BMJ · Véronique Pierrat1, 2, Laetitia Marchand-Martin 1, Catherine Arnaud 3, Monique Kaminski1, Matthieu Resche- Rigon 4 , Cécile Lebeaux 1 , Florence Bodeau-Livinec 1,5 , François

Confidential: For Review O

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Neurodevelopmental outcome at 2 years for preterm

children born at 22 to 34 weeks’ gestation in France in 2011: The EPIPAGE-2 cohort study.

Journal: BMJ

Manuscript ID BMJ.2017.037914

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 16-Feb-2017

Complete List of Authors: PIERRAT, Veronique; Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), , ; CHU Lille, Department of Neonatal Medicine, Jeanne de Flandre Hospital, F-59000 Lille, France, Neonatal Medicine Marchand-Martin, laetitia; Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France Arnaud, Catherine; INSERM UMR1027, Kaminski, Monique; INSERM, Hôpital Tenon, Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France Resche Rigon, Matthieu; Hopital Saint Louis, Department of Biostatistics et Medical Informatics lebeaux, cecile; Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France Bodeau-Livinec, Florence; Ecole des Hautes Etudes en Santé Publique (EHESP) Rennes, Sorbonne Paris Cité, France Goffinet, François; Port-Royal Maternity Unit, Department of Obstetrics and Gynaecology, Cochin University Hospital, Assistance Publique Hôpitaux de Paris; Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France Marret, Stephane; Department of Neonatal medicine - Intensive care - Neuropediatrics, Rouen University Hospital, Rouen France. ; INSERM U 1254 - Neovasc team - Perinatal handicap, Institute of Biomedical Research and Innovation, Normandy University, Rouen, France Ancel, Pierre-Yves; INSERM, Hôpital Tenon, UMR 953, Epidemiological Research in Perinatal Health and Women’s and Children Health,; Clinical Research Unit, Center for Clinical Investigation P1419, Cochin Broca Hôtel-Dieu Hospital, Paris, France astruc, dominique; University Hospital of Strasbourg, France Kuhn, Pierre; University Hospital of Strasbourg

https://mc.manuscriptcentral.com/bmj

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nlyMatis, Jacqueline; University Hospital of Strasbourg Joly, Laurence; University Hospital, Bordeaux Mazeiras, Gael; Department of Neonatology, La Côte Basque Hospital david, alexandra; Department of Neonatology, University Hospital of Pau, lecomte, benedicte; University Hospital Estaing, Clermont-Ferrand Vendittelli, Francoise; Clermont Université, Université d\'Auvergne, EA 4681 PEPRADE, EA 4681 PEPRADE; Service de Santé Publique, Centre Hospitalier Universitaire de Clermont Ferrand, Santé Publique datin-dorriere, valerie; Department of Neonatology, University Hospital of Caen guillois, bernard; Department of Neonatology, University Hospital of Caen, University of Caen Normandie, UFR de Médecine, PFRS, Caen, France Burguet, Antoine; University Hospiyal Dijon Sagot, Paul; CHU de Dijon, Service de Gynécologie Obstétrique Roué, Jean-Michel; CHRU de Brest beuchee, Alain; Department of Neonatology and CIC Inserm 1414; University Hospital of Rennes, Rennes1 University, Rennes Rouget, Florence; Department of Pediatrics, University Hospital, Inserm-Irset U 1085, Rennes saliba, elie; University Hospital of Tours, INSERM U 930, Neonatal Intensive Care, François Rabelais University of Tours - CHU Clocheville Favreau, Amelie; University Hospital of Tours, Neonatology, CHU Clocheville Bednarek, Nathalie; Department of Neonatal Pediatrics, University Hospital, Reims Loron, gauthier; Department of Neonatal Pediatrics, University Hospital, Reims mougey, clemence; Department of Neonatology, University Hospital of Besançon Thiriez, Gerard; Department of Neonatology, University Hospital of Besançon lardennois, caroline; Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital, Rouen bruel, henri; Department of Neonatal Pediatrics, Jacques Monod Hospital, Le Havre Durrmeyer, Xavier; Department of Neonatal Pediatrics and Intensive Care, CHI, CRC, Créteil Granier, Michèle; Hopital Sud Francilien, NICU Boileau, Pascal; Inserm U1153 , Equipe de recherche en Epidémiologie Obstétricale, Périnatale et Pédiatrique (EPOPé), Centre de Recherche Epidémiologie et Biostatistique Sorbonne Paris Cité (CRESS), Université Paris Descartes Kayem, Gilles; Department of Obstetrics and Gynecology, Trousseau Hospital, APHP, Paris, France; Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in pregnancy, Paris Descartes University Carbajal, Ricardo; AP-HP, HOPITAL TROUSSEAU, Service des Urgences Pédiatriques lapillonne, alexandre; Department of Neonatology, Paris Descartes University, APHP Necker Hospital, Paris Jarreau, Pierre-Henri; Service de Médecine et Réanimation Néonatales de Port-Royal, Hôpitaux Universitaire Paris Centre Site Cochin, Université Paris V René Descartes and Assistance Publique Hôpitaux de Paris Cambonie, Gilles; Department of Neonatal Medicine, Arnaud de Villeneuve Hospital, Montpellier University Hospital, souski-medioni, isabelle; Department of Neonatal Medicine, Caremeau Hospital, Nîmes Menguy, Anne-Claude; Department of Neonatal Medicine, St Jean Hospital, Perpignan General Hospital Bedu, Antoine; Department of neonatal pediatrics and intensive care,

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nlyLimoges University Hospital Mons, Fabienne; Department of neonatal pediatrics and intensive care, Limoges University Hospital valdes, valérie; Department of neonatal pediatrics and intensive care, Adolphe Pinard Maternity Unit, Nancy Fresson, Jeanne; Réseau Périnatal Lorrain, Nancy, France; Department of Medical Information, University Hospital of Nancy alberge, corinne; Children Intensive Care unit, University Hospital, Toulouse, France. INSERM U 1027 INSERM, Toulouse, France. Paul-Sabatier University, Toulouse Dicky, Odile; Department of Neonatology, University Hospital, Toulouse, France, INSERM U 1027 INSERM, Toulouse, France.Paul-Sabatier University Truffert, Patrick; CHU Lille, Department of Neonatal Medicine, Jeanne de Flandre Hospital, F-59000 Lille mitha, Ayoub; CHU Lille, Department of Neonatal Medicine, Jeanne de Flandre Hospital, F-59000 Lille Charkaluk, Marie-Laure; INSERM UMR 1153, Obstretrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in Pregnancy, Paris Descartes University, Paris, France; UCLille, F-59000 Lille, France; Service de Néonatologie, Hôpital Saint Vincent de Paul, Groupement des Hôpitaux de l'Institut Catholique Lillois/Faculté de Médecine et Maïeutique, F-59000 Lille gire, catherine; Department of Neonatal Pediatrics and Intensive Care, Nord Hospital, Marseille Boubred, Farid; Department of Neonatal Pediatrics and Intensive Care, Conception Hospital, Marseille dercole, Claude; Department of Gynecology and Obstetrics, Nord Hospital, Marseille BONGAIN, André; University Hospital, Department of Obstetric And Gynecology Rozé, Jean-Cristophe; Nantes University Hospital, Department of paediatric medicine FLAMANT, Cyril; CHU Hopital Mere Enfant, Gascouin, Geraldine; Angers University Hospital, Department of Neonatalogy leke, Andre; PériTox UMI-01, Université de Picardie Jules Verne, Department of Neonatal Pediatrics and Intensive Care, University Hospital of Amiens Goudjil, sabrina; GRAMFC Inserm U1105, Université de Picardie Jules Verne, Department of Neonatal Pediatrics and Intensive Care, University Hospital of Amiens Debeir, Michel; Department of Pediatrics, Chambéry Claris, Olivier; Hôpital Edouard Herriot, Department of Neonatal Medicine Picaud, Jean-Charles; Lyon University Hospital Centre, Neonatology Debillon, Thierry; Grenoble Alps University, CNRS, TIMC-IMAG, UMR 5525 ThEMAS, F38041 Grenoble, France; Neonatal Intensive Care Unit, Grenoble University Hospital, Grenoble Patural, Hugues; Saint-Étienne University Hospital poulichet, anne; Department of Neonatology, University Hospital of Pointe à Pitre, French West Indies, Guadeloupe Abrial, Aude; Department of Neonatology, University Hospital of Pointe à Pitre, French West Indies, Guadeloupe, France Favre, Anne; Department of Neonatal Pediatrics and Intensive Care, Andrée Rosemon Hospital, Cayenne Buende, Sophie; Hospital of Saint Laurent du Maroni, Guyane Flechelles, olivier; University Hospital, Fort de France, Martinique ramful, duksha; Pediatric and Neonatal Intensive Care Unit, Félix Guyon University Hospital, Saint-Denis, Reunion Island; INSERM, CIC 1410, Saint-Pierre, Reunion Island

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nlyRobillard, Pierre-Yves; Centre Hospitalier Universitaire Sud-Réunion, Neonatology, Perinatal Epidemiology Benhammou , Valérie; Inserm U1153 , Equipe de recherche en Epidémiologie Obstétricale, Périnatale et Pédiatrique (EPOPé), Centre de Recherche Epidémiologie et Biostatistique Sorbonne Paris Cité (CRESS), Université Paris Descartes Morgan, Andrei; Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France

Keywords: preterm infant; cohort study; cerebral palsy; developmental disabilities

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Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks’ gestation in

France in 2011: The EPIPAGE-2 cohort study.

Véronique Pierrat1, 2, Laetitia Marchand-Martin1, Catherine Arnaud3, Monique Kaminski1, Matthieu Resche-Rigon4, Cécile Lebeaux1, Florence Bodeau-Livinec 1,5, François Goffinet1, 6, Stéphane Marret7,8, Pierre-Yves Ancel1,9 and the EPIPAGE-2 writing group.

1. Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France

2. CHU Lille, Department of Neonatal Medicine, Jeanne de Flandre Hospital, F-59000 Lille, France

3. Inserm U 1027, F-31000 France; Paul-Sabatier University, Toulouse, F-31400 France; Purpan, Clinical epidemiology Unit, Toulouse, F-31300 France

4. Biostatistics and Medical Information Department, AP-HP Saint-Louis Hospital, Paris, France. ECSTRA Clinical Epidemiology and Statistics for Applied Research Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), Inserm, Paris, France; Paris Diderot - Paris 7, Paris, France

5. Ecole des Hautes Etudes en Santé Publique (EHESP) Rennes, Sorbonne Paris Cité, France

6. Maternité Port-Royal, Université Paris Descartes, Groupe Hospitalier Cochin Broca Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, DHU Risques et Grossesse, Paris, France.

7. Department of Neonatal medicine - Intensive care - Neuropediatrics, Rouen University Hospital, Rouen France

8. INSERM U 1254 - Neovasc team - Perinatal handicap, Institute of Biomedical Research and Innovation, Normandy University, Rouen, France.

9. Clinical Research Unit, Center for Clinical Investigation P1419, Cochin Broca Hôtel-Dieu Hospital, Paris, France

Corresponding author:

Véronique Pierrat

Obstetrical, Perinatal, and Pediatric Epidemiology Team (EPOPé), Inserm U 1153

Bâtiment Recherche, Hôpital Tenon

4 Rue de la Chine

75020 Paris

France

Email: [email protected]

Keywords: preterm infant; cohort study; cerebral palsy; developmental disabilities.

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ABSTRACT

Objectives To describe outcomes of neonates born from 22-34 weeks’ gestation (WG) in 2011 and to evaluate changes since 1997.

Design Population-based cohort studies, EPIPAGE and EPIPAGE-2

Setting France

Participants 5170 neonates born alive in 2011 at 22-34 completed WG, with 4199 children surviving at 2 years corrected age (CA) and included in the follow-up. Comparison of outcomes reported for 3334 (1997) and 2418 (2011) neonates born alive in the 9 French regions participating in both studies.

Main outcome measures Survival; cerebral palsy (2000 European consensus definition); failure on the neurodevelopmental Ages and Stages Questionnaire (ASQ; at least one of 5 domains showing failure) if completed between 22 and 26 months CA, in children without cerebral palsy, blindness or deafness; and survival without severe/moderate neuro-motor or sensory disabilities (cerebral palsy with Gross Motor Function Classification System levels 2-5, uni- or bilateral blindness or deafness). Results are given as percentage of outcome measures with exact binomial 95% confidence intervals.

Results Among neonates born at 22-31 and 32-34 WG, survival at 2 years CA was 84.3% (83.2 to 85.4) and 98.6% (97.8 to 99.2). None of the infants born at 22-23 weeks survived. Data on cerebral palsy were available for 3599 infants (86% of the eligible population). The overall rate of cerebral palsy at 24-31 and 32-34 WG was 4.6% (3.9 to 5.5) and 1.0% (0.5 to 1.9) (p <. 001). Data for ASQs analysis were available for 2637 children (63% of the eligible population). The proportion of children with ASQ failure at 24-26, 27-31 and 32-34 WG were 50.2% (44.5 to 55.8), 40.7% (38.3 to 43.2) and 36.2% (32.4 to 40.1), respectively (p<0.001). Communication was the most frequently failed domain for each gestational age group. Survival without severe/moderate neuro-motor or sensory disabilities among live births at 22-31 WG increased from 1997 to 2011, from 74.6% (72.7 to 76.5) to 80.5% (78.7 to 82.3) (p<0.001). At 32-34 WG, the proportion of children with cerebral palsy had declined (p=0.004).

Conclusions Although rates of survival and survival without severe/moderate neuro-motor or sensory disabilities in children born preterm have improved in France during the past 2 decades, these children remain at high risk of developmental delay. Standardized follow-up with post-discharge interventions may improve outcomes and needs further evaluation.

Words: 373

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What is already known on this topic

Survival of preterm neonates has increased all over the world, with a concomitant decrease in severe neonatal morbidities

Preterm neonates remain at high risk of neurodevelopmental sequelae, but the outcome of neonates born very and moderately preterm in the 2000s has rarely been reported.

For children born at extremely low gestational ages, neurodevelopmental outcomes have been mainly described in the context of active perinatal care.

What this study adds

In France from 1997 to 2001, severe neonatal morbidities in children born preterm decreased, accompanied by a significant increase in survival without severe/moderate neuro-motor or sensory disabilities at age 2 years and a decrease in cerebral palsy rates by half.

Despite improvements in outcomes, a high risk of developmental delay persisted for all children born preterm, which suggests the need to include all preterm children in structured follow-up programs.

In a national context of non-active intervention for infants at extremely low gestational age, rates of survival and survival without severe disabilities are low as compared to countries with active perinatal care.

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INTRODUCTION

Survival of preterm babies has increased all over the world, with a concomitant decrease in severe neonatal

morbidity. 1–4 However, the risk of neurodevelopmental and behavioural disabilities remains high in children

5–10 and adults11–13born preterm. At extremely low gestation (< 27 weeks’ gestation (WG)), ethical questions

are crucial, and most the recent national cohort studies have focused on extremely preterm birth. 8 14–17 In

absolute numbers, infants born very (27-31 WG) and moderately preterm (32-34 WG) represent a larger

proportion of preterm births accounting for more children with motor/cognitive/behavioural deficits and

learning disabilities.18 19

These populations of very and moderately preterm neonates have been poorly investigated in the post-

surfactant era, but knowledge of specific developmental domains affected at preschool age could lead to

targeted intervention and prevention of later disabilities. For infants born at extremely low gestation, a

consistent theme in the literature is that increased survival may come at the expense of increased long-term

sequelae 20 with controversies focused on treatment decisions. 21 A 2010 European survey exploring

national guidelines of resuscitation for infants born at 22-25 WG found little consensus on how care is

managed. 22 As in seven other European countries, 22 France favoured non-intervention for infants born

before 24 WG, 23 24 with provision of comfort care until death for those born alive. 25 26

We need updated information on outcomes for infants born at different gestational ages (GAs) and in

different settings to guide health policy, advise physicians in perinatal management, provide comprehensive

information to facilitate parents’ involvement in shared-decision-making, and benchmark outcomes.27 The

original EPIPAGE cohort collected data on all very preterm births in 9 French regions during 1997 and

assessed the surviving children at age 5 and 8 years.18 19 The 2011 EPIPAGE-2 cohort is a national cohort,

designed to investigate outcomes and their changes over the past 15 years for children born from 22 to 34

WG.28 Substantial improvements in neonatal survival, accompanied by a large reduction in severe neonatal

morbidity, has already been reported although survival remained low before 25 WG 2 as compared to other

countries.1 3 29

In the present study, we analysed neuro-motor, sensory and neurodevelopmental outcomes at 2 years

corrected age (CA) for children born alive from 22 to 34 WG included in the EPIPAGE-2 cohort. We

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compared rates of survival, survival without neuro-motor and sensory disabilities and cerebral palsy (CP)

with children born alive in 1997.

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METHODS

Study design

EPIPAGE-2 is a prospective national population-based cohort scheduled to follow preterm children up to the

age of 12 years. Infants born at 22 to 34 completed WG in France were eligible for inclusion. The study

began on March 28, 2011. Recruitment took place at birth in all maternity units. Infants born at 22 to 26 WG

were recruited during an 8-month period, those born at 27 to 31 WG during a 6-month period and those born

at 32-34 WG, during a 5-week period. 28

Population

At recruitment, parents of 5170 preterm infants, born alive at 22-34 WG, agreed to participate in the study.

All survivors (n=4467) were enrolled for longitudinal follow-up; 24 died after discharge and parents of 244

declined further participation. Thus, 4199 children were included in follow-up.

Patient involvement

Patients were not involved in setting the research question or the outcome measures, nor were they involved

in developing plans for design of the study. Implementation at 2 years was supported by parents’

associations. Parents demonstrated overwhelming support for the study through high follow-up rates and by

providing testimonials (displayed on the EPIPAGE-2 website at https://epipage2.inserm.fr/index.php/fr/cote-

parents/temoignages). EPIPAGE-2 maintains contact with parents in the cohort through newsletters, letters,

and its website. National parent’s associations assisted with the dissemination of the results.

Data collection and evaluation methods

Data for children at 2 years CA were collected by using two standardized questionnaires, one completed by

the referring physician and the other by the parents.

CP and sensory deficits

For children at 2 years CA, results of a detailed neurologic examination, performed by the referring

physician (neonatologist, paediatrician or general practitioner), were reported in the pre-coded physician

questionnaire. CP was defined according to the diagnostic criteria of the Surveillance of Cerebral Palsy in

Europe (SCPE) network,30 and motor ability was graded by using the 5-level Gross Motor Function

Classification System (GMFCS).31

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Data on vision and hearing were obtained from medical reports available during the medical examination.

Visual impairment was classified as severe (bilateral) or moderate (unilateral) in case of blindness.

Squinting and the need for glasses were also recorded. Auditory impairment was classified as severe

(bilateral) or moderate (unilateral) in case of deafness. Severe neuro-motor or sensory disabilities included

any of non-ambulatory CP (GMFCS level 3- 5) or severe visual or auditory impairment; moderate disability

included GMFCS-level 2 CP and/or moderate visual or auditory impairment.

Overall neurodevelopment

The child’s development was assessed with the second version of the 24-month Ages and Stages

Questionnaire (ASQ)32 validated in France33 and completed by parents; data were analysed if completed

between 22 and 26 months CA in children without CP, deafness, blindness or severe congenital brain

malformations. Each questionnaire includes 30 items covering 5 developmental domains: communication

abilities, gross motor skills, fine motor skills, problem-solving abilities and personal-social skills. Items are

scored on a 3-point scale depending on whether the child performs the task: “Yes” (10 points), “Sometimes”

(5 points) or “Not yet” (0 points). Responses are summed to give a score of 0 to 60 per domain and an

overall maximum ASQ score of 300 points. Analyses were based on 1) total ASQ score, using a cut-off of

220, to identify children at risk of a developmental quotient (DQ) < 85 (sensitivity 85%, specificity 72%);33

and 2) domain specific scores, compared with established screening cut-off points, to define ASQ failure as

a score of less than 2 SDs below the mean on any of the 5 domains (sensitivity 87%, specificity 77% for DQ

< 85).32 We also report the number and nature of domains with failure.

Other significant disabilities at 2 years CA

Significant disabilities affecting respiratory or gastrointestinal systems were recorded. Respiratory disability

was defined as the need for continuous respiratory support or oxygen and gastrointestinal disability as the

need for parenteral nutrition and/or enteral feeding through a nasogastric tube or gastrostomy.34

Comparison of the 1997 and 2011 EPIPAGE cohorts

Children eligible for comparison were those born alive at 22-34 WG from the 1997 and 2011 cohorts in the

9 regions participating in both studies.35 Outcome measures at 2 years CA were rates of survival, survival

without severe/moderate neuro-motor or sensory disabilities among live births, and CP among survivors.

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Data management and statistics

Results are presented for each GA group (22-26, 27-31 and 32-34 WG), and by week for those born at 22-

26 WG. First, summary data on maternal, obstetric and neonatal characteristics are presented for the 3 GA

groups and compared with those lost to follow-up. Second, for children examined at 2 years CA,

percentages of CP and visual and hearing impairments are presented, as are percentages of low ASQ scores

and ASQ failure. Third, rates of total survival and survival without severe/moderate neuro-motor and

sensory disabilities among live births are reported. Survival, CP and ASQ results are presented for complete

cases; sensitivity analyses were performed with multiple imputations and by inverse-probability weighting

to account for selective dropouts and missing information at 2 years CA. Management of missing data is

presented in supplemental file 3. Fourth, to document trends over time, we compared 1997 and 2011 rates of

survival, survival without severe/moderate neuro-motor or sensory disabilities among live births and CP

among survivors. Cohort data were obtained from the entire year in 1997 and from March 28 to December

31 in 2011. Analyses for 1997 were run for the entire year and then separately for April to December.

Results did not differ, and thus1997 data are presented for the whole year. Finally, factors associated with

CP or ASQ failure were studied for complete cases by using multiple logistic models. Variables entered into

the models were GA, sex, single or multiple pregnancies, small-for-gestational age (SGA) defined as birth

weight <10th percentile for GA and sex based on French intrauterine growth “EPOPé” curves 36 and parents’

socioeconomic status defined as the highest occupational status for occupations of the mother and the father,

or mother only if a single parent.

Percentages are given with their exact 95% binomial confidence intervals and medians (interquartile ranges

(IQR)). For analyses performed on the overall cohort, we used weighted percentages and GA adjustments in

the multivariable analysis to account for differences in sampling between GA groups. We compared groups

of infants using a Chi-squared test. All tests were two-sided; p < .05 was considered statistically significant.

Statistical analyses were performed using SAS v9.4 software.

Ethics

Recruitment and data collection occurred only after families had received information and agreed to

participate in the study. This study was approved by the National Data Protection Authority (CNIL

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no.911009) and by appropriate ethics committees (Consultative Committee on the Treatment of Data on

Personal Health for Research Purposes - reference no. 10.626, Committee for the Protection of People

Participating in Biomedical Research - reference CPP SC-2873).

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RESULTS

EPIPAGE-2: neurodevelopmental outcomes and overall survival at 2 years CA

Population

Among 4199 children included in the current study, physician questionnaires were available for 3600 (81%

of the eligible children/86% of children with parental consent for follow-up) and parental questionnaires for

3689 (83% of eligible children/88% of those with consent) (Figure 1). All but one neonate born at 22-23

WG (n= 148) died in the neonatal period. This survivor was born at 23 WG and 6 days and was therefore

included with those born at 24 WG.

Characteristics of children with a 24-month physician evaluation are described in supplemental table 1 and

comparisons between responders and non-responders to physician and parental questionnaires are in

supplemental table 2. Non-responders were more frequently born after 31 WG, to younger mothers or

mothers born outside France, to parents with a lower socio-economic level, and less frequently fed

breastmilk at discharge than responders; however, the main neonatal outcomes did not differ between

groups.

CP and sensory outcomes

Physician examinations were performed at a median of 24.2 months CA (IQR 23.1 to 25.7). CP information

was available from 3599/3600 questionnaires. CP was diagnosed in 137 children: bilateral spastic CP in 120

(88.3%), unilateral spastic CP in 15 (10.0%) and dyskinetic or unclassifiable CP in 2. The overall rate of CP

was 4.6% at 24-31 WG, decreasing from 6.9% to 4.3% between 24-26 and 27-31 WG. At 32-34 WG, the CP

rate was 1.0% (Table 1). Severe auditory or visual impairment was reported in less than 1% of children. The

proportion of children wearing glasses decreased with increasing GA.

Overall, the rate of severe/moderate neuro-motor or sensory disabilities decreased from 6.0% at 24-26 WG

to 3.2% at 27-31 WG and 1.0% at 32-34 WG.

Neurodevelopmental outcome

Parental questionnaires were collected at a median of 24.3 months CA (IQR 23.5 to 26.3). Among the 3689

parental questionnaires available, analysis of ASQ was possible for 2637 children (59% of the eligible

children/63% of those with consent). 131 questionnaires were excluded because of CP, deafness or blindness

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(n=121), or severe congenital brain malformations (n= 10), leaving 2506 questionnaires in the complete-case

analysis. Median ASQ scores increased from 223 at 24-26 WG to 235 at 32-34 WG (Table 2). A low total

score was observed in 38.1% of children born at 24-31 WG and 34.7% of those born at 32-34 WG; 42.0%

and 36.2%, respectively, showed failure in at least one ASQ domain. Median total scores by number of

domains showing failure are shown in supplemental figure 1. Most children failed only 1 domain of the

ASQ but a substantial proportion of children born extremely preterm (24-26 WG; 7.7%) failed 4or 5

domains. The most frequently failed domains were communication and personal-social in all GA groups.

Proportions of children showing failure in either of these domains decreased with increasing GA but were

still 17.8% and 13.3%, respectively, at 32-34 WG. Although children with CP were excluded, 16.6% of

children born at 24-26 WG showed failed in the gross motor domain as compared with 5.1% at 32-34 WG.

Other significant disabilities

Nine children born at 24 to 31 WG (0.3% (0.1 to 0.6)) still needed oxygen at 2 years CA, 28 (1%, (0.6 to

1.4)) received enteral nutrition by tube or gastrostomy and 3 (0.1%, (0 to 0.3)) parenteral nutrition. The

proportion of children fed by tube or gastrostomy was 2.7% (1.4 to 4.7) at 24-26 WG and 0.7% (0.4 to 1.2)

at 27-31 WG. Overall, 11children (0.4% (0.2 to 0.8)) had respiratory or gastrointestinal disabilities

associated with CP and/or deafness or blindness. Less than 0.5% of children born at 32-34 WG had

respiratory or gastrointestinal disabilities.

Overall survival at 2 years CA and dropout analyses

Among live births, survival at 2 years CA increased with increasing GA and, after multiple imputations,

survival without severe/moderate neuro-motor and sensory disabilities was 48.5%, 90.0 % and 97.5% at 24-

26, 27-31 and 32-34 WG, respectively (Table 3). Among survivors at 2 years CA, rates of CP were only

slightly modified after multiple imputation, but rates of ASQ failure increased in each GA range. Results of

sensitivity analyses are shown in supplemental table 3. Outcomes for children born at 22-26 WG are

presented by gestational week in supplemental table 4.

Comparison of outcomes in children born in 1997 and 2011 (9 regions)

Neonates born alive at 22-34 WG in the 9 regions participating in both EPIPAGE studies totalled 3334 in

1997 and 2418 in 2011; 2262 (1997) and 1696 (2011) were alive at 2 years CA with outcome data available.

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No infant born at 22-23 WG survived in either period. Children born at 25-34 WG but not those born at 24

WG showed a substantial improvement in survival and survival without neuro-motor or sensory impairment.

The same trend was found for rates of CP among survivors (Figure 2). At 32-34 WG, survival and survival

without severe neuro-motor or sensory impairment tended to improve and rates of CP markedly declined

(supplemental table 5).

Factors associated with CP and ASQ failure in the EPIPAGE-2 cohort

We examined factors associated with CP and ASQ failure in children born at 24-31 WG (Table 4). GA was

the only significant predictor of CP; male sex, SGA and low parental socioeconomic status increased the

risk of ASQ failure. For those born at 32-34 WG, there were insufficient cases of CP to study factors

associated with CP; only SGA and low parental socioeconomic status were associated with ASQ failure

(supplemental table 6).

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DISCUSSION

In this French population-based cohort of neonates born at 22-34 WG, we found a marked improvement in

rates of survival and survival without severe/moderate neuro-motor and sensory disabilities at 2 years CA

between 1997 and 2011 from 25 WG onward. The overall rate of CP decreased by half and, in 2011, a large

proportion of children with CP were mildly impaired (GMFCS level-1). However, after excluding children

with CP, blindness, deafness or severe congenital brain malformations, 42% of those born at 24-31 WG and

36% of those born at 32-34 WG showed ASQ failure and were considered at risk of developmental delay.

Failures in the ASQ communication and personal-social domains were the most commonly observed.

The strengths of the EPIPAGE-2 study include the population-based cohort design, at a national level, with

prospective enrolment of a large number of infants born extremely but also very and moderately preterm,

whose outcome has been infrequently reported in the post-surfactant era. We used standardized definitions

of outcomes following international recommendations 27 and allowing comparisons with other international

cohorts. In addition, we were able to obtain face-to-face assessments to diagnose CP and we explored the

full range of development with the ASQ to better understand the profiles of development by GA group.

The main limitation of the study was the number of children lost to follow-up, although the follow-up rate

was high in terms of the size of the cohort. Results from other studies37 suggest an excess of poorly

performing children among those not evaluated because children from more disadvantaged families are

more often non-responders. The proportion of children with severe overall impairment did not vary by

socioeconomic status, but underestimation of children with moderate cognitive impairment is usually

observed.15 We also found a social bias in participation. Several strategies were tested to account for missing

data. Using multiple imputations did not modify the rate of CP but demonstrated a consistent increase across

GA groups in the proportion of children showing ASQ failure. Whichever strategy was used, the magnitude

of the difference between the 3 preterm groups was similar. Another limitation is the lack of cognitive

evaluation, considered the most difficult area to assess at age 2 years. We used the ASQ, a parent-based

developmental questionnaire, reported as useful to identify children at risk of a DQ< 85.38 The correlation

between the ASQ score and a standardized, professionally administered developmental test score is higher in

preterm than term born children39 and increases with increasing age at assessment. Two years seems a

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reliable period to assess neurodevelopment with the ASQ.33 40 However, because the ASQ is not a diagnostic

instrument, we did not include these results, as a marker of cognition, in a composite impairment score,

which limits comparison with other findings.8 14 15

CP rates greatly decreased in all GA categories from 25 WG onward. These results are consistent with those

of CP registers describing decreased prevalence of CP over time, and a substantial reduction in the most

severe forms, especially in very and moderately low-birth-weight neonates.41–43 As for other cohorts based

on GA5, we did not find a reduction in the most severe forms (data not shown), but the number of children

with severe CP was too small to observe such a difference. The decrease in the rate of CP provides “real

world” additional evidence for the effectiveness of strategies adopted in the perinatal period including

increased use of antenatal steroids, caesarean deliveries, and surfactant and decreased use of postnatal

corticosteroids, concomitant with an overall decrease in severe neonatal morbidities, 2 although the

respective role of each strategy is unknown.42

The proportion of children with ASQ failure was high in our cohort. On the basis of ASQ-3 reference

values, 12% to 17% of children from the general population are considered to need further evaluation in one

developmental domain at 2 years.32 44 Higher proportions have been found in children born preterm at the

same age: 41% of those born before 28 WG and 22% at 28-31 WG in a Dutch hospital-based cohort 45; 46%

in a French regional-based cohort of children born at less than 32 WG.33 Nevertheless ASQ-3 identifies

more children at risk of developmental delay than those diagnosed with professionally administered

psychometric tests.45 The risk of potential over-identification has been widely debated, but children with

suspected delay may represent a group at risk for future academic difficulties and could require dedicated

support systems.46 In each GA group, communication was the most frequent failed domain, followed by the

personal-social domain. For children born at 32-34 WG, the proportion with a failed communication score

was still 17%. The question of intervention is crucial in this later group. In the Bavarian Longitudinal Study,

stability of poor language performance from 20 months to 8 years of age was greater for preterm than term

children.47 In many countries, children born moderately preterm are excluded from systematic monitoring of

neurodevelopment. Given the high prevalence of births after 31 WG, identifying early the children at risk of

later difficulties to propose targeted interventions may have a broad impact on learning disabilities.

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Compared to countries with active resuscitation in cases of extremely low GA,3 48 or with individual

assessment of the infant’s condition at birth,5 rates of survival and survival without severe/moderate neuro-

motor or sensory disabilities in France were poor for children born at 24 WG and earlier, with no

improvement between 1997 and 2011. In The Netherlands, where perinatal care at extremely low gestation

is comparable to that in France22, the proportion of children with severe/moderate disabilities at 2 years was

higher than those reported in France but included children with cognitive impairments.49 In France, rate of

CP for children born at 24-26 WG showed no clear trend, with an overall rate of 7%. Reported rates of CP in

surviving infants born at 22-26 WG vary from 7% in Sweden14, 10% in Australia8 to14% in the United

Kingdom5. Reporting sensory outcomes at extremely low gestation is also essential because impairment

increases with decreasing GA and with age, in particular for visual impairment. Less than 1.5% of the

children born at 22 to 26 WG showed severe sensory impairments. In the EXPRESS cohort, the frequencies

of blindness and visual impairment increased between 30 months’ CA14 and 6.5 years, with children born

before 25WG showing the highest risk of visual problems.50 Compared to children born at 27-31 or 32-34

WG, a higher proportion of children born at 24-26 WG showed ASQ failure in the gross motor domain.

Most children showed failure on the most complex gross motor items: “jump with both feet” (Not yet =93%)

and “kicking a ball” (“Not yet” or “sometimes” = 78%) (Data not shown). Some of these children will be

likely identified later as children with developmental coordination disorders.51 Comparisons with cohorts

involving psychometric tests are difficult. In EPICure-25 at 36 months and EXPRESS14 at 30 months, more

than 80% of the children were considered to have normal cognitive development or only mild cognitive

impairment. However the predictive value of the Bayley-III for later IQ and long term outcome is still

debated.52 In the EPICure-2 cohort, use of the mental developmental index of the Bayley-II instead of the

Bayley-III resulted in a significant reduction in the proportion of children with scores in the normal range,

from 80% to 65%5, which appears more in accordance with our results.

Context of the study

This study aimed to describe outcomes at 2 years CA in a large group of preterm babies, born at 22-34 WG.

The proportion of infants at risk of developmental delay was high, even for those born at 32-34WG, which

supports the proposal that all preterm neonates should be included in follow-up networks. Children lost to

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follow-up are at increased risk of developmental problems, and how to include these children into follow-up

systems is a real question. Besides the development of follow-up organization is the question of the

intervention itself. The wide range of domains showing failure should favour multifaceted neonatal and

post-discharge intervention programs. The sustainability of outcome improvement related to interventions is

still debated, but post-discharge interventions aimed at strengthening parents’ well-being and sensitive-

responsive parenting to the child may help improve outcomes over time. 53,54

This study was embedded in an extensive description of practices around birth at extremely low gestation in

a country where active perinatal intervention is not recommended.25 Our results suggest that despite “pre-

selection” of “low-risk” extremely preterm patients for active treatment, neurodevelopmental outcomes did

not differ greatly from those observed in countries with recommended active treatment.6 15 48 They invite

questioning perinatal strategies in countries with similar recommendations. However, improving outcomes

at extremely low GA requires a complex change in philosophy of care and close cooperation not only

between obstetricians and neonatologists, but also developmental specialists, parent associations and

policymakers. Efficient regionalized referral systems and antenatal steroids are usually the main focus of

intervention advocated to improve outcome,55 but countries reporting better outcomes also differ in quality

of family-centred care and follow-up organization.14

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CONCLUSION

In this national population-based cohort of preterm neonates, we showed improvements in survival at 2

years without neuro-motor disabilities in each GA group. The rate of CP decreased by half, but the risk of

developmental delay was high, even in children born moderately preterm. Several neurodevelopmental

domains appear altered, favouring multifaceted interventions. However, strategies to improve long-term

outcomes in these populations need further evaluation.

Words: 4000

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Contributors: VP, LMM and PYA had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. VP, CA, MK, FBL and SM conceptualized the study and wrote the manuscript. LMM and MRR performed the statistical analysis. CL coordinated data collection and had responsibility for technical support. PYA obtained funding and supervised the study. All authors contributed to the plan analysis and interpretation of the results, and reviewed and approved the final manuscript. All members of the writing group were involved in the regional organisation for data collection, reviewed and approved the final manuscript.

EPIPAGE-2 writing group

D. Astruc, University Hospital of Strasbourg, France, P. Kuhn, University Hospital of Strasbourg, France, J. Matis, University Hospital of Strasbourg, France, L. Joly, Department of Neonatology, University Hospital, Bordeaux, France, G. Mazeira, Department of Neonatology, La Côte Basque Hospital, Bayonne, France, A. David, Department of Neonatology, University Hospital of Pau, France, B. Lecomte, University Hospital Estaing, Clermont-Ferrand, France, F. Vendittelli, University Hospital Estaing, Clermont-Ferrand, France, V. Datin-Dorriere, Department of Neonatology, University Hospital of Caen, France, B. Guillois, Department of Neonatology, University Hospital of Caen, University of Caen Normandie, UFR de Médecine, PFRS, Caen, France, A. Burguet, Department of Neonatal Pediatrics, University Hospital, Dijon, France, P. Sagot, Department of Gynecology and Obstetrics, University Hospital, Dijon, France, JM. Roué, University Hospital Brest, France, A. Beuchée, Department of Neonatology and CIC Inserm 1414; University Hospital of Rennes, Rennes1 University, Rennes, France, F. Rouget, Department of Pediatrics, University Hospital, Inserm-Irset U 1085, Rennes, France, E. Saliba , University Hospital of Tours, INSERM U 930, Neonatal Intensive Care, François Rabelais University of Tours - CHU Clocheville, Tours, France, A. Favreau , University Hospital of Tours, Neonatology, CHU Clocheville, Tours, France, N. Bednarek, Department of Neonatal Pediatrics, University Hospital, Reims, France, G. Loron, Department of Neonatal Pediatrics, University Hospital, Reims, France, C. Mougey, Department of Neonatology, University Hospital of Besançon, France, G. Thiriez, Department of Neonatology, University Hospital of Besançon, France, S. Marret, Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital-Laboratory of microvascular endothelium and neonatal brain lesions, Rouen, France, C. Lardennois, Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital, Rouen, France, H. Bruel, Department of Neonatal Pediatrics, Jacques Monod Hospital, Le Havre, France, X.

Durremeyer, Department of Neonatal Pediatrics and Intensive Care, CHI, CRC, Créteil, France, M.

Granier, Department of Neonatal Pediatrics, Sud Francilien Hospital, Evry, France, P. Boileau, Department of Neonatal Pediatrics, Poissy Saint Germain University Hospital, Poissy, France, G. Kayem, Department of Obstetrics and Gynecology, Trousseau Hospital, APHP, Paris, France; Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in pregnancy, Paris Descartes University, France, R. Carbajal, Emergency Department, Hôpital Armand-Trousseau, Paris, France; Inserm UMR 1153 Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in Pregnancy, Paris Descartes University, France; UPMC, Paris, France, A. Lapillonne, Department of Neonatology, Paris Descartes University, APHP Necker Hospital, Paris, France, PH.

Jarreau, Service de Médecine et Réanimation Néonatales de Port-Royal, Hôpitaux Universitaire Paris Centre Site Cochin, Université Paris V René Descartes and Assistance Publique Hôpitaux de Paris, Paris, France, G. Cambonie, Department of Neonatal Medicine, Arnaud de Villeneuve Hospital, Montpellier University Hospital, France, I. Souksi-Médioni, Department of Neonatal Medicine, Caremeau Hospital, Nîmes University Hospital, France, AC. Menguy, Department of Neonatal Medicine, St Jean Hospital, Perpignan General Hospital, France, A. Bédu, Department of neonatal pediatrics and intensive care, Limoges University Hospital, Limoges, France, F. Mons, Department of neonatal pediatrics and intensive care, Limoges University Hospital, Limoges, France, V. Valdes, Department of neonatal pediatrics and intensive care, Adolphe Pinard Maternity Unit, Nancy, France, J. Fresson, Réseau Périnatal Lorrain, Nancy, France; Department of Medical Information, University Hospital of Nancy, France, C. Alberge, Children Intensive Care unit, University Hospital, Toulouse, France. INSERM U 1027 INSERM, Toulouse, France. Paul-Sabatier University, Toulouse, France, C. Arnaud, INSERM U 1027 INSERM, Toulouse, France,

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Paul-Sabatier University, Toulouse, France, O Dicky, Department of Neonatology, University Hospital, Toulouse, France, INSERM U 1027 INSERM, Toulouse, France.Paul-Sabatier University, Toulouse, France P. Truffert, Department of Neonatal Medicine, Jeanne de Flandre Hospital, F-59000 Lille, France, A.

Mitha, CHU Lille, Department of Neonatal Medicine, Jeanne de Flandre Hospital, F-59000 Lille, France, ML. Charkaluk, INSERM UMR 1153, Obstretrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, DHU Risks in Pregnancy, Paris Descartes University, Paris, France; UCLille, F-59000 Lille, France; Service de Néonatologie, Hôpital Saint Vincent de Paul, Groupement des Hôpitaux de l'Institut Catholique Lillois/Faculté de Médecine et Maïeutique, F-59000 Lille, France, C. Gire, Department of Neonatal Pediatrics and Intensive Care, Nord Hospital, Marseille, France, F. Boubred, Department of Neonatal Pediatrics and Intensive Care, Conception Hospital, Marseille, France, C. D’Ercole, Department of Gynecology and Obstetrics, Nord Hospital, Marseille, France, A. Bongain, Department of Gynecology and Obstetrics, University Hospital of Nice, France, JC. Rozé, Department of Neonatology, CHU Nantes, Nantes, France, C. Flamant, Nantes University, Department of Neonatology, Maternité Régionale, Clinical Epidemiology and Biostatistics Department France, Nantes University, INSERM CIC004, Nantes, France, G. Gascoin, Department of Neonatal Medicine, Angers University Hospital, Angers, France. A. Leke, PériTox UMI-01, Université de Picardie Jules Verne, Department of Neonatal Pediatrics and Intensive Care, University Hospital of Amiens, Picardie, France, S. Goudjil, GRAMFC Inserm U1105, Université de Picardie Jules Verne, Department of Neonatal Pediatrics and Intensive Care, University Hospital of Amiens, Picardie, France, M. Debeir, Department of Pediatrics, Chambéry, France O. Claris, Department of Neonatal Pediatrics and Intensive Care, University Hospital, Lyon, France, JC. Picaud, Department of Neonatology,Human Nutrition Research Center, Hospital E. Herriot, Lyon, France, T. Debillon, Grenoble Alps University, CNRS, TIMC-IMAG, UMR 5525 ThEMAS, F38041 Grenoble, France; Neonatal Intensive Care Unit, Grenoble University Hospital, Grenoble, France, H. Patural, Unités de réanimation néonatale et pédiatrique, pôle Mère-Enfant, centre hospitalo-universitaire de Saint-Étienne, avenue Albert-Raimond, 42055 Saint-Étienne cedex 02, France, A. Poulichet, Department of Neonatology, University Hospital of Pointe à Pitre, French West Indies, Guadeloupe, France, A Abrial, Department of Neonatology, University Hospital of Pointe à Pitre, French West Indies, Guadeloupe, France, A. Favre, Department of Neonatal Pediatrics and Intensive Care, Andrée Rosemon Hospital, Cayenne, Guyane, S. Buende, Hospital of Saint Laurent du Maroni, Guyane, O.

Fléchelles, University Hospital, Fort de France, Martinique, D. Ramful , Pediatric and Neonatal Intensive Care Unit, Félix Guyon University Hospital, Saint-Denis, Reunion Island; INSERM, CIC 1410, Saint-Pierre, Reunion Island, PY. Robillard, Pediatric and Neonatal Intensive Care Unit, Sud Reunion University Hospital, Saint-Pierre, Reunion Island, France, V Benhammou, Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France, L Foix-L’Hélias, Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France, Andrei Morgan, Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France

EPIPAGE-2 study group

Alsace: D Astruc, P Kuhn, B Langer, J Matis (Strasbourg), C Ramousset; Aquitaine: X Hernandorena (Bayonne), P Chabanier, L Joly-Pedespan (Bordeaux), MJ Costedoat, A Leguen; Auvergne: B Lecomte, D Lemery, F Vendittelli (Clermont-Ferrand); Basse-Normandie: G Beucher, M Dreyfus, B Guillois (Caen), Y Toure; Bourgogne: A Burguet, S Couvreur, JB Gouyon, P Sagot (Dijon), N Colas; Bretagne: J Sizun (Brest), A Beuchée, P Pladys, F Rouget (Rennes), RP Dupuy (St-Brieuc), D Soupre (Vannes), F Charlot , S Roudaut; Centre: A Favreau , E Saliba (Tours), L Reboul; Champagne-Ardenne: N Bednarek, P Morville (Reims), V Verrière; Franche-Comté: G Thiriez (Besançon), C Balamou; Haute-Normandie: L Marpeau , S Marret (Rouen), C Barbier; Ile-de-France: G Kayem (Colombes), X Durrmeyer (Créteil), M Granier (Evry), M Ayoubi , A Baud , B Carbonne , L Foix L’Hélias, F Goffinet, PH Jarreau , D Mitanchez (Paris), P Boileau (Poissy), L Cornu, R Moras; Languedoc-Roussillon: P Boulot , G Cambonie , H Daudé (Montpellier), A Badessi, N Tsaoussis; Limousin: A Bédu, F Mons (Limoges), C Bahans; Lorraine: MH Binet, J Fresson, JM Hascoët, A Milton, O Morel, R Vieux (Nancy), L Hilpert; Midi-Pyrénées: C Alberge,

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C Arnaud, C Vayssière (Toulouse), M Baron; Nord-Pas-de-Calais: ML Charkaluk, V Pierrat, D Subtil, P Truffert (Lille), S Akowanou, D Roche; PACA et Corse: C D’Ercole, C Gire, U Simeoni (Marseille), A Bongain (Nice), M Deschamps; Pays de Loire: B Branger (FFRSP), JC Rozé, N Winer (Nantes), V Rouger, C Dupont; Picardie: J Gondry, G Krim (Amiens), B Baby; Rhône-Alpes: M Debeir (Chambéry), O Claris, JC Picaud, S Rubio-Gurung (Lyon), C Cans, A Ego, T Debillon (Grenoble), H Patural (Saint-Etienne), A Rannaud; Guadeloupe: E Janky, A Poulichet, JM Rosenthal (Point à Pitre), E Coliné; Guyane: A Favre (Cayenne), N Joly; Martinique: S Châlons (Fort de France), V Lochelongue; La Réunion : PY Robillard (Saint-Pierre), S Samperiz, D Ramful (Saint-Denis). Inserm UMR 1153: PY Ancel, V Benhammou, B Blondel, M Bonet, A Brinis, ML Charkaluk, A Coquelin, M Durox, L Foix-L’Hélias, F Goffinet, M Kaminski, G Kayem, B Khoshnood, C Lebeaux, L Marchand-Martin, V Pierrat, J Rousseau, MJ Saurel-Cubizolles, D Sylla, D Tran, L Vasante-Annamale, J Zeitlin. Guarantor: Véronique PIERRAT

Competing interests: All authors have completed the Unified Completed Interest Form at www.icmj.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work [or describe if any]; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Funding: This project has been funded with support from

1) The French Institute of Public Health Research/Institute of Public Health and its partners: the French Health Ministry, the National Institute of Health and Medical Research (INSERM), the National Institute of Cancer, and the National Solidarity Fund for Autonomy (CNSA).

2) The National Research Agency through the French EQUIPEX program of investments in the future (reference ANR-11-EQPX-0038).

3) The PREMUP Foundation The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Ethical approval: This study was approved by the National Data Protection Authority (CNIL no.911009) and by appropriate ethics committees (Consultative Committee on the Treatment of Data on Personal Health for Research Purposes - reference no. 10.626, Committee for the Protection of People Participating in Biomedical Research - reference CPP SC-2873). Acknowledgments: We are grateful for the participation of all families of preterm infants in the EPIPAGE-2 cohort study and for the cooperation of all maternity and neonatal units in France. We thank parents’ associations (SOS prema, Collectif interassociatif autour de la naissance (CIANE), Jumeaux et plus) for their overwhelming support and their involvement in the dissemination of the results. We thank the EPIPAGE-2 Study Group for its substantial contribution to the conception, design, and acquisition of data.

Competing interests: None

Data sharing: The EPIPAGE studies are subject to a data sharing policy that may be downloaded from www.epipage2.inserm.fr

Transparency declaration: The lead author (the manuscript’s guarantor) affirms that the manuscript is honest, accurate and transparent account of the study being reported; that no important aspects of the study

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have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Figure legends

Figure 1: Flow of the study population: EPIPAGE-2 cohort.

Figure 1 legend:

* No survivor at 22 weeks and only one survivor at 23 weeks + 6 days.

Abbreviation : ASQ, Ages and Stages Questionnaire

Figure 2: Comparison of outcomes between EPIPAGE (1997) and EPIPAGE-2 (2011) cohorts for children

included in the 9 regions participating to both studies.

Figure 2 legend:

Vertical bars represent exact 95 % Confidence Intervals.

* Rates of survivors without moderate or severe neuro-motor or sensory disabilities at 2 years CA among

livebirths. Severe neuro-motor or sensory disabilities: cerebral palsy GMFCS levels 3-5 or bilateral deafness

or blindness; moderate neuro-motor or sensory disabilities: cerebral palsy GMFCS level-2 or unilateral

deafness or blindness

† Rates of cerebral palsy among survivors at 2 years CA.

. Percentages are presented on imputed data. Vertical bars represent exact 95 % Confidence Intervals.

Abbreviations: CA, corrected age; CI, Confidence Interval.

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Figure 1. Flow chart of the study population: EPIPAGE2 cohort.

Live born infants with gestational age between 22 and 34 completed

weeks

n=5567

Parents refuse participation n=397

Live born infants with gestational age between 22 and 34 completed

weeks with parental consent

n=5170

Died in delivery rooms n=290

Died in NICUs n=413

Discharged home alive eligible for follow-up*

n=4467

Died between discharge and 2 years n=24

Follow-up refused by parents n=244

Survivors at 2 years included to the follow-up

n=4199

Physician questionnaire at 2

years corrected age

Parental questionnaire at 2

years corrected age

n=3600 n=3689

Cerebral palsy data available

n=3599

Completed between 22 and

26 months' corrected age

Hearing data available

n=3517

n=2732

Vision data available

n=3400

ASQ data available

n=2637

* No survivor at 22 weeks and only one survivor at 23 weeks + 6 days.

Abbreviation : ASQ, Ages and Stages Questionnaire

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Table 1. Cerebral palsy, hearing and vision disabilities at 2 years corrected age (CA) by gestational age groups.

Total 24-31 weeks* 24-26 weeks* 27-31 weeks Total 32-34 weeks p-value†

(n=2714) (n=450) (n=2264) (n=886)

Cerebral palsy 128/2714 4.6 (3.9 to 5.5) 31/450 6.9 (4.7 to 9.6) 97/2264 4.3 (3.5 to 5.2) 9/885 1.0 (0.5 to 1.9) <.001

GMFCS level-5 8/2714 0.3 (0.1 to 0.6) 3/450 0.7 (0.1 to 1.9) 5/2264 0.2 (0.1 to 0.5) 0/885 0 -

GMFCS level -3/4 24/2714 0.9 (0.6 to 1.3) 5/450 1.1 (0.4 to 2.6) 19/2264 0.8 (0.5 to 1.3) 0/885 0 -

GMFCS level -2 39/2714 1.4 (1.0 to 1.9) 12/450 2.7 (1.4 to 4.6) 27/2264 1.2 (0.8 to 1.7) 3/885 0.3 (0.1 to 1.0)

GMFCS level -1 57/2714 2.1 (1.6 to 2.7) 11/450 2.4 (1.2 to 4.3) 46/2264 2.0 (1.5 to 2.7) 6/885 0.7 (0.2 to 1.5)

Hearing

Deafness 19/2651 0.7 (0.4 to 1.1) 6/442 1.4 (0.5 to 2.9) 13/2209 0.6 (0.3 to 1.0) 4/866 0.5 (0.1 to 1.2) 0.28

Bilateral deafness 13/2651 0.5 (0.2 to 0.8) 6/442 1.4 (0.5 to 2.9) 7/2209 0.3 (0.1 to 0.7) 4/866 0.5 (0.1 to 1.2)

Unilateral deafness 6/2651 0.2 (0.1 to 0.5) 0/442 0 6/2209 0.3 (0.1 to 0.6) 0/866 0

Vision

Blindness 10/2553 0.4 (0.2 to 0.7) 3/421 0.7 (0.1 to 2.1) 7/2132 0.3 (0.1 to 0.7) 2/847 0.2 (0 to 0.9) 0.51

Bilateral blindness 5/2553 0.2 (0.1 to 0.4) 2/421 0.5 (0.1 to 1.7) 3/2132 0.1 (0 to 0.4) 1/847 0.1 (0 to 0.7)

Unilateral blindness 5/2553 0.2 (0.1 to 0.5) 1/421 0.2 (0 to 1.3) 4/2132 0.2 (0.1 to 0.5) 1/847 0.1 (0 to 0.7)

Squinting‡ 152/2533 5.9 (5.1 to 6.9) 30/416 7.2 (4.9 to 10.1) 122/2117 5.8 (4.8 to 6.8) 30/840 3.6 (2.4 to 5.1) 0.003

Wearing glasses‡ 180/2527 7.0 (6.1 to 8.1) 38/418 9.1 (6.5 to 12.3) 142/2109 6.7 (5.7 to 7.9) 35/842 4.2 (2.9 to 5.7) <.001

Neuro-motor or sensory disabilities§ 93/2524 3.6 (2.9 to 4.4) 25/420 6.0 (3.9 to 8.7) 68/2104 3.2 (2.5 to 4.1) 8/834 1.0 (0.4 to 1.9) <.001

Severe 45/2524 1.7 (1.3 to 2.3) 12/420 2.9 (1.5 to 4.9) 33/2104 1.6 (1.1 to 2.2) 5/834 0.6 (0.2 to 1.4)

Moderate 48/2524 1.8 (1.4 to 2.5) 13/420 3.1 (1.7 to 5.2) 35/2104 1.7 (1.2 to 2.3) 3/834 0.4 (0.1 to 1.0)

Abbreviation: GMFCS, Gross Motor Function Classification System

Data are number of events/number in each group, percentages and exact 95% binomial confidence intervals. Denominators vary according to the number of missing data for each variable. Percentages are weighted to account for

differences in sampling process between gestational age groups.

* Including one survivor born at 23 weeks + 6 days.

† Comparison between gestaConal age groups 24-26 weeks / 27-31 weeks / 32-34 weeks.

‡ For children without blindness.

§ Severe neuro-motor or sensory disabilities: cerebral palsy GMFCS levels 3-5 and/or bilateral deafness and/or bilateral blindness; moderate neuro-motor or sensory disabilities: cerebral palsy GMFCS level-2 and/or unilateral

deafness and/or unilateral blindness. Six infants had associated severe or moderate cerebral palsy and sensory disabilities.

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Table 2. Results for the Ages and Stages Questionnaire for children without cerebral palsy, sensory disabilities or severe congenital brain malformations at 2 years corrected age (CA) by

gestational age groups.

Total 24-31 weeks* 24-26 weeks* 27-31 weeks Total 32-34 weeks p-value†

(n=1884) (n=313) (n=1571) (n=622)

Total ASQ

median[IQR] 1884 229 [199 to 255] 313 223 [185 to 250] 1571 230 [200 to 255] 622 235 [205 to 260] <.001

Low ASQ (<220)‡ 725/1884 38.1 (35.9 to 40.4) 146/313 46.6 (41.0 to 52.3) 579/1571 36.9 (34.5 to 39.3) 216/622 34.7 (31.0 to 38.6) 0.014

ASQ failure§ 797/1884 42.0 (39.7 to 44.2) 157/313 50.2 (44.5 to 55.8) 640/1571 40.7 (38.3 to 43.2) 225/622 36.2 (32.4 to 40.1) <.001

No. of failed domains

0 1087/1884 58.0 (55.8 to 60.3) 156/313 49.8 (44.2 to 55.5) 931/1571 59.3 (56.8 to 61.7) 397/622 63.8 (59.9 to 67.6) <.001

1 441/1884 23.4 (21.5 to 25.4) 76/313 24.3 (19.6 to 29.4) 365/1571 23.2 (21.2 to 25.4) 139/622 22.3 (19.1 to 25.8)

2 171/1884 8.9 (7.7 to 10.3) 38/313 12.1 (8.7 to 16.3) 133/1571 8.5 (7.1 to 10.0) 51/622 8.2 (6.2 to 10.6)

3 101/1884 5.3 (4.4 to 6.4) 19/313 6.1 (3.7 to 9.3) 82/1571 5.2 (4.2 to 6.4) 24/622 3.9 (2.5 to 5.7)

4-5 84/1884 4.3 (3.4 to 5.3) 24/313 7.7 (5.0 to 11.2) 60/1571 3.8 (2.9 to 4.9) 11/622 1.8 (0.9 to 3.1)

By domain

Communication 484/1884 25.3 (23.4 to 27.4) 106/313 33.9 (28.6 to 39.4) 378/1571 24.1 (22.0 to 26.3) 111/622 17.8 (14.9 to 21.1) <.001

Gross motor 204/1884 10.6 (9.2 to 12.0) 52/313 16.6 (12.7 to 21.2) 152/1571 9.7 (8.3 to 11.2) 32/622 5.1 (3.5 to 7.2) <.001

Fine motor 211/1884 11.2 (9.8 to 12.7) 38/313 12.1 (8.7 to 16.3) 173/1571 11.0 (9.5 to 12.7) 65/622 10.5 (8.2 to 13.1) 0.75

Problem solving 217/1884 11.5 (10.1 to 13.0) 40/313 12.8 (9.3 to 17.0) 177/1571 11.3 (9.7 to 12.9) 68/622 10.9 (8.6 to 13.7) 0.69

Personal-social 334/1884 17.4 (15.7 to 19.2) 78/313 24.9 (20.2 to 30.1) 256/1571 16.3 (14.5 to 18.2) 83/622 13.3 (10.8 to 16.3) <.001

Abbreviations: ASQ, Ages and Stages Questionnaire; IQR, interquartile range.

For ASQ administered at 22-26 months corrected age, 131 infants with cerebral palsy, deafness, blindness or severe congenital anomalies were excluded.

Data are number of events/number in group, percentages and exact 95% binomial confidence intervals, unless otherwise noted. Percentages and medians are weighted to account for differences in sampling process between

gestational age groups.

* Included one survivor born at 23 weeks + 6 days.

† Comparison of gestaConal age groups 24-26 weeks / 27-31 weeks / 32-34 weeks, adjusted for age at examination in months.

‡ A global score < 220 has a sensiCvity of 85% and a specificity of 72% for idenCfying children at risk of having a developmental quotient < 85 (Flamant, 2011).

§ For each domain, a score of less than 2 SD below the mean of the US ASQ-3 reference was considered failure. Global ASQ was considered failure with failure in at least one domain.

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Table 3. Survival, rates of cerebral palsy and ASQ failure at 2 years corrected age (CA) among complete cases and after multiple imputations by gestational age groups.

Missing

data

analysis

Total 22-31 weeks 22-26 weeks 27-31 weeks Total 32-34 weeks

% (95% CI) % (95% CI) % (95% CI) % (95% CI)

Among livebirths,

Survival * CC 84.3 (83.2 to 85.4) 51.7 (48.6 to 54.7) 93.1 (92.1 to 94.0) 98.6 (97.8 to 99.2)

Survival without neuro-motor

or sensory disabilities†,‡

MI 81.2 (79.9 to 82.4) 48.5 (45.4 to 51.6) 90.0 (88.8 to 91.1) 97.5 (96.4 to 98.5)

Among survivors at 2 years CA§,

Cerebral palsy CC 4.6 (3.9 to 5.5) 6.9 (4.7 to 9.6) 4.3 (3.5 to 5.2) 1.0 (0.5 to 1.9)

MI 4.8 (4.0 to 5.6) 7.2 (4.9 to 9.6) 4.4 (3.6 to 5.3) 1.1 (0.4 to 1.7)

ASQ failure ll CC 42.0 (39.7 to 44.2) 50.2 (44.5 to 55.8) 40.7 (38.3 to 43.2) 36.2 (32.4 to 40.1)

MI 47.8 (45.5 to 50.2) 55.8 (50.8 to 60.9) 46.7 (44.2 to 49.2) 42.7 (38.7 to 46.7)

Abbreviations: CC, complete cases analysis; MI, multiple imputations; ASQ, Ages and Stages Questionnaire.

Data are % (exact 95% confidence intervals). Total % are weighted to account for differences in sampling process between gestational age groups.

* No missing value for survival at 2 years.

† Moderate or severe neuro-motor or sensory disabilities. Severe neuro-motor or sensory disabilities: cerebral palsy GMFCS levels 3-5 and/or bilateral deafness and/or bilateral

blindness; moderate neuro-motor or sensory disabilities: cerebral palsy GMFCS level-2 and/or unilateral deafness and/or unilateral blindness.

‡ For some children who survived, the disability status was unknown because they were lost to follow-up, so only MI estimation is possible.

§ All but one neonate born at 22-23 weeks died.

ll For each domain, a score of less than 2 SD below the mean of the US ASQ-3 reference was considered failure. Global ASQ was considered failure with failure in at least one

domain. Infants with cerebral palsy, deafness, blindness or severe congenital anomalies were excluded.

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Table 4. Factors associated with cerebral palsy and ASQ failure for children at 2 years corrected age (CA) who were born at 24-31 weeks’ gestation.

Cerebral palsy

Model 1

aOR (95%CI) p-value

Model 2

aOR (95%CI) p-value ASQ failure*

Model 1

aOR (95%CI) p-value

Model 2

aOR (95%CI) p-value

Gestational age (weeks)

24 5/51 (9.8) 4.4 (1.5 to 12.4) <.001 3.3 (1.0 to 10.2) 0.010 24/35 (68.6) 3.4 (1.6 to 7.1) 0.020 3.6 (1.7 to 7.7) 0.012

25 15/142 (10.6) 4.8 (2.3 to 9.8) 4.0 (1.9 to 8.3) 47/92 (51.1) 1.6 (1.0 to 2.6) 1.7 (1.1 to 2.8)

26 11/257 (4.3) 1.8 (0.8 to 3.9) 1.7 (0.8 to 3.7) 86/186 (46.2) 1.3 (0.9 to 1.9) 1.3 (0.9 to 1.9)

27 22/279 (7.9) 3.4 (1.8 to 6.6) 2.8 (1.4 to 5.6) 82/183 (44.8) 1.2 (0.9 to 1.7) 1.1 (0.7 to 1.5)

28 16/340 (4.7) 2.0 (1.0 to 4.0) 1.8 (0.9 to 3.7) 94/240 (39.2) 1.0 (0.7 to 1.4) 0.9 (0.7 to 1.3)

29 21/405 (5.2) 2.2 (1.1 to 4.2) 1.9 (1.0 to 3.6) 110/268 (41.0) 1.1 (0.8 to 1.5) 1.1 (0.8 to 1.5)

30 21/538 (3.9) 1.6 (0.9 to 3.1) 1.6 (0.8 to 3.0) 159/384 (41.4) 1.1 (0.8 to 1.4) 1.0 (0.8 to 1.4)

31 17/702 (2.4) 1 1 195/496 (39.3) 1 1

Sex

Female 57/1285 (4.3) 1 0.52 1 0.53 322/897 (35.6) 1 <.001 1 <.001

Male 71/1429 (4.9) 1.1 (0.8 to 1.6) 1.1 (0.8 to 1.6) 475/987 (47.7) 1.7 (1.4 to 2.1) 1.9 (1.5 to 2.3)

Pregnancy

Single 92/1812 (4.9) 1 0.17 1 0.24 509/1224 (41.4) 1 0.30 1 0.070

Multiple 36/902 (4.0) 0.8 (0.5 to 1.1) 0.8 (0.5 to 1.2) 288/660 (43.0) 1.1 (0.9 to 1.3) 1.2 (1.0 to 1.5)

Small-for-gestational age †

No 97/1772 (5.4) 1 0.048 1 0.040 496/1216 (40.4) 1 0.015 1 0.012

Yes 31/942 (3.2) 0.7 (0.4 to 1.0) 0.6 (0.4 to 1.0) 301/668 (44.7) 1.3 (1.1 to 1.6) 1.3 (1.1 to 1.6)

Parents’ socio-economic

status ‡

Professional 26/606 (4.3) 1 0.46 1 0.42 177/468 (37.5) 1 0.003 1 0.002

Intermediate 27/568 (4.5) 1.1 (0.6 to 1.9) 1.1 (0.6 to 1.9) 170/434 (38.9) 1.1 (0.8 to 1.4) 1.1 (0.8 to 1.4)

Administrative, public

service, self-employed,

students

29/708 (4.1) 1.0 (0.6 to 1.7) 1.0 (0.6 to 1.7) 197/458 (42.8) 1.3 (1.0 to 1.7) 1.3 (1.0 to 1.7)

Shop assistants, service

workers 14/358 (3.7) 0.9 (0.4 to 1.7) 0.8 (0.4 to 1.6) 124/248 (49.9) 1.7 (1.2 to 2.4) 1.8 (1.3 to 2.4)

Manual workers 20/291 (6.6) 1.6 (0.9 to 2.9) 1.6 (0.9 to 2.9) 73/169 (42.1) 1.2 (0.9 to 1.9) 1.4 (0.9 to 2.0)

Unemployed 5/64 (7.0) 1.7 (0.6 to 4.7) 1.8 (0.6 to 4.9) 22/39 (56.9) 2.4 (1.2 to 4.6) 2.4 (1.2 to 4.8)

Abbreviation: ASQ, Ages and Stages Questionnaire.

Data are number of events/number in groups (percentages) odds ratio (exact 95% binomial confidence intervals). Denominators vary according to the number of missing data for each variable. Percentages are weighted to account

for differences in sampling process between gestational age groups.

Model 1: adjusted for gestational age and only for ASQ for age at evaluation in completed months.

Model 2: adjusted for gestational age, gender, single or multiple pregnancies, small-for-gestational age and parents’ socioeconomic status and only for ASQ for age at evaluation in completed months.

*A score of more than 2 SD below the mean score for the US ASQ-3 reference group on any domain was considered failure. Infants with cerebral palsy, deafness, blindness or severe congenital brain anomalies were excluded.

† Small-for-gestational age was defined as birth weight less than the 10th percentile for gestational age and sex based on French intrauterine growth curves (Ego 2016).

‡ Defined as the highest occupaConal status between occupaCons of the mother and father, or mother only if a single parent.

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