Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks’ gestation in France in 2011: EPIPAGE-2 cohort studyBMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3448 (Published 16 August 2017) Cite this as: BMJ 2017;358:j3448
- Véronique Pierrat, neonatologist and researcher12,
- Laetitia Marchand-Martin, statistician1,
- Catherine Arnaud, associate professor of public health3,
- Monique Kaminski, director of research1,
- Matthieu Resche-Rigon, professor in biostatistics4,
- Cécile Lebeaux, medical doctor1,
- Florence Bodeau-Livinec, associate professor of epidemiology15,
- Andrei S Morgan, postdoctoral research fellow and neonatologist1,
- François Goffinet, professor of obstetrics and gynecology16,
- Stéphane Marret, professor of paediatrics78,
- Pierre-Yves Ancel, professor of public health19,
- and the EPIPAGE-2 writing group
- 1Obstetrical, Perinatal, and Pediatric Epidemiology Team, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM, Paris, France; Paris Descartes University, Paris, France
- 2CHU Lille, Department of Neonatal Medicine, Jeanne de Flandre Hospital, F-59000 Lille, France
- 3INSERM UMR 1027, Université Toulouse III Paul Sabatier, Toulouse, France
- 4Biostatistics and Medical Information Department, AP-HP Saint-Louis Hospital, Paris, France
- 5École des Hautes Études en Santé Publique (EHESP), Rennes, France
- 6Maternité Port-Royal, Université Paris Descartes, Groupe Hospitalier Cochin Broca Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, DHU Risques et Grossesse, Paris, France
- 7Department of Neonatal Pediatrics, Intensive care, and Neuropediatrics, Rouen University Hospital, Rouen, France
- 8Research Unit U1245, Institute for Research and Innovation in Biomedicine, Rouen, France
- 9Clinical Research Unit, Center for Clinical Investigation P1419, Cochin Broca Hôtel-Dieu Hospital, Paris, France
- Correspondence to: V Pierrat Obstetrical, Perinatal, and Pediatric Epidemiology Team (EPOPé), INSERM U 1153, Bâtiment Recherche, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France
- Accepted 13 July 2017
Objectives To describe neurodevelopmental outcomes at 2 years corrected age for children born alive at 22-26, 27-31, and 32-34 weeks’ gestation in 2011, and to evaluate changes since 1997.
Design Population based cohort studies, EPIPAGE and EPIPAGE-2.
Participants 5567 neonates born alive in 2011 at 22-34 completed weeks’ gestation, with 4199 survivors at 2 years corrected age included in follow-up. Comparison of outcomes reported for 3334 (1997) and 2418 (2011) neonates born alive in the nine regions participating in both studies.
Main outcome measures Survival; cerebral palsy (2000 European consensus definition); scores below threshold on the neurodevelopmental Ages and Stages Questionnaire (ASQ; at least one of five domains below threshold) if completed between 22 and 26 months corrected age, in children without cerebral palsy, blindness, or deafness; and survival without severe or moderate neuromotor or sensory disabilities (cerebral palsy with Gross Motor Function Classification System levels 2-5, unilateral or bilateral blindness or deafness). Results are given as percentage of outcome measures with 95% confidence intervals.
Results Among 5170 liveborn neonates with parental consent, survival at 2 years corrected age was 51.7% (95% confidence interval 48.6% to 54.7%) at 22-26 weeks’ gestation, 93.1% (92.1% to 94.0%) at 27-31 weeks’ gestation, and 98.6% (97.8% to 99.2%) at 32-34 weeks’ gestation. Only one infant born at 22-23 weeks survived. Data on cerebral palsy were available for 3599 infants (81.0% of the eligible population). The overall rate of cerebral palsy at 24-26, 27-31, and 32-34 weeks’ gestation was 6.9% (4.7% to 9.6%), 4.3% (3.5% to 5.2%), and 1.0% (0.5% to 1.9%), respectively. Responses to the ASQ were analysed for 2506 children (56.4% of the eligible population). The proportion of children with an ASQ result below threshold at 24-26, 27-31, and 32-34 weeks’ gestation were 50.2% (44.5% to 55.8%), 40.7% (38.3% to 43.2%), and 36.2% (32.4% to 40.1%), respectively. Survival without severe or moderate neuromotor or sensory disabilities among live births increased between 1997 and 2011, from 45.5% (39.2% to 51.8%) to 62.3% (57.1% to 67.5%) at 25-26 weeks’ gestation, but no change was observed at 22-24 weeks’ gestation. At 32-34 weeks’ gestation, there was a non-statistically significant increase in survival without severe or moderate neuromotor or sensory disabilities (P=0.61), but the proportion of survivors with cerebral palsy declined (P=0.01).
Conclusions In this large cohort of preterm infants, rates of survival and survival without severe or moderate neuromotor or sensory disabilities have increased during the past two decades, but these children remain at high risk of developmental delay.
EPIPAGE-2 writing group: D Astruc, P Kuhn, J Matis, L Joly, G Mazeira, A David, B Lecomte, F Vendittelli, V Datin-Dorriere, B Guillois, A Burguet, P Sagot, JM Roué, A Beuchée, F Rouget, E Saliba, A Favreau, N Bednarek, G Loron, C Mougey, G Thiriez, S Marret, C Lardennois, H Bruel, X Durrmeyer, M Granier, P Boileau, G Kayem, R Carbajal, A Lapillonne, PH Jarreau, G Cambonie, I Souksi-Médioni, AC Menguy, A Bédu, F Mons, V Valdes, J Fresson, C Alberge, C Arnaud, O Dicky, P Truffert, A Mitha, ML Charkaluk, C Gire, F Boubred, C D’Ercole, A Bongain, JC Rozé, C Flamant, G Gascoin, A Leke, S Goudjil, M Debeir, O Claris, JC Picaud , T Debillon, H Patural, A Poulichet, A Abrial, A Favre, S Buende, O Fléchelles, D Ramful, PY Robillard, V Benhammou, L Foix-L’Hélias (see web appendix 9).
EPIPAGE-2 study group: D Astruc, P Kuhn, B Langer, J Matis, C Ramousset, X Hernandorena, P Chabanier, L Joly-Pedespan, MJ Costedoat, A Leguen, B Lecomte, D Lemery, F Vendittelli, G Beucher, M Dreyfus, B Guillois, Y Toure, A Burguet, S Couvreur, JB Gouyon, P Sagot, N Colas, J Sizun, A Beuchée, P Pladys, F Rouget, RP Dupuy, D Soupre, F Charlot, S Roudaut, A Favreau, E Saliba, L Reboul, N Bednarek, P Morville, V Verrière, G Thiriez, C Balamou, L Marpeau, S Marret, C Barbier, G Kayem, X Durrmeyer, M Granier, M Ayoubi, A Baud, B Carbonne, L Foix L’Hélias, F Goffinet, PH Jarreau, D Mitanchez, P Boileau, L Cornu, R Moras, P Boulot, G Cambonie, H Daudé, A Badessi, N Tsaoussis, A Bédu, F Mons, C Bahans, MH Binet, J Fresson, JM Hascoët, A Milton, O Morel, R Vieux, L Hilpert, C Alberge, C Arnaud, C Vayssière, M Baron, ML Charkaluk, V Pierrat, D Subtil, P Truffert, S Akowanou, D Roche, C D’Ercole, C Gire, U Simeoni, A Bongain, M Deschamps, B Branger, JC Rozé, N Winer, V Rouger, C Dupont, J Gondry, G Krim, B Baby, M Debeir, O Claris, JC Picaud, S Rubio-Gurung, C Cans, A Ego, T Debillon, H Patural, A Rannaud, E Janky, A Poulichet, JM Rosenthal, E Coliné, A Favre, N Joly, S Châlons, V Lochelongue, PY Robillard, S Samperiz, D Ramful, PY Ancel, V Benhammou, B Blondel, M Bonet, A Brinis, ML Charkaluk, A Coquelin, C Duffaut, M Durox, L Foix-L’Hélias, F Goffinet, M Kaminski, G Kayem, B Khoshnood, C Lebeaux, E Lorthe, L Marchand-Martin, AS Morgan, V Pierrat, J Rousseau, MJ Saurel-Cubizolles, D Sylla, D Tran, L Vasante-Annamale, J Zeitlin (see web appendix 9).
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, Soins Palliatifs et Accompagnement en MAternité (SPAMA)) 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.
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, ASM, FBL, and SM conceptualised 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 analysis plan 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. VP is the guarantor.
Funding: This project has been funded with support from the following organisations: 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); The National Research Agency through the French EQUIPEX program of investments in the future (reference ANR-11-EQPX-0038); the PREMUP Foundation; Fondation de France (reference 00050329); and Fondation pour la Recherche Médicale (reference SPF20160936356). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations 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.
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).
Data sharing: The EPIPAGE studies are subject to a data sharing policy that may be downloaded from http://epipage2.inserm.fr/index.php/en/.
Transparency: The manuscript’s guarantor (VP) affirms that the manuscript is honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.