potential confounders. Overall, 46% of children with a small lexicon size had ≥1 of these domains below the threshold, as compared with only 22% of children without a small lexicon size. CONCLUSIONS: These results highlight the usefulness of the MacArthur-Bates Communication Developmental Inventories in preterm children, especially those who do not participate in specialized follow-up. A small lexicon size points to developmental difficulties in language and increased risk for other developmental and neurobehavioral functions.

Mortality and severe morbidity of very preterm infants: comparison of two French cohort studies.

BACKGROUND: In Reunion Island, a French overseas department, the burden of preterm birth and perinatal mortality exceed those observed in mainland France, despite similar access to standard perinatal care. The purpose of the study was to compare the outcome of two cohorts of NICU-admitted very preterm infants born between 24 and 31 weeks of gestation (WG): the registry-based OGP (Observatoire de la Grande Prématurité, Reunion Island, 2008-2013) cohort, and the nationwide EPIPAGE-2 (mainland France, 2011) observational cohort. METHODS: The primary outcome was adverse neonatal outcomes defined as a composite indicator of in-hospital mortality or any of three following severe morbidities: bronchopulmonary dysplasia (BPD), necrotising enterocolitis, or severe neurological injury (periventricular leukomalacia or grade III-IV intraventricular haemorrhages). Logistic regression modelling adjusting for confounders was performed. RESULTS: A total of 1272 very preterm infants from the Reunionese OGP cohort and 3669 peers from the mainland EPIPAGE-2 cohort were compared. Adverse neonatal outcomes were more likely observed in the OGP cohort (32.6% versus 26.6%, p <  0.001), as result of both increased in-hospital mortality across all gestational age strata and increased BPD among the survivors of the 29-31 WG stratum. After adjusting for gestational age, gender and multiple perinatal factors, the risk of adverse neonatal outcomes was higher in the OGP cohort than in the EPIPAGE-2 cohort across all gestational age strata. CONCLUSIONS: Despite similar guidelines for standard perinatal care, very preterm infants born in Reunion Island have a higher risk for death or severe morbidity compared with those born in mainland France.

Preterm premature rupture of membranes at 22-25 weeks' gestation: perinatal and 2-year outcomes within a national population-based study (EPIPAGE-2).

BACKGROUND: Most clinical guidelines state that with early preterm premature rupture of membranes, obstetric and pediatric teams must share a realistic and individualized appraisal of neonatal outcomes with parents and consider their wishes for all decisions. However, we currently lack reliable and relevant data, according to gestational age at rupture of membranes, to adequately counsel parents during pregnancy and to reflect on our policies of care at these extreme gestational ages. OBJECTIVE: We sought to describe both perinatal and 2-year outcomes of preterm infants born after preterm premature rupture of membranes at 22-25 weeks' gestation. STUDY DESIGN: EPIPAGE-2 is a French national prospective population-based cohort of preterm infants born in 546 maternity units in 2011. Inclusion criteria in this analysis were women diagnosed with preterm premature rupture of membranes at 22-25 weeks' gestation and singleton or twin gestations with fetus(es) alive at rupture of membranes. Latency duration, antenatal management, and outcomes (survival at discharge, survival at discharge without severe morbidity, and survival at 2 years' corrected age without cerebral palsy) were described and compared by gestational age at preterm premature rupture of membranes. RESULTS: Among the 1435 women with a diagnosis of preterm premature rupture of membranes, 379 were at 22-25 weeks' gestation, with 427 fetuses (331 singletons and 96 twins). Median gestational age at preterm premature rupture of membranes and at birth were 24 (interquartile range 23-25) and 25 (24-27) weeks, respectively. For each gestational age at preterm premature rupture of membranes, nearly half of the fetuses were born within the week after the rupture of membranes. Among the 427 fetuses, 51.7% were survivors at discharge (14.1%, 39.5%, 66.8%, and 75.8% with preterm premature rupture of membranes at 22, 23, 24, and 25 weeks, respectively), 38.8% were survivors at discharge without severe morbidity, and 46.4% were survivors at 2 years without cerebral palsy, with wide variations by gestational age at preterm premature rupture of membranes. Survival at 2 years without cerebral palsy was low with preterm premature rupture of membranes at 22 and 23 weeks but reached approximately 60% and 70% with preterm premature rupture of membranes at 24 and 25 weeks. CONCLUSION: Preterm premature rupture of membranes at 22-25 weeks is associated with high incidence of mortality and morbidity, with wide variations by gestational age at preterm premature rupture of membranes. However, a nonnegligible proportion of children survive without severe morbidity both at discharge and at 2 years' corrected age.

Histologic Chorioamnionitis and Bronchopulmonary Dysplasia in Preterm Infants: The Epidemiologic Study on Low Gestational Ages 2 Cohort.

OBJECTIVE: To investigate the association between histologic chorioamnionitis (HCA) and bronchopulmonary dysplasia (BPD) in very preterm infants, both in a general population and for those born after spontaneous preterm labor and after preterm premature rupture of membranes (pPROM). STUDY DESIGN: This study included 2513 live born singletons delivered at 24-31 weeks of gestation from a national prospective population-based cohort of preterm births; 1731 placenta reports were available. HCA was defined as neutrophil infiltrates in the amnion, chorion of the membranes, or chorionic plate, associated or not with funisitis. The main outcome measure was moderate or severe BPD. Analyses involved logistic regressions and multiple imputation for missing data. RESULTS: The incidence of HCA was 28.4% overall: 38% in cases of preterm labor, 64% in cases of pPROM, and less than 5% in cases of vascular disorders. Overall, the risk of BPD after adjustment for gestational age, sex, and antenatal steroids was reduced for infants with HCA (HCA alone: aOR 0.6 [95% CI 0.4-0.9]; associated with funisitis: aOR 0.5 [95% CI 0.3-0.8]). This finding was explained by the high rate of BPD and low rate of chorioamnionitis among children with fetal growth restriction. HCA was not associated with BPD in the preterm labor (13.4% vs 8.5%; aOR 0.9; 95% CI 0.5-1.8) or in the pPROM group (12.9% vs 12.1%; aOR 0.6; 95% CI 0.3-1.3). CONCLUSION: In homogeneous groups of infants born after preterm labor or pPROM, HCA is not associated with BPD.

Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis.

BACKGROUND: There are conflicting results regarding tocolysis in cases of preterm premature rupture of membranes. Delaying delivery may reduce neonatal morbidity because of prematurity and allow for prenatal corticosteroids and, if necessary, in utero transfer. However, that may increase the risks of maternofetal infection and its adverse consequences. OBJECTIVE: The objective of the study was to investigate whether tocolytic therapy in cases of preterm premature rupture of membranes is associated with improved neonatal or obstetric outcomes. STUDY DESIGN: Etude Epidémiologique sur les Petits Ages Gestationnels 2 is a French national prospective, population-based cohort study of preterm births that occurred in 546 maternity units in 2011. Inclusion criteria in this analysis were women with preterm premature rupture of membranes at 24-32 weeks' gestation and singleton gestations. Outcomes were survival to discharge without severe morbidity, latency prolonged by ≥48 hours and histological chorioamnionitis. Uterine contractions at admission, individual and obstetric characteristics, and neonatal outcomes were compared by tocolytic treatment or not. Propensity scores and inverse probability of treatment weighting for each woman were used to minimize indication bias in estimating the association of tocolytic therapy with outcomes. RESULTS: The study population consisted of 803 women; 596 (73.4%) received tocolysis. Women with and without tocolysis did not differ in neonatal survival without severe morbidity (86.7% vs 83.9%, P = .39), latency prolonged by ≥48 hours (75.1% vs 77.4%, P = .59), or histological chorioamnionitis (50.0% vs 47.6%, P = .73). After applying propensity scores and assigning inverse probability of treatment weighting, tocolysis was not associated with improved survival without severe morbidity as compared with no tocolysis (odds ratio, 1.01 [95% confidence interval, 0.94-1.09], latency prolonged by ≥48 hours (1.03 [95% confidence interval, 0.95-1.11]), or histological chorioamnionitis (1.03 [95% confidence interval, 0.92-1.17]). There was no association between the initial tocolytic drug used (oxytocin receptor antagonists or calcium-channel blockers vs no tocolysis) and the 3 outcomes. Sensitivity analyses of women with preterm premature rupture of membranes at 26-31 weeks' gestation, women who delivered at least 12 hours after rupture of membranes, women with direct admission after the rupture of membranes and the presence or absence of contractions gave similar results. CONCLUSION: Tocolysis in cases of preterm premature rupture of membranes is not associated with improved obstetric or neonatal outcomes; its clinical benefit remains unproven.

Doxapram for apnoea of prematurity and neurodevelopmental outcomes at age 5-6 years.

OBJECTIVE: To assess the long-term neurodevelopmental impact of doxapram for treating apnoea of prematurity. DESIGN: Secondary analysis of the French national cohort study EPIPAGE-2. Recruitment took place in 2011. A standardised neurodevelopmental assessment was performed at age 5-6 years. A 2:1 propensity score matching was used to control for the non-randomised assignment of doxapram treatment. SETTING: Population-based cohort study. PATIENTS: All children born before 32 weeks' gestation alive at age 5-6 years. INTERVENTIONS: Blind and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes at age 5-6 years assessed by trained paediatricians and neuropsychologists: cerebral palsy, developmental coordination disorders, IQ and behavioural difficulties. A composite criterion for overall neurodevelopmental disabilities was built. RESULTS: The population consisted of 2950 children; 275 (8.6%) received doxapram. Median (IQR) gestational age was 29.4 (27.6-30.9) weeks. At age 5-6 years, complete neurodevelopmental assessment was available for 60.3% (1780 of 2950) of children and partial assessment for 10.6% (314 of 2950). In the initial sample, children receiving doxapram had evidence of greater clinical severity than those not treated. Doxapram treatment was associated with overall neurodevelopmental disabilities of any severity (OR 1.43, 95% CI 1.07 to 1.92, p=0.02). Eight hundred and twenty-one children were included in the 2:1 matched sample. In this sample, perinatal characteristics of both groups were similar and doxapram treatment was not associated with overall neurodevelopmental disabilities (OR 1.09, 95% CI 0.76 to 1.57, p=0.63). CONCLUSIONS: In children born before 32 weeks' gestation, doxapram treatment for apnoea of prematurity was not associated with neurodevelopmental disabilities.

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.

Neurodevelopment and healthcare utilisation at age 5-6 years in bronchopulmonary dysplasia: an EPIPAGE-2 cohort study.

OBJECTIVE: We aimed to study neurodevelopmental outcomes and healthcare utilisation at age 5-6 years in very preterm children with bronchopulmonary dysplasia (BPD). DESIGN: Prospective and national population-based study. SETTING: All the neonatal units in 25 French regions (21 of the 22 metropolitan regions and 4 overseas regions). PATIENTS: Children born before 32 weeks' gestation in 2011. INTERVENTIONS: Blind, comprehensive and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years. MAIN OUTCOME MEASURES: Overall neurodevelopmental disabilities, behavioural difficulties, developmental coordination disorders, full-scale IQ, cerebral palsy, social interaction disorders, rehospitalisation in the previous 12 months and detailed developmental support. RESULTS: Of the 3186 children included, 413 (11.7%) had BPD. The median gestational age of children with BPD was 27 weeks (IQR 26.0-28.0) and without BPD was 30 weeks (28.0-31.0). At age 5-6 years, 3150 children were alive; 1914 (60.8%) had a complete assessment. BPD was strongly associated with mild, moderate and severe overall neurodevelopmental disabilities (OR 1.49, 95% CI 1.05 to 2.20; 2.20, 1.41 to 3.42 and 2.71, 1.67 to 4.40). BPD was associated with developmental coordination disorders, behavioural difficulties, lower IQ score as well as rehospitalisation in the last 12 months and developmental support. The association between BPD and cerebral palsy was statistically significant before adjustment but not in adjusted analyses. CONCLUSIONS: BPD was strongly and independently associated with many neurodevelopmental disabilities. Improving medical and neurodevelopmental management of BPD in very preterm children should be a priority to reduce its long-term consequences.