Dr Christophe Au

Milesi

REMERCIEMENTS

Aux membres du jury, A Monsieur le Professeur Gilles Cambonie, Pour l'honneur que vous me faites de présider ce jury, veuillez accepter le témoignage de ma sincère reconnaissance. Merci également pour le soin que vous apportez à la formation des internes, pour votre encadrement, pour les connaissances que vous m'avez transmises et votre soutien ainsi que de m'offrir la chance de poursuivre mon parcours au sein de votre équipe.

A Monsieur le Professeur François Rivier, Pour avoir accepté de siéger parmi les membres du jury, soyez assuré de ma reconnaissance. Pour avoir amené votre expertise et enrichi mon parcours lors de mon passage dans votre service de neuro-pédiatrie.

A Monsieur le Docteur Thomas Roujeau, Pour l'honneur d'avoir accepté de participer à ce jury, veuillez recevoir mes remerciements et ma reconnaissance pour l'intérêt que vous avez manifesté pour ce travail.

A Madame le Docteur Sabine Durand, Je te remercie, et les mots sont faibles, de m'avoir confié ce sujet et proposé d'encadrer cette thèse, pour le temps que tu m'as consacré. Tu as été une directrice de thèse formidable. Audelà, merci pour ta disponibilité, ta justesse et ta rigueur ; pour l'exemple que tu es. J'ai hâte de poursuivre mon chemin en néonatalogie à tes côtés.

Au Dr Odile Plan, pour m'avoir conseillée et beaucoup aidée dans le recueil des informations concernant le devenir de chaque enfant, pour ce temps que tu m'as consacré sans lequel ce travail n'aurait pu voir le jour.

Aux médecins des CAMPS de la région, particulièrement les Docteurs Thevenot et De Potter qui m'ont accueillie au sein de leurs établissements pour me confier les parcours des enfants qu'ils suivent. Merci à vous de m'avoir partagé votre regard sur le devenir de vos patients.

A Clémentine Combes, pour ton aide précieuse, pour m'avoir appris les rudiments des statistiques, pour avoir lancé et relancé toutes ces analyses et avoir apporté les derniers détails sur les résultats de cette thèse. Merci infiniment.

Aux enfants et à leurs familles que j'ai rencontrés pendant mes études puis mon internat, pour la confiance accordée, les joies et les peines partagées.

A ma famille,

A mes parents, pour votre transmission, votre exemple, vos trajectoires personnelles et professionnelles, conjointes et séparées, qui m'ont montré tous les chemins possibles de la curiosité, de la passion, de la diversité.

A toi Maman, pour ta douceur, ta force, ta patience et ton amour infinis qui nous ont toujours portés avec Paul. Pour m'avoir accompagnée dans tous les instants de ma vie. Je sais que nos parcours à tous les deux sont une de tes fiertés ; et nous sommes fiers et reconnaissants d'être tes deux enfants.

A toi Papa, pour avoir cru en nous, nos projets et ce que nous allions devenir. Pour ton amour aussi infini et inconditionnel que celui de maman. Pour les fou-rires, les folies, la musique (beaucoup de musique). Quelle chance de vous avoir comme parents.

A toi, Paul, mon petit frère, merci à celui que tu as été, es et seras, qui a toujours su observer le monde dans tous ses détails et qui illustre si bien sa complexité. Pardon pour les larmes et bravo pour ton humour, ta sensibilité, ta justesse, ton difficile et long combat, ton inéluctable ténacité.

A ma grand-mère maternelle Nicole, pour avoir toujours été prévenante et rassurante, pour les moments quotidiens que j'ai eu la chance de partager avec toi et Papi pendant de si longues années, pour tout ce que tu m'as appris et les longues soirées à Limonest ; je ne te remercierai jamais assez, ma Mamie, pour tout ce que tu fais pour moi.

A mon grand-père Michel, parce que toi et Mamie accourez si souvent (même au milieu de la nuit !) pour être à mes côtés pour me soutenir. Pour toutes les histoires que tu m'as racontées, pour la sérénité et la sécurité que tu m'as transmises. Je mesure la chance de vous avoir tous les deux aujourd'hui pour ce jour particulier.

A ma grand-mère paternelle Nicole, pour ta dévotion envers chacun de tes petits-enfants. J'admire ta force silencieuse immense, ton intelligence, ton attention. Je suis fière de notre complicité, des moments que nous avons passés juste ensemble. Merci d'être venue aujourd'hui pour partager ce beau moment avec moi.

A mon grand-père, Gilbert. Pour ton caractère dont j'ai hérité plus que je n'ose l'avouer. Comme tu me manques. Jamais je n'aurais cru présenter ce travail sans toi. Aux précieux souvenirs que tu m'as construits et qui façonneront toute ma vie.

A Cathy, mon deuxième prénom. Pour tout ce qu'on partage de fort, pour la fibre parisienne, pour les fou-rires, pour les soirées en famille together.

A Isabelle, pour l'inspiration que tu me transmets. Toujours un peu loin mais malgré tout beaucoup là. Merci pour ta douceur, ta « discrète » excentricité, ta sensibilité. Tu es trop chouette et pas trop piquette.

A Alain, pour ton pur esprit, ton humour imbattable, ta sérénité, ton élan belge, ta capacité à ambiancer les repas de famille. Tu es une personne incroyable. Votre présence, à Isabelle, Cathy et toi aujourd'hui compte énormément pour moi, je ne peux vous remercier assez d'être aussi présents et d'avoir en plus traversé le pays pour ce jour particulier.

A Fabrice, pour ta générosité, ta rigueur, ton énergie, merci pour ton soutien et pour la nouvelle famille que nous formons ensemble.

A Olivier et Vincent, mon ascendance directe que je ne peux renier tant je vous ressemble (et je ne parle pas seulement de la taille). Grâce à vous (ou à cause de vous ? je ne sais plus vraiment) l'esprit familial se perpétue et sévit dans le sud de la France maintenant.

A Lakti, ma tante de coeur, car tu as toujours eu les mots justes, cette force tranquille qui lève toute complexité en quelques instants.

A mes cousins, Rachel, Adrien, Matthieu, Charles, Louise-Anne, Constance, Pauline. Mes protégés qui m'ont rapidement dépassée dans tous les sens du terme.

A Léo, mon grand Léo, j'adore me rappeler comme tu étais minuscule, tu es devenu si grand et si génial. Je te souhaite tout le bonheur que tu mérites pour le début de ta vie d'adulte, ton nouveau départ nantais, mais reviens assez vite s'il te plait.

A Barbara, je ne pouvais évidemment pas oublier de te réserver quelques mots qui ne diront jamais assez la place toute particulière que tu as dans mon coeur ; merci à tout ce que tu représentes, ma Barbara in Paris.

A André et Myriam, pour votre proximité chaleureuse, votre accompagnement pour mes premiers pas dans le sud et bien sûr tous les souvenirs partagés en famille.

A Juliette, ma grande-tante, toujours si discrète mais présente.

Aux Matussière, ma famille de coeur, pour tout ce qu'on a partagé.

A Agnès, quel bonheur de t'avoir auprès de moi pour cette occasion. Merci d'être toujours avec nous, avec maman, pour le meilleur et le reste.

A Julien, pour nos soirées virtuelles, pour ton accent du nord, nos retrouvailles devenues éparses, j'espère te retrouver bientôt.

A Vassilis, pour cette rencontre qui n'aurait jamais dû avoir lieu, cette soirée au théâtre. Pour me pousser à vivre à cent à l'heure, à découvrir ce que je n'aurais jamais osé approcher. Merci de ne pas trop relever mes bizarreries, d'accepter ce qui ne te ressemble pas, d'apprécier mes divagations. Pour nos différences qui nous unissent, le foyer que nous formons, ce que nous construisons ensemble. Vraiment, pour ton amour, ton courage, ton soutien qui me portent tous les jours, je n'exprimerai jamais assez bien ma gratitude.

A mes amis,

A ma Louise, bien sûr, toi la première car toujours toi aux premières loges de toute remarque, exclamation, interrogation, tout effroi, cauchemar à n'importe quelle heure du jour ou de la nuit. Sans censure, sans peur, sans formalité. Merci pour notre amitié exceptionnelle.

A mes premiers colocataires, les inséparables, ceux de l'ère perpignanaise qui ne fut qu'une courte période de notre interminable amitié ; A nos premiers pas d'internes ensemble… sans vous je n'y serai jamais arrivée.

A Boris, personne ne sait vraiment pourquoi ni comment nous en sommes arrivés à devenir d'aussi proches amis mais vraiment, j'ai de la chance de t'avoir. Merci pour ton écoute, tes conseils, ton déhanché sur Toxic, tes troubles obsessionnels et compulsifs. Je vais continuer à hanter ta vie un long moment.

A Philippe, la toute première personne que j'ai croisée à l'aube de mon internat, précisément les premières minutes de mon arrivée à Carémeau. Même si tu as failli nous tuer dans les ronds-points de Perpignan, je te dois beaucoup. Merci également de m'aider à lutter contre ma chips-addiction. Bref, tu es en or.

A Marion, que dire, notre vraie histoire commence le jour où… je vous ai déjà raconté l'épisode de la gastro de Perpi ? Ma Marion, je suis tellement fière de toi, de nous, de nos bêtises. Tu mets tellement de paillettes dans ma vie. Je t'ai préparé un trousseau de clés, tu viens t'installer à l'appart s'il te plait ? A Mathilde, avec qui j'aurais vécu les deux plus merveilleuses colocs de l'histoire des colocs. J'adore me vautrer sur le canapé avec toi sous une tonne de plaids en décortiquant toute notre vie avec nos super-tisanes ou un verre de vin (pas plus, sinon faut te tenir les cheveux), te regarder jouer à la PS comme une vraie professionnelle, chanter ton plus beau registre musical, dessiner des oreilles, enquêter sur les pires tueurs en série. C'est si Jean Michel évident d'être ton amie.

A Mérédith, pour ta sagesse, ta spontanéité, la façon dont tu mets si facilement les mots sur ce qu'on ressent pour nous guider, dont tu veilles sur nous. J'aime ta maladresse autant que ta justesse, tes aventures improbables, tes passions soudaines pour des loisirs toujours plus folkloriques, ton optimisme, ton engagement. Merci d'être là.

A Louis, pour notre amitié foudroyante : un matin je te croisais en pyjama sans savoir trop qui tu étais et le lendemain c'était parti pour toutes les pires blagues du monde, les interminables parties de jeux vidéo, les faits absurdes, un peu louches et surtout peu racontables que nous partageons.

A François, pour cette amitié introduite par alliance comme on dit, pour ton incroyable capacité à passer du discours le plus sérieux aux pires inepties, parce que tu es capable de nous faire croire n'importe quoi avec Mathilde, parce que tu veilles aussi un peu sur nous un peu tout le temps pour nous éviter de faire trop n'importe quoi.

« Mais avant tout »… Je vous aime, vous le savez, mais pas trop non plus.

A Maxime, El Professor, merci d'avoir éprouvé une once d'intérêt pour moi un jour qui a fait naître notre super amitié interminable. Merci pour la joie, l'amour, les films d'horreur, le confinement, les fous rires, les endormissements inopinés sur le canapé, les débats interminables, les combats de luchador, les techniques imparables pour échapper aux zombies, les concerts privés, le sauvetage de l'humanité, la Fée Fagot. Merci pour le Notrepellier que nous avons édifié. Je sais que vous serez toujours là avec Mathilde et ça signifie tellement pour moi.

A Réjane, pour notre coup de foudre amical, notre trio infernal avec Boris, (heureusement que nous sommes là pour le remettre sur le droit chemin). Je me rappellerai toujours notre journée à la librairie BD de Nîmes qui a scellé notre amitié. 4 ans plus tard, rien n'a changé. Ah si, tu as dépassé les 30 ans.

A Armel, merci (je ne m'étendrai pas plus pour éviter tout embarrassement).

A Baptiste, mon Baptou, pour nos conversations de fin de soirées à l'internat (après tes siestes stratégiques), parce que nous étions les derniers en pistes donc les meilleurs.

A Céline, pour avoir autant encouragé Maxime à descendre les poubelles, pour avoir fait partie de Notrepellier avec indulgence. Merci d'être là, Petroushka, pour partager avec enthousiasme nos découvertes littéraires un peu tranchées.

A Klément, pour être avec ma Marion préférée. Je suis heureuse de t'avoir enfin rencontré après tout ce temps.

A la joyeuse équipe de l'internat de Carémeau que je n'ai pas encore citée, ma première maison, merci pour ce semestre dingue. Sans vous, ça n'aurait vraiment pas été pareil. Willy, pour ton talent comédien inégalable et tes exploits autour d'une poubelle un certain 31, Ophélie, pour entraîner tout le monde sur la piste de danse en un clin d'oeil, Elise, pour tes aventures que tu mènes de front avec tes projets pro, Marion F, pour ton humeur éclatante intarissable, Sarah, pour ton énergie positive (et tes superbes cocktails), Karl, pour nous trouver les belles pépites à écouter en soirée, Arthur, pour ta gentillesse et ta sensibilité, Rémi, pour le plus gros sprint que tu as tapé après qu'on t'a trollé sur le téléphone de garde, Chloé, pour nos entraînements dans la salle commune (même si j'ai vite lâché l'affaire), Irma, pour ta joie pétillante et notre team salle de naissance, Agathe, la reine des soirées KRMO, Camille, pour tes histoires de ZUP et ton rire inimitable, Charlène et Claire pour vos joyeuses histoires de S1.

Au Yacht, merci de m'avoir intégrée à votre joyeuse bande. Pb, pour ta gentillesse et tes blagues d'anesth-réa. Meryem, pour ta douceur et nos confidences. Sarah, pour avoir succombé au charme de la pédiatrie, c'est forcément parce que tu es une fille bien. Marine, pour tes costumes improbables, ton énergie et avec Charles, pour les idées foireuses qui vous passent par la tête à chaque soirée après quelques grammes. Jawad et Pauline, pour nos soirées mondaines sur les belles terrasses de Port-Marianne, les quatro caffeyche, parce que vous n'êtes pas nets et qu'on se marre bien quand même. Dorian, pour ton humour inégalable et la patience avec laquelle tu supportes Vass.

A Maxime et Victorine, des super copains que je n'aurais pas eu l'occasion de rencontrer sans un petit coup de main de la vie. Vous êtes formidables et j'espère qu'un jour nous attraperons vraiment Crocmou. A Mathilde, Claudia, Camille, Charlotte, Sondra je ne compte plus nos années d'amitié, c'est indécent. Tout est dit, vous étiez là et vous êtes encore là. Je suis fière de notre parcours à toutes, je n'en reviens pas vraiment d'ailleurs. Merci pour ce super week end ensemble, vivement les prochains… A Claire, pour nos confessions, ta sollicitude, ta sensibilité, ta voix merveilleuse.

A mes amies de la faculté, les galériennes, Estelle, Romane, Solange et Audrey. Nous touchons du bout des doigts ce que nous rêvions depuis les bancs de la fac, quel bonheur d'avoir fait ce chemin avec vous.

A Diane, mon binôme, mon double, ma future co-…, je te suis à la trace. Passer ce cap me terrifie un peu moins maintenant que je sais que je le passerai avec toi.

A Marion, ma Goulard, ma compagne de galères, je suis heureuse que tu reviennes parmi nous parce que tu m'avais franchement manqué.

A mes co-internes Réunionnaises, Emeline, Tamara, Anne. Pour les courses de poses de KTVO et de KTEC, pour avoir couru comme des dingues avec vous dans les couloirs après des appels lunaires de la salle de naissance, pour l'esprit rebelle que nous avons cultivé, pour avoir failli rester coincées au fond de Grand Bassin avec Tamara, quels merveilleux moments nous avons passé. Vous êtes parfaites, ne changez pas.

A Charles, pour m'avoir encouragée dans mes travers de grande folle, pour notre complicité qui nous a permis de partager quelques virions, pour avoir affronté ensemble l'adversité et élevé des phacochères, ces 6 mois n'auraient clairement pas eu la même couleur sans toi, anfaite.

A Guillaume G et Nabilla, le trio de choc du premier semestre, inoubliable.

A Cécile et Raphaëlle, pour m'avoir coachée pour ce troisième semestre, pour notre entente parfaite, mes deux vieilles. A Benjamin, pour m'avoir appris plein de choses de la médecine et vraiment pas que de la pédopsychiatrie.

A Lena, pour notre solidarité et notre découverte d'ADV ensemble. A Marie, parce que tu rayonnes toujours quoiqu'il arrive, tu es précieuse ma petite Marie.

Au groupe infernal formé avec vous, Clément, Larry, Camille, Maud, Cyril, Olivia en « pédiatrie si la famille ». Je ne sais pas quel souvenir nous avons laissé au service mais pour moi il est mémorable. Ils sont mémorables d'ailleurs, tout particulièrement le plaquage par Cyril l'intrépide alors que Maud la psychiatre essayait de médier la situation et que Clément et moi les deux lâches étions cachés dans le bureau. Ce semestre avec vous était beaucoup trop court. A Maud, pour cette belle rencontre, ma partenaire de piapia préférée, la redécouverte des soirées pyjama à l'aube de nos 30 ans.

A Julie B et Guillaume C, merci pour notre trio, pour m'avoir aidée à ne pas être trop nulle, pour avoir reconnu mes talents de sudiste, pour les soirées alcoolisées interminables et vos bêtises. Merci pour le spectacle. Je vous adore.

A mon équipe de ce semestre d'été, Margot, Eve, Manon, les vieilles, pour avoir toléré mes élucubrations, mes égarements, mes sautes d'humeur. Elisa, Laure-Alice, nos deux perles, pour avoir géré de ouf comme on dit dans le service. Aux quatre filles des SIP, Elise, Clémence, Pauline, Illies (hehe), les petits jeunes très bientôt grands, toujours à manigancer dans votre ruche, vous étiez top. Vivement nos prochaines soirées à devenir n'importe qui en faisant n'importe quoi.

Juliette, mi-co-interne mi-cheffe, enfin nous travaillons ensemble. Même si j'apprécierais de te voir un peu moins souvent, cela reste sympathique d'être ton interne. Enfin, tu sais comme je t'adore.

A mes chefs et collègues,

A l'équipe de néonatalogie de Nîmes, Nassiba, Caroline, Thibault, Maryam, Serge, Julia, Gaëlle, Aurélie, Joëlle, pour mes premiers pas en néonatalogie, vos encouragements, votre bienveillance, votre encadrement. Aux puéricultrices et auxiliaires de puériculture du service, pour m'avoir fait découvrir de si près les soins aux tout petits. A Massimo, pour votre écoute, votre humour, vos encouragements, vos enseignements qui resteront toujours ancrés à la fois dans ma mémoire et dans ma pratique.

A l'équipe de neuropédiatrie du Pr Rivier, Sarai, Pierre, Julie, Agathe, Blanca, Danielle, les puéricultrices et auxiliaires, pour ce semestre si riche en émotions et en connaissances, pour nous avoir enseigné le B.A-BA de la neurologie et le soin tout particulier que vous apportez à vos patients.

A l'équipe de pédiatrie générale de Perpignan et de Nîmes, pour ma formation essentielle et polyvalente de pédiatre.

A l'équipe de cardio-pneumo-pédiatrie, Marika, Johan, Marie, Grégoire, Sophie, merci de m'avoir accueillie dans votre équipe et de m'avoir partagé vos connaissances. A Oscar, Victor, pour m'avoir supportée et avoir osé imaginer qu'un jour je comprendrais le sens des shunts intracardiaques. A Floriane, pour avoir fait bloc avec nous dans l'adversité du « 2 », pour la facilité déconcertante avec laquelle tu drives une tonne de choses à la fois, pour nos soirées entre filles.

A l'équipe de néonatalogie du CHU de Saint-Denis, Duk, Anthony, Isabelle, Claire, Marie, Mathilde, Léa, Sylvain, Shaam, Ioulia, Tereza, Audrey, pour votre accueil ; pour ce semestre si formateur et épanouissant, la confiance que vous m'avez accordée tout en restant présents et rassurants, les décharges d'adrénaline comme je n'avais jamais connu, les challenges de pose en temps record de KTVO (je devais le souligner car c'était vraiment exceptionnel).

Et enfin, la dernière mais pas des moindres, l'équipe de médecine néonatale et réanimation pédiatrique du CHU de Montpellier : les médecins, les infirmières et puéricultrices, les auxiliaires, les smurettes. Merci pour votre pédagogie, la patience et la bienveillance avec laquelle vous me formez depuis mon quatrième semestre. La part que vous avez prise dans mon parcours est immense, je suis fière de poursuivre mon parcours avec vous. Florence, Odile, Camille, vous étiez mes premières cheffes quand je suis arrivée dans le service, merci pour votre énergie et pour ces premiers pas qui m'ont confortée dans la voie de la néonatalogie. Renaud, Maud, Vincent, vous m'avez vite plongée dans le bain de la réanimation ; c'était un semestre intense, j'ai tant appris en si peu de temps. Vous m'avez formée avec beaucoup de bonne humeur, de liberté et de sécurité, ces quelques mois ont été décisifs. Christophe et Julien, pour avoir eu la patience de m'enseigner les rudiments de la réanimation pédiatrique, merci pour votre pédagogie et avoir rendu ce secteur un peu moins vertigineux à mes yeux. Sophie, parce que quand on sera grandes avec Manon on voudrait être comme toi. Bénédicte et Anaïs, pour votre douceur, votre rigueur et votre calme exemplaires. Damien, pour ces dernières semaines ensemble au secteur parents-enfants avec nos petits protégés. Héléna et Laurène, pour votre énergie et vos bons conseils, Maliha, pour les gardes que nous avons faites ensemble, pour ton investissement dans la formation des jeunes médecins, Chloé et Sita, pour votre exemple ; pour quelques aventures en salle de naissance marquantes vécues ensemble et cette année de cours de néonatalogie, Stéphanie, nous n'avons pas eu l'occasion de souvent travailler ensemble, j'espère que ce n'est que partie remise. increase risks of adverse neurological outcome [START_REF] Bolisetty | Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants[END_REF][START_REF] Futagi | Neurodevelopmental outcome in children with intraventricular hemorrhage[END_REF]. The risk seems to be higher and the neurological impairment more severe in case of post hemorrhagic ventricular dilatation (PHVD) (4-7). The onset of PHVD is estimated in Europe around 50% of grade 3 and 4 IVH [START_REF] Brouwer | European perspective on the diagnosis and treatment of posthaemorrhagic ventricular dilatation[END_REF].

Table des matières

The pathogenesis of PHVD is complex, secondary of an obstruction of arachnoid by blood components and arachnoiditis, impairing cerebro-spinal fluid (CSF) circulation and resorption.

The resulting ventricular dilatation increases intracranial pressure, leading to parenchymal compression and ischemic lesions in the surrounding white matter [START_REF] Leijser | Preterm brain injury: Germinal matrix-intraventricular hemorrhage and post-hemorrhagic ventricular dilatation[END_REF].

Options and timing for treatment of progressive PHVD are still controversial for neonatologists and neurosurgeons in Europe ( 8) and even at national level [START_REF] Garreres | Prise en charge de l'hydrocéphalie post hémorragique chez le nouveau-né prématuré : cohorte rétrospective locale et enquête nationale[END_REF].

Pharmacological therapeutics (diuretics, fibrinolytic injections) did not demonstrate their effectiveness [START_REF] Whitelaw | Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation[END_REF][START_REF] Whitelaw | Intraventricular streptokinase after intraventricular hemorrhage in newborn infants[END_REF]. We currently recognize two treatment strategies : temporizing and Several studies tried to determine the best time to intervene because symptoms of PHVD are non specific and late in premature infants [START_REF] Kaiser | Cerebrospinal fluid pressure during post haemorrhagic ventricular dilatation in newborn infants[END_REF]. Ventricular enlargement is usually quantified with measurement of Levene index using cranial ultrasound (CUS) [START_REF] Levene | Measurement of the growth of the lateral ventricles in preterm infants with real-time ultrasound[END_REF]. Studies commonly use the Levene index as an intervention threshold, broadly divided in two approaches : early intervention when conducted before ventricular Levene index crosses ≥ 97 th percentile + 4mm for gestational age (GA) versus late intervention when ventricular Levene index already crosses this limit. Those retrospective investigations demonstrate positive impacts of an early approach on neurological outcome [START_REF] Whitelaw | Management of posthaemorrhagic ventricular dilatation[END_REF][START_REF] Leijser | Posthemorrhagic ventricular dilatation in preterm infants: When best to intervene?[END_REF]. The ELVIS trial published recently finally showed a beneficial effect of early intervention for PHVD on reducing mortality and severe neurodevelopmental disability [START_REF] Vries Ls De | Treatment thresholds for intervention in posthaemorrhagic ventricular dilation: a randomised controlled trial[END_REF][START_REF] Cizmeci | Assessment of Brain Injury and Brain Volumes after Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled ELVIS Trial[END_REF].

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We ran a retrospective and descriptive study in preterm infants developing PHVD in our center in order to determine factors influencing neurological outcome at 24 months. The primary outcome was neurodeveloppmental outcome at 24 months corrected age (CA) according to demographic, clinical factors, the type of intervention and its timing. Secondary objectives were to assess mortality, different neurological, sensory and developmental morbidities and permanent shunt requiring. We hypothesized that active and early management would be associated with a favorable neurological prognosis.

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PATIENTS AND METHODS

Patients

We conducted a monocentric retrospective study. Inclusion criteria were patients with a grade 3 or 4 IVH according to Papile classification (1), an evolutive PHVD mentioned by the radiologist in CUS medical reports, born with a gestational age under 33 weeks at birth and a weight at birth ≤ 1500g between January 2003 and December 2019. These patients were identified with local database of premature children hospitalized in the Arnaud de Villeneuve University Regional Hospital, Montpellier, France. Non-inclusion criteria were outborn children, significant congenital anomalies or bilateral grade 4 IVH, periventricular leukomalacia (PVL) diagnosed on CUS or brain injuries from another etiology (stroke, asphyxia).

Cranial ultrasound

For each CUS, Levene index ( 14) was measured by radiologist and reported in medical reports. If not mentioned, it was retrospectively measured on reviewed imaging data by the investigator C. Mazzoleni with radiological expertise control. We defined radiological intracranial hypertension by a resistance index measure on the anterior cerebral artery > 0.85 without patent ductus arteriosus. We determined timing of treatment with Levene index from the last CUS recorded before first intervention. We classified timing in 2 groups : 1/ Levene index between 97th percentile and 97th percentile + 4 mm according to gestational age, setting early timing of intervention, 2/ Levene index ≥ 97 th percentile + 4 mm according to gestational age, setting late timing.

Intervention

Temporizing interventions for PHVD included CSF punctures (transfontanellar and lumbar punctures), sub-galeal shunt, external shunt and ventricular reservoir. Ventricular-peritoneal shunt was considered as a permanent intervention. Data at age at intervention, efficacy and complications of each procedure were noted. Complications included infection, reservoir or shunt obstruction or displacement, shunt revision.

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Follow-up

We collected informations about mortality and morbidity. Concerning mortality, age and context of death (limitation or withdrawal of intensive care or maximal resuscitation) were analyzed. For surviving children, neurodevelopmental outcome at 24 months' CA was collected in medical records in regional medico-psycho-social centers. We used the standardized neurological assessment (Annex 1). months corrected age and number of reintervention since birth were analyzed.

Data analysis

Descriptive analyses were performed to study data distribution among surviving and not surviving infants in neonatal period. We also divided surviving children in 2 groups based on a neurodevelopmental composite outcome : 1/ Favorable outcome, defined by the absence or the presence of mild alteration at 24 months' assessment : Brunet Lezine Score ≥ 70 or presence/absence of at least one mild anomaly in standard neurological assessment, 2/ Unfavorable outcome, defined by moderate to severe alteration at 24 months assessment :

Brunet Lezine Score < 70 or presence of at least one moderate to severe anomaly in standard neurological assessment or presence of cerebral palsy.

Descriptive statistics were expressed as medians and quartiles for quantitative variables and as number of patients and percentages for qualitative variables. We used the Fisher's test and Wilcoxon test to compare the baseline characteristics, primary and secondary outcomes in the two study groups. We performed multivariate analysis by logistic regression to identify factors associated with a favorable outcome. We adjusted our model on variables that are already proven in the literature and variables that are significant in univariate analysis : sex, gestational age in weeks (wGA) (stratified in < 28 wGA or 28-32 wGA), complete prenatal corticosteroid cure, -29 -grade 4 IVH, periventricular leukomalacia (PVL), temporizing intervention or not. We could not adjust on timing of intervention (early or late) because of small numbers of patients.

A p-value ≤ 0.05 was retained for significance. Statistical analyses were performed using the SAS University Edition software.

As our study period extends over 16 years, we wanted to analyze the "time effect". We modelized proportions of very preterm birth, active treatment, timing of intervention and neurological outcome according to year of birth.

Data collection

IRB's approval was obtained according to the local procedure. Data were collected from computerized or paper medical records and anonymized. An informative note was sent to children's parents, no one requested withdrawal of the study.

35%, p = 0.728). Among treated children, 100% of children with unfavorable outcome were treated in a late timing. Those with favorable outcome were treated early or late in the same proportion (p = 0.054). There were twice more VPS inserted in children with an unfavorable outcome (24%) compared with favorable outcome (12%) (p = 0.656). Unusually, the proportion of cases crossing ≥ 97 th percentile + 4mm threshold did not differ between groups (p = 1), in the same way for radiological intracranial hypertension (p = 0.707).

In In multivariate analysis conducted over 34 cases, two factors were associated with a favorable outcome at 24 months of CA (Table 8) : absence of associated grade 4 IVH (adjusted odd ratio : 7.9, confidence interval [1.2-52.5], p = 0.032) and complete prenatal corticosteroid cure (adjusted odd ratio : 6.2, confidence interval [1.1-34.6], p = 0.037). This model explained 65% of cases and the Hosmer-Lemeshow test was 0.831.

Secondary outcomes

We compared secondary outcomes between children with intervention for PHVD or not and for treated infants, we compared early and late intervention. Results are presented in Table 8.

Overall cerebral palsy rate among survivors was 30% (n = 13/43).

No child, in each group, developed epilepsy.

Children undergoing active treatment had a higher survival rate (p < 0.001). Among survivors secondary outcomes did not reach statistical difference.

Concerning timing of intervention, no difference was observed for survival. No cerebral palsy, hearing deficit or VPS-requirement occurred in infants treated early whereas it was present respectively in 31%, 27% and 36% of infants treated later. We must highlight that walking age was in median 3 months earlier in the group "late treatment" even if it was not significant. ASQ scores and Developmental Quotient of Brunet Lezine are difficult to interpret because of small numbers of patients.

Finally, walking age is very close between children with or without intervention, no difference was observed according to timing of treatment.

DISCUSSION

We studied neurological outcome at 24 months of CA of infants born under 33 wGA with PHVD over a period of 16 years. Our follow-up rate was high since we were able to collect data for primary outcome from 79% patients surviving at 24 months. Death rate was high and more than a half of deaths were consecutive of withdrawal of intensive care. Half of survivors had a favorable outcome. Majority of sequelae concern fine motricity, behaviour and language skills for children mildly or not impaired. Gross motor impairment was mostly observed in children with moderate or severe sequelae. We observed cerebral palsy in one third of surviving children.

In our sample, we found few factors to explain this difference of outcome. Male sex, uncomplete prenatal corticosteroid cure and grade 4 IVH were more frequent characteristics in children with the greater disabilities. Literature already identified these variables as factors worsening prognosis of preterm infants [START_REF] Shankaran | Outcomes Following Post-Hemorrhagic Ventricular Dilatation among Infants of Extremely Low Gestational Age[END_REF]. We did not find any effect of active treatment of PHVD. Early treatment did not show any benefit either but it's a striking fact that children treated in a late timing all have an unfavorable outcome. Multivariate analysis identified grade 4 IVH and incomplete corticosteroid cure as the most impacting factors on outcome.

Our global mortality rate (60%) was higher than in the literature where estimations vary from 20% to 52% [START_REF] Garreres | Prise en charge de l'hydrocéphalie post hémorragique chez le nouveau-né prématuré : cohorte rétrospective locale et enquête nationale[END_REF][START_REF] Whitelaw | Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions[END_REF][START_REF] Van Zanten | Neurodevelopmental outcome of post-hemorrhagic ventricular dilatation at 12 and 24 months corrected age with high-threshold therapy[END_REF]. Among treated children, our mortality rate was 28%, also higher than numbers observed in other cohorts, from 8,4% to 13% [START_REF] Cizmeci | Assessment of Brain Injury and Brain Volumes after Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled ELVIS Trial[END_REF][START_REF] Limbrick | Neurosurgical treatment of progressive posthemorrhagic ventricular dilation in preterm infants: a 10-year single-institution study[END_REF].These comparisons must be taken with caution because inclusion criteria were disparate and ethical issues are necessarily considered.

The intervention rate in our sample was 28%, lower than 30-72% previously observed [START_REF] Murphy | Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome[END_REF][START_REF] Brouwer | European perspective on the diagnosis and treatment of posthaemorrhagic ventricular dilatation[END_REF][START_REF] Limbrick | Neurosurgical treatment of progressive posthemorrhagic ventricular dilation in preterm infants: a 10-year single-institution study[END_REF][START_REF] Bock | Early surgical management and long-term surgical outcome for intraventricular hemorrhage-related posthemorrhagic hydrocephalus in shunttreated premature infants[END_REF][START_REF] Brouwer | Cognitive and neurological outcome at the age of 5-8 years of preterm infants with posthemorrhagic ventricular dilatation requiring neurosurgical intervention[END_REF]. In our series, 4 children over 10 were not treated even though Levene index crossed the 97 th percentile + 4mm threshold, revealing important part of therapeutic abstention despite severity of dilatation. Ethical factors, multidisciplinary discussions and family all participate to medical decisions to intervene or not. In our sample, children undergoing intervention were thus older, with better clinical condition, making more obvious the benefit to conduct such procedures. Moreover, children treated early might have presented a less severe or rapid ventricular dilatation course and a more stable clinical condition allowing an early intervention.

In our cohort, VPS requirement in survivors was 14%, consistent with literature where we can observe rates going from 12 to 20% [START_REF] Brouwer | Neurodevelopmental outcome of preterm infants with severe intraventricular hemorrhage and therapy for post-hemorrhagic ventricular dilatation[END_REF][START_REF] Garreres | Prise en charge de l'hydrocéphalie post hémorragique chez le nouveau-né prématuré : cohorte rétrospective locale et enquête nationale[END_REF][START_REF] Vries Ls De | Treatment thresholds for intervention in posthaemorrhagic ventricular dilation: a randomised controlled trial[END_REF]. Conversion rate of temporizing neurosurgical procedures in VPS was 100%. Other authors also found high rates of conversion, between 65 and 94% [START_REF] Bock | Early surgical management and long-term surgical outcome for intraventricular hemorrhage-related posthemorrhagic hydrocephalus in shunttreated premature infants[END_REF][START_REF] Wellons | Shunting outcomes in posthemorrhagic hydrocephalus: results of a Hydrocephalus Clinical Research Network prospective cohort study[END_REF].

Regarding [START_REF] De Vries | Early versus late treatment of posthaemorrhagic ventricular dilatation: results of a retrospective study from five neonatal intensive care units in The Netherlands[END_REF]. This difference was not statistically significant though. In another retrospective study by Brouwer et al, infants treated early had a significantly higher developmental quotient using Griffiths Mental Developmental Scale [START_REF] Luiz | The construct validity of the Griffiths Scales of Mental Development[END_REF] than infants treated later [START_REF] Brouwer | Neurodevelopmental outcome of preterm infants with severe intraventricular hemorrhage and therapy for post-hemorrhagic ventricular dilatation[END_REF]. No difference for cerebral palsy was noted. In the multicentric study by Leijser et al, infants treated at an early stage had the same cognitive and motor outcome at 24 months' (in normal range) than infants without intervention.

On the opposite, children treated later had lower cognitive and motor scores than children without intervention. Survivors with intervention also showed higher rates of impairments than those without, especially CP [START_REF] Leijser | Posthemorrhagic ventricular dilatation in preterm infants: When best to intervene?[END_REF].

Recently [START_REF] Cizmeci | Randomized Controlled Early versus Late Ventricular Intervention Study in Posthemorrhagic Ventricular Dilatation: Outcome at 2 Years[END_REF].

The rationale for early intervention is underlied by deleterious effects of prolonged pressure injuries on the surrounding white matter. White matter might present very early alterations of perfusion on Apparent Diffusion Coefficient sequences on Magnetic Resonance Imaging before volume reduction [START_REF] Brouwer | Effects of Posthemorrhagic Ventricular Dilatation in the Preterm Infant on Brain Volumes and White Matter Diffusion Variables at Term-Equivalent Age[END_REF]. Brain growth (total cerebrum, cerebellum and thalami) is significantly impaired in children with PHVD treated ≥ 97 th percentile + 4mm [START_REF] Jary | Impaired brain growth and neurodevelopment in preterm infants with posthaemorrhagic ventricular dilatation[END_REF]. In a nested substudy of ELVIS trial, it was reported that the Kidokoro score was significantly better and ventricular volumes were significantly smaller in the early treatment group [START_REF] Cizmeci | Assessment of Brain Injury and Brain Volumes after Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled ELVIS Trial[END_REF]. In the EPIPAGE cohort, the odd ratio of the association between cystic periventricular lesions and PHVD was 5.3

(CI, 3.0-9.5) adjusted for GA [START_REF] Larroque | White matter damage and intraventricular hemorrhage in very preterm infants: the EPIPAGE study[END_REF], highlighting the risk of severe white matter injury by evolutive ventriculomegaly. Study of cerebral haemodynamics and oxygenation on little series of patients illustrates an improvement after CSF drainage [START_REF] Kempley | Changes in cerebral artery blood flow velocity after intermittent cerebrospinal fluid drainage[END_REF][START_REF] Norooz | Decompressing posthaemorrhagic ventricular dilatation significantly improves regional cerebral oxygen saturation in preterm infants[END_REF] even when ventricular index is retablished < 97 th percentile + 4mm [START_REF] Van Alfen-Van Der Velden | Cerebral hemodynamics and oxygenation after serial CSF drainage in infants with PHVD[END_REF]. PHVD has also been associated with increasing of abnormal amplitude-integrated EEG and delayed latencies of evoked potentials, earlier than elevation of intracranial pressure. They normalize after CSF drainage [START_REF] Olischar | Cerebrospinal fluid drainage in posthaemorrhagic ventricular dilatation leads to improvement in amplitudeintegrated electroencephalographic activity[END_REF][START_REF] Vries | The role of short latency somatosensory evoked responses in infants with rapidly progressive ventricular dilatation[END_REF][START_REF] Klebermass-Schrehof | Can neurophysiological assessment improve timing of intervention in posthaemorrhagic ventricular dilatation? Arch Dis Child Fetal Neonatal Ed[END_REF]. In our study, we have no usable data over duration or severity of PHVD reflecting the degree of white matter compression but it might have played a role according to these findings. Grade 4 IVH or other white matter injuries being closely linked to worse neurological outcome, their prevention is our main issue.

In our series, the proportion of children with a Levene index crossing the 97 th percentile + 4mm threshold was the same regardless neurological outcome. It constrasts with observations of Srinivasakumar et al, illustrating the relation of maximal anterior horn width, thalamo-occipital distance and ventricular index with neurodevelopmental outcomes at 18-24 months on assessment using the Bayley Scales of Infant Development [START_REF] Srinivasakumar | Posthemorrhagic ventricular dilatation-impact on early neurodevelopmental outcome[END_REF]. In the retrospective study by Leijser et al, when the ventricular size is much larger, the associated developmental outcomes are worse [START_REF] Leijser | Posthemorrhagic ventricular dilatation in preterm infants: When best to intervene?[END_REF], supporting the interest in avoiding such degrees of ventricular dilatation when possible.

Our study has several limitations due to its retrospective and monocentric design and a relatively small surviving patient cohort. We have many missing data about chronology and duration of ventricular dilatation. A majority of children died, 9 were lost to follow up. 82% children had no Brunet-Lezine score available when it was part of our primary composite outcome. Our results did not reach statistical significance probably because of a lack of power.

The study period extends over 16 years while medical practices have changed, PHVD management evolved. We used ventricular index [START_REF] Levene | Measurement of the growth of the lateral ventricles in preterm infants with real-time ultrasound[END_REF][START_REF] Brouwer | New reference values for the neonatal cerebral ventricles[END_REF] to quantify ventricular size and set this threshold a posteriori but it was not necessary a criterion for monitoring nor intervening for some children. Other criteria were often used by radiologists or clinicians : anterior horn width, « ballooning shape » of lateral ventricle, clinic symptoms of intracranial hypertension, increased resistance index on doppler of anterior cerebral artery. For example, the anterior horn width does not change with maturation, is more reproductible and might be a more sensitive marker for early dilatation [START_REF] Whitelaw | Management of posthaemorrhagic ventricular dilatation[END_REF][START_REF] Brouwer | New reference values for the neonatal cerebral ventricles[END_REF][START_REF] Davies | Reference ranges for the linear dimensions of the intracranial ventricles in preterm neonates[END_REF]. In Figure 4, we show that over time, leading interventions in our center is not a more frequent option and intervening early remains rare among our patients.

Our study included a large cohort of patients even if a majority of children did not survive.

We gathered numbers of data on CUS parameters for each child in particular Levene index and the timing of intervention despite the retrospective nature of this study. CUS were performed by radiologists regularly limiting diagnosis and treatment delay when children were asymptomatic.

Evaluation at 24 months of CA was studied by a trained pediatrician based on a standardized clinical neurological assessment. Our primary outcome included different aspects of development to be the most exhaustive on children's follow up. Later evaluation is required to appreciate evolution in early childhood or teenage and in other domains like praxies, learning, behavior and social abilities.

Perspectives for management of PHVD is evolving across neonatal centers. When active treatment is decided, early intervention should be conducted as soon as possible. Avoiding high degrees of ventricular dilatation should be our main issue to protect white matter from irreversible damages, hoping for a favorable neurological outcome for our patients. When ethical questioning is raised, pre-existing parenchymal injuries, absence of corticosteroid maturation and severity of PHVD should guide our discussions. In light of current literature and our results, new management of PHVD in our center should succeed to optimize the care of infants with PHVD.

CONCLUSION

Half of children with PHVD following high grade IVH had a normal or mild neurological alteration at follow up. The group of children with greater disabilities were more often males, with uncomplete corticosteroid cure and grade 4 IVH. Our hypothesis was not validated : in our study, we did not find an influence of active intervention nor timing of intervention.

However our study encourages to intervene early, when Levene index is < 97 th percentile + 4 mm, since children treated in a late timing all had an unfavorable outcome. Literature suggests that avoiding large degrees of ventricular dilatation should be our main objective. When ethical questioning is raised, the evolution of PHVD itself in particular when it escapes treatment should guide decisions. Temporizing interventions should not be interpreted as a risk factor of adverse outcome but as a reflect of a turning point in ventricular dilatation's evolution, worsening prognosis in this way.

-39 - -40 - Figure 3a. Primary outcome repartition in followed-up children. Figure 3b. Degree of anomaly (no, mild or moderate to severe) in each area according to standard neurological examination (Annex 1) in followed-up children.

No alteration 21%

Mild alteration 29%

Moderate to severe alteration 50%

1 4 . 4 4 . 5 2 INTRODUCTION

 44452 ABBREVIATIONS ........................................................................................................ --2 INTRODUCTION ......................................................................................................... --3 PATIENTS AND METHODS .......................................................................................... --3.1 Patients ......................................................................................................................... --3.2 Cranial ultrasound ......................................................................................................... --3.3 Intervention .................................................................................................................. --3.4 Follow-up ...................................................................................................................... --3.5 Data analysis ................................................................................................................. --3.6 Data collection .............................................................................................................. --4 RESULTS .................................................................................................................... --4.1 Description of population .............................................................................................. --4.2 Interventions ................................................................................................................. --4.3 Maternal and neonatal characteristics ........................................................................... --Primary outcome ........................................................................................................... --Secondary outcomes ..................................................................................................... --5 DISCUSSION .............................................................................................................. --6 CONCLUSION ............................................................................................................. --7 FIGURES .................................................................................................................... --8 TABLES ...................................................................................................................... --9 BIBLIOGRAPHY .......................................................................................................... --10 ANNEX ................................................................................................................... --11 CERTIFICAT DE CONFORMITE ................................................................................. --12 SERMENT D'HIPPOCRATE ....................................................................................... --13 ABSTRACT .............................................................................................................. --RESUME ............................................................................................................................ --Intraventricular hemorrhage (IVH) remains a frequent and significant neurological complication of prematurity. Severe IVH (grade 3 or 4 according to Papile classification (1)) occured in 17.2% of children born at 23 through 34 weeks of gestation in French cohorts (2). IVH

  permanent interventions. In clinical practice, temporizing interventions consist in tapping exceeding CSF (repeated lumbar punctures or ventricular punctures) and temporary surgical interventions (ventricular subgaleal and external shunts). Feasibility and efficiency of such procedures are variable. Temporizing procedures can be used until PHVD decreases or, if permanent shunt (ventriculo-peritoneal shunt) is needed, until children gain weight, maturity and CSF proteins decreases to allow this surgery.

Figure 4 ,

 4 we did not observe time effect on the use of temporizing interventions or timing of treatment. The proportion of surviving children born under 27 wGA seems to have increased over time whereas the proportion of favorable outcome remained stable.

Figure 1 .

 1 Figure 1. Flow chart of infants born under 33 weeks of gestational age (wGA) in our cohort following grade 3 and 4 intraventricular hemorrhage with post-hemorrhagic ventricular dilatation. IVH : intraventricular hemorrhage. PHVD : post-hemorrhagic ventricular dilatation.

Figure 2 .

 2 Figure 2. Flow chart presenting different temporizing interventions and permanent interventions in our sample. CSF : Cerebrospinal Fluid. VPS : Ventriculoperitoneal shunt.

  Figure 3a.

Figure 3 .

 3 Figure 3. Repartition of primary outcome and sequaele in followed-up children (n = 34).Figure3a. Primary outcome repartition in followed-up children. Figure3b. Degree of anomaly (no, mild or moderate to severe) in each area according to standard neurological examination (Annex 1) in followed-up children.

Figure 4a .

 4a Figure 4a. Proportion of survivalFigure 4b. Proportion of infants born on total included population (n = 108).under 27 wGA among survivors (n = 43).

Figure 4c .

 4c Figure 4c. Propotion of interventionFigure 4d. Proportion of intervention in early timing on total included population (n = 108).among treated children (n = 25).

Figure 4e .

 4e Figure 4e. Proportion of no or mild neurological alteration among followed-up children (n = 34).

Figure 4 .

 4 Figure 4. Proportions (%) of survival (4a), extremely preterm infants (4b), intervention (4c), timing of intervention (4d) and primary outcome (4e) according to years of birth over the study period. wGA : weeks of gestational age.

  It was adapted from the Amiel Tison Neurological Assessment (19) considering fine and gross motor skills, language and cognitive skills, behavior, hearing and vision. It categorized children's developmental areas in 3 groups : no anomaly, mild or moderate to severe anomaly. If available, we recorded the Brunet Lezine score (20). This score evaluates moderate to severe delay if global developmental score is < 70 (21). Results of Ages and Stages Questionnaires (22) were also collected. Walking age, presence of epilepsy and cerebral palsy (CP) were recorded. CP was defined according to the European Cerebral Palsy Network (23). Gross Motor Function Classification System Expanded and Revised (24) evaluated level of motor impairment for children with CP. Presence of ventricular-peritoneal shunt at 24

  neurodevelopmental outcome at 24 months of CA in our series, temporizing interventions should not be considered as a risk factor of worse outcome. Indeed, no difference of outcome between children with intervention or not was observed but almost all children with intervention had a Levene index ≥ 97 th percentile + 4mm. Temporizing interventions might be a reflection of a turning point in dilatation's severity, worsening prognosis in this way. However we found a trend regarding timing of intervention in favor of early treatment. This observation is in accordance with current literature. In a retrospective study among 95 preterm patients with PHVD following grade 3 IVH, De Vries et al found that children with late treatment (Levene index ≥ 97 th percentile + 4mm) developed moderate or severe disabilities at 24 months of CA in 26% of cases (considering epilepsy, motor, cognitive and sensorial impairment) VS 16% in those treated early or 14% in children without intervention

  , the Early Versus Late Ventricular Intervention Study Group (ELVIS group)

	conducted a multicentric randomized controlled trial, including 126 preterm infants born ≤ 34
	wGA with a grade 3 or 4 IVH across 14 NICU in Europe, USA and Netherlands. Infants were
	randomized in two arms treated early or late (considering Levene Index, AHW and/or thalamo-
	occipital distance). The objective was a ventricular index < 97 th percentile over 7-10 days
	following first intervention. First results published in 2018 found no significant reduction in VP
	shunt insertion and in mortality in early intervention as compared with later intervention (17).
	Finally, earlier intervention reduced death or severe neurodevelopmental disability (set by Bayley
	score < -2 SD and/or CP) in a model adjusted on gestational age, severity of IVH and cerebellar
	injury

  Neurological standardized assessment, adapted from the Amiel Tison Neurological Assessment.

	100% 10 ANNEX						100%
	80% 60%	7		27	14 Normal, no anomaly 17	6 Mild anomaly 60% 80%	9	3 Moderate to severe 3 anomaly
	0% 20% 40% Gross motor skills 8	16	falls -Protection when 10 9 before 18 months -Walk acquisition		0% when falls 20% 40% -No protection 2 after 18 months -Walk acquisition	7	7 -No walk alone 6
		2003-06 2007-10 2011-14 2015-19 -Climbs staircases		2003-06 2007-10 2011-14 2015-19
	Fine motor skills	Survival	Death -Stacks 6 cubes		-Tower of 2	< 27 wGA	≥ 27 wGA -Pathological
					-Nests 3 objects		-Nests 3 objects	grasping
								-No stack
								-No nest
	Language and			-Sentences of 2		-Words but no	-Jargon
	100% cognitive skills			words			100% sentence	-Can't point
	80% 60%	10		35	-Names objets/pictures 17 21 -Pretends to call		4 objects/pictures 60% 80% -Points without naming	7	4 objects/pictures 4 -No relationships play
	40%				-Imagination games	40% -Points or names	-Brings objects to
	5 2003-06 2007-10 2011-14 2015-19 8 7 4 Behavior disorder 20% 0% None		1 2003-06 2007-10 2011-14 2015-19 1 3 1 body parts 0% 20% his mouth -No imagination games -Need to calm down -Throws objects
		Intervention	No intervention		the child	Early timing	Late timing -Stereotypical
								-Attention lability	activities
								-Self or hetero
								aggresivness
								-Significant sleep
					100%			disturbances
	Visual or hearing impairment		None 80% 60%	1	10	3 -Corrected with 3 glasses/hearing impairment without	-Visual impairment despite of glasses/hearing aid
					40%	4		hearing aid	or cochlear implants
	Annex 1.				20%		4	5	4
					0%
						2003-06 2007-10 2011-14 2015-19
						No or mild	Moderate to severe

RESULTS

Description of population

The distribution of patients is presented in detail in a flow chart (Figure 1). In total, 173 children born under 33 weeks of gestation with PHVD following grade 3 or unilateral 4 IVH were admitted, representing 8% (n = 173/2049) of the preterm infants admitted in our center over the study period. After excluding children according to criteria mentioned above, a total of 108 children were included in this study. 44% (n = 47/108) had been diagnosed with a grade 3 hemorrhage and 57% (n = 61/108) with an unilateral grade 4.

Surviving rate was 40% (n = 43/108). 60% (n = 39/65) of deaths occurred ≤ 14 th day of life and 54% of these deaths (n = 35/65) after decision of limitation or withdrawal of intensive care. No child died between discharge from NICU and follow-up at 24 months CA.

In our cohort, temporizing interventions occurred in 23% of cases (n = 25/108), and 42% (n = 18/43) in the group of surviving children. 36% (n = 17/47) of grade 3 IVH led to an intervention, 13% for grade 4 (n = 8/61).

Among survivors, assessment at 24 months of CA was available for 79% of children (n = 34/43). Of these 34 children, 18% (n = 6/34) had a Brunet-Lezine evaluation recorded in their medical files. Informations about neurological standard assessment and presence of cerebral palsy was available for all of them.

Interventions

A flow chart sums up carried out procedures in our cohort (Figure 2). Of all 108 children, lumbar or transfontanellar punctures were laid for 23% of them (n = 25/108) and always as first-line treatment. One child did not undergo temporizing intervention but a VPS was inserted at 4 months of CA after an intracranial hypertension clinical presentation.

After first-line treatment, 44% of children (n= 11/25) did not undergo further interventions, 24%

(n = 6/25) were treated by neurosurgical procedures, and 28% (n = 7/25) died. 57% (n = 4/7) of deaths after first-line treatment were consecutive to a decision of intensive care withdrawal. For one child, PHVD recovered after lumbar punctures in neonatal period and VPS was only placed at 6 months of CA after acute intracranial hypertension.

-31 -20% (n = 5/25) children underwent temporizing neurosurgical procedures as second line treatment. These procedures led to complications for 80% (n = 4/5) of cases. Sub-galeal shunts were placed for 3/5 infants, 2/3 died after complications. For the surviving child, sub-galeal shunt was effective and VPS was placed because PHVD persisted. Ventricular reservoir was used for one child, no complication was observed. One child was treated with external shunt, complicated with meningitis. For one child, VPS was used as a second-line treatment but dysfunction occurred on abdominal cyst and it was temporary replaced by an external drainage. 100% (n = 5/5) of temporizing surgical procedures led to VPS insertion among survivors. VPS requirement at 24 months among survivors undergoing temporizing neurosurgical procedures represented 14% (n = 6/43) of cases. 100% (n = 6/6) of VPS were still present at 24 months of CA.

Maternal and neonatal characteristics

Comparisons of maternal and neonatal characteristics between children who survived or not are summed up in Table 1. The 2 groups were comparable for gestation characteristics. Male sex was similar in 2 groups. However, complete prenatal corticosteroid cure was higher in survivors (65%) than in dead children (46%) but this difference was not statistically significant (p = 0.075).

Survivors had higher gestational age (median of 27 weeks of gestation VS 25.1 weeks, p < 0.001) and less likely to present grade 4 IVH (30% VS 74%, p < 0.001). Concerning the evolution of PHVD itself (Table 2), diagnosis was made early : in median at 5 days of life for children who survived and 3 days of life for dead children (p < 0.001).

Children who died after a decision of intensive care withdrawal had 77% grade 4 IVH (n = 27/35).

Infants with PHVD who had a temporizing intervention for progressive PHVD were compared with those who did not have an intervention. These results are presented in Table 3.

Those with an intervention presented a less severe clinical condition : they had a higher gestational age (median of 27.7 weeks of gestation VS 25.4 weeks, p < 0.001), had less parenchymal damages (grade 4 IVH in 32% cases VS 64%, p = 0.006), less bronchopulmonary dysplasia (16% VS 56%, p = 0.011) and lower death rate (28% VS 72%, p < 0.001). Paradoxically, they presented more severe necrotizing enterocolitis (17% VS 1.7%, p = 0.022). Clinical evolution of PHVD (Table 4) was more severe among treated children, with radiological intracranial hypertension (resistance index > 0.85 on anterior cerebral artery without patent ductus arteriosus) occurring in 60% of cases, more than 25% of children with no intervention (p = 0.003).

Almost all treated children had a Levene index crossing the 97 th percentile + 4mm threshold (96% of cases, n = 23/24) whereas 43% (n = 31/83) did not undergo temporizing interventions despite a Levene index across this limit (p < 0.001).

Among treated infants, demographic comparisons according to timing of intervention are presented in Table 5. We can notice in the group "early intervention" some trends : a lower gestational age [START_REF] Whitelaw | Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions[END_REF][START_REF] Futagi | Neurodevelopmental outcome in children with intraventricular hemorrhage[END_REF] wGA VS 28,3 wGA, p = 0.058), a higher frequence of complete prenatal corticosteroid cure (67% VS 42%, p = 0.378). Children also presented higher rates of grade 4 IVH (50% VS 26%, p = 0.344). These results must be taken with caution because of the small numbers of analyzed children.

Primary outcome

Half of the children (n = 17/34) had no or mild neurodevelopmental alteration at 24 months CA assessment, 41% of them (n = 7/17) had no anomaly. 50% of children (n = 17/34) had a moderate to severe neurodevelopmental alteration at 24 months CA assessment. Details of affected neurodevelopmental domains in the 2 groups are in Figure 3. The most frequently and severely affected area concerns language and cognitive skills. Fine motor skills seems to be more frequently impaired than gross motor skills. Sensory areas are also often severely impaired. All children with visual impairment wore corrective lenses. Half of the children with hearing impairment wore hearing aids (n = 2/4) and cochlear implants for the other half (n = 2/4).

An analysis was conducted to compare children with favorable outcome (no or mild neurodevelopmental alteration) and those with unfavorable outcome (moderate to severe neurodevelopmental alteration), according to the treatment and its timing.

For interpretation of results and identification of potential confusion bias in our primary outcome, we also compared children with a favorable neurological outcome and those with an unfavorable outcome in Table 6. No significant demographic difference was observed but we underlined a higher rate of complete corticosteroid cure in children with a favorable outcome (82% VS 47%, p = 0.07). There were fewer male sex (53% VS 76%, p = 0.281), PVL (5.9% VS 24%, p = 0.335) in this group.

Concerning PHVD characteristics and treatment, results of the univariate analysis are shown in Table 7. These results were not statistically significant either except for the proportion of grade 4 IVH in children with unfavorable outcome (47% VS 12%, p = 0.057). A few more temporizing interventions were conducted in children with an unfavorable outcome (47% VS Ø Je donnerai mes soins gratuits à l'indigent et n'exigerai jamais un salaire au-dessus de mon travail.

Ø Admis (e) dans l'intérieur des maisons, mes yeux ne verront pas ce qui s'y passe, ma langue taira les secrets qui me seront confiés, et mon état ne servira pas à corrompre les moeurs, ni à favoriser le crime.

Ø Respectueux (se) et reconnaissant (e) envers mes Maîtres, je rendrai à leurs enfants l'instruction que j'ai reçue de leurs pères.

Ø Que les hommes m'accordent leur estime si je suis fidèle à mes promesses. Que je sois couvert (e) d'opprobre et méprisé (e) de mes confrères si j'y manque.

-56 -