LyTONEPAL: long term outcome of neonatal hypoxic encephalopathy in the era of neuroprotective treatment with hypothermia: a French population-based cohort

Thierry Debillon, Nathalie Bednarek, Anne Ego, LyTONEPAL Writing Group, Pierre-Yves Ancel, Olivier Baud, Marie-Laure Charkaluk, Clothilde Desrobert, Cyril Flamant, Pierre Gressens, Gilles Kayem, Stephane Marret, Juliana Patkail, Loic Senthiles, Elie Saliba, Thierry Debillon, Nathalie Bednarek, Anne Ego, LyTONEPAL Writing Group, Pierre-Yves Ancel, Olivier Baud, Marie-Laure Charkaluk, Clothilde Desrobert, Cyril Flamant, Pierre Gressens, Gilles Kayem, Stephane Marret, Juliana Patkail, Loic Senthiles, Elie Saliba

Abstract

Background: Hypoxic-ischemic encephalopathy (HIE) is a rare neonatal condition affecting about 1‰ births. Despite a significant improvement in the management of this condition in the last ten years, HIE remains associated with high rates of death and severe neurological disability. From September 2015 to March 2017, a French national cohort of HIE cases was conducted to estimate the extent of long-term moderate and severe neurodevelopmental disability at 3 years and its determinants.

Methods: This prospective population-based cohort includes all moderate or severe cases of HIE, occurring in newborns delivered between 34 and 42 completed weeks of gestation and admitted to a neonatal intensive care unit. Detailed data on the pregnancy, delivery, and newborn until hospital discharge was collected from the medical records in maternity and neonatology units. All clinical examinations including biomarkers, EEG, and imaging were recorded. To ensure the completeness of HIE registration, a registry of non-included eligible neonates was organized, and the exhaustiveness of the cohort is currently checked using the national hospital discharge database. Follow-up is organized by the regional perinatal network, and 3 medical visits are planned at 18, 24 and 36 months. One additional project focused on early predictors, in particular early biomarkers, involves a quarter of the cohort.

Discussion: This cohort study aims to improve and update our knowledge about the incidence, the prognosis and the etiology of HIE, and to assess medical care. Its final objective is to improve the definition of this condition and develop prevention and management strategies for high-risk infants.

Trial registration: NCT02676063 . Date of registration (Retrospectively Registered): February 8, 2016.

Keywords: Cohort; Hypoxic ischemic encephalopathy; Late preterm and term births; Population-based study; Therapeutic hypothermia.

Conflict of interest statement

For each eligible neonate, an information form was delivered to parents. A first oral consent to participate were requested by the neonatologist at the inclusion concerning the baseline data collection during hospitalization. If this consent was not obtained, the parents signed the information form to refuse their participation. In this case and according to French regulations, these neonates were registered in the inventory of non-included eligible neonates with the collection of anonymous minimal data.

At the end of the neonatal hospitalization a second but written consent was requested to participate to the standardized follow-up, and was signed by both parents and the neonatologist. Babies of parents who refused to participate were followed-up according to the usual practices of the center. According to French regulations, parents have a permanent right of access and rectification to their personal data, and can also leave the cohort at any time.

According the French law, the study protocol, including ethics and consent to participate, was approved by the Advisory National Committee on the treatment of personal health data for research purposes (Comité Consultatif sur le Traitement de l’Information en matière de Recherche sur la Santé, approval granted November 20, 2014; reference number 14.724. The authorizations were obtained:

  1. from the National French data protection authority (Commission Nationale Informatique et Libertés) on March 27, 2015; DR-2015-136

  2. and from the Regional Ethics committee CPP South-East V (Comité de Protection des Personnes Sud Est; Institutional Review Board n°5891) on July 18, 2014.

Not applicable (anonymous and collective data only).

The authors declare that they have no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

    1. Kurinczuk JJ, Barralet JH, Redshaw M, Brocklehurst P. Monitoring the incidence of neonatal encephalopathy-what next? Report to the patient safety research Programme. Oxford: National Perinatal Epidemiology Unit; 2005.
    1. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696–705. doi: 10.1001/archneur.1976.00500100030012.
    1. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86(6):329–338. doi: 10.1016/j.earlhumdev.2010.05.010.
    1. Yates HL, McCullough S, Harrison C, Gill AB. Hypoxic ischaemic encephalopathy: accuracy of the reported incidence. Arch Dis Child Fetal Neonatal Ed. 2012;97(1):F77–F78. doi: 10.1136/adc.2011.301240.
    1. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR, Pemberton PJ, Stanley FJ. Intrapartum risk factors for newborn encephalopathy: the western Australian case-control study. BMJ. 1998;317(7172):1554–1558. doi: 10.1136/bmj.317.7172.1554.
    1. Smith J, Wells L, Dodd K. The continuing fall in incidence of hypoxic-ischaemic encephalopathy in term infants. BJOG. 2000;107(4):461–466. doi: 10.1111/j.1471-0528.2000.tb13262.x.
    1. Thornberg E, Thiringer K, Odeback A, Milsom I. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Paediatr. 1995;84(8):927–932. doi: 10.1111/j.1651-2227.1995.tb13794.x.
    1. Pierrat V, Haouari N, Liska A, Thomas D, Subtil D, Truffert P, Groupe d'Etudes en Epidemiologie P Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study. Arch Dis Child Fetal Neonatal Ed. 2005;90(3):F257–F261. doi: 10.1136/adc.2003.047985.
    1. Aylward GP. Perinatal asphyxia: effects of biologic and environmental risks. Clin Perinatol. 1993;20(2):433–449. doi: 10.1016/S0095-5108(18)30402-0.
    1. Levene ML, Kornberg J, Williams TH. The incidence and severity of post-asphyxial encephalopathy in full-term infants. Early Hum Dev. 1985;11(1):21–26. doi: 10.1016/0378-3782(85)90115-X.
    1. MacDonald HM, Mulligan JC, Allen AC, Taylor PM. Neonatal asphyxia. I. Relationship of obstetric and neonatal complications to neonatal mortality in 38,405 consecutive deliveries. J Pediatr. 1980;96(5):898–902. doi: 10.1016/S0022-3476(80)80574-9.
    1. Low JA, Simpson LL, Tonni G, Chamberlain S. Limitations in the clinical prediction of intrapartum fetal asphyxia. Am J Obstet Gynecol. 1995;172(3):801–804. doi: 10.1016/0002-9378(95)90002-0.
    1. Milsom I, Ladfors L, Thiringer K, Niklasson A, Odeback A, Thornberg E. Influence of maternal, obstetric and fetal risk factors on the prevalence of birth asphyxia at term in a Swedish urban population. Acta Obstet Gynecol Scand. 2002;81(10):909–917. doi: 10.1034/j.1600-0412.2002.811003.x.
    1. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR, Pemberton PJ, Stanley FJ. Antepartum risk factors for newborn encephalopathy: the western Australian case-control study. BMJ. 1998;317(7172):1549–1553. doi: 10.1136/bmj.317.7172.1549.
    1. Pin TW, Eldridge B, Galea MP. A review of developmental outcomes of term infants with post-asphyxia neonatal encephalopathy. Eur J Paediatr Neurol. 2009;13(3):224–234. doi: 10.1016/j.ejpn.2008.05.001.
    1. Robertson C, Finer N. Term infants with hypoxic-ischemic encephalopathy: outcome at 3.5 years. Dev Med Child Neurol. 1985;27(4):473–484. doi: 10.1111/j.1469-8749.1985.tb04571.x.
    1. Robertson CM, Finer NN. Educational readiness of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Dev Behav Pediatr. 1988;9(5):298–306. doi: 10.1097/00004703-198810000-00009.
    1. Robertson CM, Finer NN, Grace MG. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr. 1989;114(5):753–760. doi: 10.1016/S0022-3476(89)80132-5.
    1. Toet MC, Groenendaal F, Osredkar D, van Huffelen AC, de Vries LS. Postneonatal epilepsy following amplitude-integrated EEG-detected neonatal seizures. Pediatr Neurol. 2005;32(4):241–247. doi: 10.1016/j.pediatrneurol.2004.11.005.
    1. Pisani F, Orsini M, Braibanti S, Copioli C, Sisti L, Turco EC. Development of epilepsy in newborns with moderate hypoxic-ischemic encephalopathy and neonatal seizures. Brain Dev. 2009;31(1):64–68. doi: 10.1016/j.braindev.2008.04.001.
    1. Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet. 2012;379(9814):445–452. doi: 10.1016/S0140-6736(11)61577-8.
    1. Azzopardi D, Brocklehurst P, Edwards D, Halliday H, Levene M, Thoresen M, Whitelaw A, Group TS: The TOBY study Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr. 2008;8:17. doi: 10.1186/1471-2431-8-17.
    1. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365(9460):663–670. doi: 10.1016/S0140-6736(05)17946-X.
    1. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–1584. doi: 10.1056/NEJMcps050929.
    1. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013;1:CD003311.
    1. Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, Gustafson KE, Leach TM, Green C, Bara R, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012;366(22):2085–2092. doi: 10.1056/NEJMoa1112066.
    1. Saliba E, Debillon T. Hypothermia for hypoxic-ischemic encephalopathy in fullterm newborns. Arch Pediatr. 2010;17(Suppl 3):S67–S77. doi: 10.1016/S0929-693X(10)70904-0.
    1. Chevallier M, Ego A, Cans C, Debillon T. Adherence to hypothermia guidelines: a French multicenter study of fullterm neonates. PLoS One. 2013;8:e83742.
    1. Amiel-Tison C. Update of the Amiel-Tison neurologic assessment for the term neonate or at 40 weeks corrected age. Pediatr Neurol. 2002;27(3):196–212. doi: 10.1016/S0887-8994(02)00436-8.
    1. Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, Malan AF. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr. 1997;86(7):757–761. doi: 10.1111/j.1651-2227.1997.tb08581.x.
    1. Murray DM, Bala P, O'Connor CM, Ryan CA, Connolly S, Boylan GB. The predictive value of early neurological examination in neonatal hypoxic-ischaemic encephalopathy and neurodevelopmental outcome at 24 months. Dev Med Child Neurol. 2010;52(2):e55–e59. doi: 10.1111/j.1469-8749.2009.03550.x.
    1. Monod N, Pajot N, Guidasci S. The neonatal EEG: statistical studies and prognostic value in full-term and pre-term babies. Electroencephalogr Clin Neurophysiol. 1972;32(5):529–544. doi: 10.1016/0013-4694(72)90063-6.
    1. d'Allest AM, Andre M, Radvanyi-Bouvet MF. Contribution of electroencephalography to the diagnosis and prognosis of perinatal asphyxia in full-term neonates. Arch Pediatr. 1996;3(Suppl 1):254s–256s. doi: 10.1016/0929-693X(96)86059-3.
    1. van Laerhoven H, de Haan TR, Offringa M, Post B, van der Lee JH. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics. 2013;131(1):88–98. doi: 10.1542/peds.2012-1297.
    1. Mietzsch U, Parikh NA, Williams AL, Shankaran S, Lasky RE. Effects of hypoxic-ischemic encephalopathy and whole-body hypothermia on neonatal auditory function: a pilot study. Am J Perinatol. 2008;25(7):435–441. doi: 10.1055/s-0028-1083842.
    1. Thoresen M, Hellstrom-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics. 2010;126(1):e131–e139. doi: 10.1542/peds.2009-2938.
    1. Barkovich AJ, Westmark K, Partridge C, Sola A, Ferriero DM. Perinatal asphyxia: MR findings in the first 10 days. AJNR Am J Neuroradiol. 1995;16(3):427–438.
    1. Kuenzle C, Baenziger O, Martin E, Thun-Hohenstein L, Steinlin M, Good M, Fanconi S, Boltshauser E, Largo RH. Prognostic value of early MR imaging in term infants with severe perinatal asphyxia. Neuropediatrics. 1994;25(4):191–200. doi: 10.1055/s-2008-1073021.
    1. McArdle CB, Richardson CJ, Hayden CK, Nicholas DA, Amparo EG. Abnormalities of the neonatal brain: MR imaging. Part II. Hypoxic-ischemic brain injury. Radiology. 1987;163(2):395–403. doi: 10.1148/radiology.163.2.3550882.
    1. Vermeulen RJ, Fetter WP, Hendrikx L, Van Schie PE, van der Knaap MS, Barkhof F. Diffusion-weighted MRI in severe neonatal hypoxic ischaemia: the white cerebrum. Neuropediatrics. 2003;34(2):72–76. doi: 10.1055/s-2003-39599.
    1. Wolf RL, Zimmerman RA, Clancy R, Haselgrove JH. Quantitative apparent diffusion coefficient measurements in term neonates for early detection of hypoxic-ischemic brain injury: initial experience. Radiology. 2001;218(3):825–833. doi: 10.1148/radiology.218.3.r01fe47825.
    1. Chiesa C, Pellegrini G, Panero A, De Luca T, Assumma M, Signore F, Pacifico L. Umbilical cord interleukin-6 levels are elevated in term neonates with perinatal asphyxia. Eur J Clin Investig. 2003;33(4):352–358. doi: 10.1046/j.1365-2362.2003.01136.x.
    1. Walsh BH, Boylan GB, Livingstone V, Kenny LC, Dempsey EM, Murray DM. Cord blood proteins and multichannel-electroencephalography in hypoxic-ischemic encephalopathy. Pediatr Crit Care Med. 2013;14(6):621–630. doi: 10.1097/PCC.0b013e318291793f.
    1. Shastri AT, Samarasekara S, Muniraman H, Clarke P. Cardiac troponin I concentrations in neonates with hypoxic-ischaemic encephalopathy. Acta Paediatr. 2012;101(1):26–29. doi: 10.1111/j.1651-2227.2011.02432.x.
    1. Simovic AM, Igrutinovic Z, Obradovic S, Ristic D, Vuletic B, Radanovic M. The significance of second generation cardiac troponin I in early screening of hypoxic-ischemic encephalopathy after perinatal asphyxia. Srp Arh Celok Lek. 2012;140(9–10):600–605. doi: 10.2298/SARH1210600S.
    1. Solberg R, Enot D, Deigner HP, Koal T, Scholl-Burgi S, Saugstad OD, Keller M. Metabolomic analyses of plasma reveals new insights into asphyxia and resuscitation in pigs. PLoS One. 2010;5(3):e9606. doi: 10.1371/journal.pone.0009606.
    1. Kumral A, Okyay E, Guclu S, Gencpinar P, Islekel GH, Oguz SS, Kant M, Demirel G, Duman N, Ozkan H. Cord blood ischemia-modified albumin: is it associated with abnormal Doppler findings in complicated pregnancies and predictive of perinatal asphyxia? J Obstet Gynaecol Res. 2013;39(3):663–671. doi: 10.1111/j.1447-0756.2012.02055.x.
    1. Bednarek N, Svedin P, Garnotel R, Favrais G, Loron G, Schwendiman L, Hagberg H, Morville P, Mallard C, Gressens P. Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia-ischemia: a potential marker of neonatal encephalopathy. Pediatr Res. 2012;71(1):63–70. doi: 10.1038/pr.2011.3.
    1. Hayakawa M, Ito Y, Saito S, Mitsuda N, Hosono S, Yoda H, Cho K, Otsuki K, Ibara S, Terui K, et al. Incidence and prediction of outcome in hypoxic-ischemic encephalopathy in Japan. Pediatr Int. 2014;56(2):215–221. doi: 10.1111/ped.12233.
    1. Simbruner G, Mittal RA, Rohlmann F, Muche R. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.Network RCT. Pediatrics. 2010;126(4):e771–e778. doi: 10.1542/peds.2009-2441.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere