# État des lieux de la prescription d'ibuprofène aux nouveau-nés prématurés d'âge gestationnel inférieur à 32 semaines d'aménorrhée pour le traitement du canal artériel : données du CHU Amiens-Picardie de 2018 à 2019

Camille Szcrupak Bouchardon

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Camille Szcrupak Bouchardon. État des lieux de la prescription d'ibuprofène aux nouveau-nés prématurés d'âge gestationnel inférieur à 32 semaines d'aménorrhée pour le traitement du canal artériel : données du CHU Amiens-Picardie de 2018 à 2019. Pediatrics. 2020. dumas-04969026

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UNIVERSITÉ DE PICARDIE JULES VERNE

FACULTÉ DE MÉDECINE D'AMIENS

Etat des lieux de la prescription d'ibuprofène aux nouveau-nés prématurés d'âge gestationnel inférieur à 32 semaines d'aménorrhée pour le traitement du canal artériel.

Données du CHU Amiens-Picardie de 2018 à 2019.

THÈSE N° 2020 – 94

POUR LE DIPLOME D'ÉTAT DE DOCTEUR EN MÉDECINE
QUALIFICATION PÉDIATRIE

Présentée et soutenue publiquement le 11 septembre 2020 par :

SZCRUPAK BOUCHARDON Camille

**Président du Jury** : Pr WALLOIS F.

**Membres du Jury** : Pr GUILÉ J.M.
Pr DJEDDI D.
Dr HARAUX E.
Dr LEKE A.

**Directeur de thèse** : Dr KONGOLO G.
À mon président de jury,

Monsieur le Professeur Fabrice WALLOIS

Professeur des Universités-Praticien Hospitaliser (Physiologie)

Responsable du Groupe de Recherches sur l'Analyse Multimodale de la Fonction Cérébrale

Chef du Service d'Explorations Fonctionnelles du Système Nerveux Pédiatrique

Chevalier dans l'Ordre des Palmes Académiques

Officier dans l'Ordre National de la Légion d'Honneur

Vous me faites l'honneur de présider ce jury et évaluer mon travail. Je vous témoigne ma
profonde et respectueuse reconnaissance.
À mon jury,

Monsieur le Professeur Jean-Marc GUILE

Professeur des Universités – Praticien Hospitalier (Pédopsychiatrie)

Coordonnateur du DES de psychiatrie

Vous me faites l'honneur d'être membre de ce jury et d'évaluer mon travail.
À mon jury,

Monsieur le Professeur Djamal DJEDDI

Professeur des Universités – Praticien Hospitalier (Pédiatrie)

Responsable du centre d'activité "Médecine Pédiatrique"

Pôle "Femme - Couple - Enfant"

Vous me faites l'honneur d'apporter votre expérience à la critique de ce travail en tant que
membre du jury de thèse.
À mon jury,

Madame le Docteur Elodie HARAUX

Maître de Conférences des Universités – Praticien Hospitalier (Chirurgie infantile)

Je vous prie de recevoir mes sincères remerciements pour avoir accepté d'évaluer mon travail.
À mon jury,

Monsieur le Docteur André LEKE

Praticien Hospitalier (Pédiatrie)

Responsable du centre d'activité "Soins intensifs de néonatalogie et unité mère-enfant"

Pôle "Femme - Couple - Enfant"

Vous me faites l'honneur d'être membre de ce jury. Je vous suis reconnaissante d'avoir partagé vos connaissances. Travailler à vos côtés m'a beaucoup appris. Merci aussi pour la confiance que vous m'avez accordée.
À mon directeur de thèse,

Monsieur le Docteur Guy KONGOLO,

Praticien Hospitalier (Pédiatrie)

Tu as accepté de m'accompagner tout au long de ce travail. Je te remercie pour ta patience, ta gentillesse et tes précieux conseils. Cela a été un plaisir de travailler avec toi. Reçois ma sincère gratitude.
### A Monsieur le Professeur Pierre TOURNEUX

Je vous remercie de m'avoir dès mon 3ème semestre, guidée sur cette voie de la néonatalogie.
Merci également pour le temps que vous passez au service des étudiants, je vous en suis
reconnaissante.

### A l'équipe du service de néonatalogie de Saint-Quentin

Je vous remercie de m'avoir transmis cette passion de la néonatalogie dès mon 1er semestre.
Merci de m'accueillir dans votre équipe dans quelques mois.

### A l'équipe de pédiatrie de Saint-Quentin

Vous m'avez fait aimer la pédiatrie générale. Merci pour votre bienveillance, ne changez pas !

### A l'équipe de soins intensifs de néonatalogie au CHU

Vous avez conforté mon choix de la néonatalogie. Merci à toute l'équipe et notamment le Dr LEKE, Sabrina, Christel, et Lucie.

### A l'équipe de réanimation pédiatrique au CHU

Mon stage d'interne n'a pas été simple mais j'ai su apprécier votre service à sa juste valeur, celle de l'exigence menant à l'excellence. Merci particulièrement à vous Ghida, Laurent, Stéphanie, Yasser, François, Sandrine, Lisa, Anne-Laure, et Coralie. Chacune et chacun à votre manière, vous m'avez permis de me réaliser dans cette spécialité. Je suis honorée de faire partie de votre équipe en novembre.

### Aux équipes des services de neurologie, cardiologie, SMUR pédiatrique et CRTLA

Merci pour votre accueil au cours de mes stages d'interne que j'ai tous beaucoup appréciés.

### A l'équipe du CAMSP

Merci à Anaïs et Cécile de m'avoir formée à la prise en charge pluridisciplinaire des enfants les plus fragiles. Je garde précieusement ces connaissances pour mes futures consultations. Merci également aux autres professionnels du centre d'avoir partagé avec moi leurs séances. Ce stage a été un réel plaisir.
### A Antoine

Pour toutes ces années passées ensemble, et sans qui tout cela ne signifierait rien. Je t'aime.

### A mes parents

Sans qui cette formation médicale n'aurait pu se faire. Merci pour votre soutien inconditionnel.
Merci aussi de m'avoir permis de grandir dans une famille unie et aimante. Je vous aime.

### A ma grande sœur

Mathilde, pour m'avoir apporté tant de confiance et de soutien dans ce que j'entreprenais. Je suis si heureuse en ta présence.

### A mon petit frère

Nicolas, pour toutes les merveilleuses années passées ensemble. Depuis mon départ pour Amiens, je suis peinée par le peu de moments que l'on peut partager.

Au reste de ma famille, Fred et Renaud, Suzanne, Hélène, Annick et Raymond, Corinne et Claude, Eliott... Pour votre soutien, votre écoute et votre bienveillance.

### A mes grands-parents

J'aurais tant aimé partager ce moment avec vous.

A ma belle-famille, Chantal et Michel, Vanessa et Jérôme, Leo, Arthur, Caroline
Pour votre gentillesse et votre accueil. Vous avez une grande place dans mon cœur.

### A Cécile

Avant tout pour ces moments de partage et de détente en dehors de toute ambiance médicale.
Durant ces études tu as été un pilier sur lequel je me suis toujours appuyée. Longue vie à notre amitié !

### A Barbara

Pour tous ces bons moments partagés ensemble en 9 ans. Ces années d'étude m'auraient paru bien longues sans toi. J'ai tant de chance de t'avoir comme amie.
A Emilie

Pour ton énergie et ta bonne humeur ; passer du temps avec toi est réjouissant. Merci de me proposer ta présence dans les moments difficiles.

A mes co-internes et aux belles rencontres durant l'internat : Céline, Juliette P., Elise, Camille K., Lucie, Ludovic, Gwendoline, Sana, Mickaël, Leslie A., Loïc, Juliette D., Solène, Chloé, Hugo, Samira, Julie, Nathalie, Lisa, Fiorella, Fétine, Hélène C., Inès, Marie, Florian, Fanny M., Justine...

A mes amis du lycée : Marie, Marguerite, Flore, Julia, Blandine, Claire, Raphaël, Maximilien.
Malgré ces années passées depuis la terminale, nous avons toujours gardé ce fort lien d'amitié.
Table des matières

<table><tr><td>Abréviations</td><td>13</td></tr><tr><td>Introduction</td><td>14</td></tr><tr><td>Matériel et méthode</td><td>15</td></tr><tr><td>Résultats</td><td>17</td></tr><tr><td>Discussion</td><td>20</td></tr><tr><td>Conclusion</td><td>23</td></tr><tr><td>Bibliographie</td><td>24</td></tr><tr><td>Figures et tableaux</td><td>27</td></tr><tr><td>Notes</td><td>33</td></tr><tr><td>Résumé</td><td>34</td></tr></table>
Prescription status of ibuprofen for the treatment of patent ductus arteriosus in preterm
infants born before 32 weeks of gestation.

CHU Amiens-Picardie data from 2018 to 2019.

Camille Szcrupak¹, Guy Kongolo¹

¹ Neonatal intensive care unit, CHU Amiens-Picardie, Hauts-de-France region, France

**Corresponding author :**

Guy Kongolo

Neonatal intensive care unit, CHU Amiens-Picardie, Hauts-de-France region, France

Tel.: +33-322-087-604

Fax: +33-322-089-781

Kongolo.guy@chu-amiens.fr

Conflict of interest: None

**Keywords:** PDA, preterm infant, ibuprofen, NICU, exposure to ibuprofen
Abbreviations

PDA: patent ductus arteriosus

PCA: postconceptional age

DA: ductus arteriosus

NICU: neonatal intensive care unit

CHUAP: university hospital center of Amiens-Picardie

WG: weeks of gestation

GA: gestational age

BW: birth weight

CRIB: Clinical Risk Index for Babies

CLD: chronic lung disease

PDAs: patent ductus arteriosus treated by surgery

NEC: necrotizing enterocolitis

NECs: necrotizing enterocolitis treated by surgery

IVH: intra-ventricular hemorrhage

NICHD: National Institute for Child Health and Development

AUDIPOG: Association of users of computerized records in pediatrics, obstetrics and gynecology

CNN: Canadian Neonatal Network

SGA: small for gestational age

LISA: Less Invasive Surfactant Administration

Plac.: placental

NOi: Inhaled nitric oxide

ATB: antibiotherapy

DV: ventricular derivation

Perc: percentile
**Introduction**

Patent ductus arteriosus (PDA) is a common problem in neonatology, especially for preterm infants [1]. Incidence of PDA varies inversely to postconceptional age (PCA) at birth [2]. The ductus arteriosus (DA) is a fetal vascular communication between the aorta and the pulmonary artery. When DA persists for many days after the birth, it can act as a bypass that deviates a more or less important part of the left ventricular flow towards the pulmonary circulation [3]. The consequences can be serious, even lethal: hemodynamic disorders, hypotension, pulmonary hemorrhage, renal failure, intraventricular hemorrhage, chronic lung disease, enterocolitis [4]. To close the DA, ibuprofen as medical treatment is in first line in France [5]. The other alternative is surgical ligation [6]. The efficacy of ibuprofen or surgical treatment for closing the ductus arterial and for preventing early pulmonary hemorrhage is well documented [7]. Whether ibuprofen confers any benefits on mortality, chronic lung disease, and neurodevelopmental outcome is still debated [8]. Despite the benefits, this treatment by ibuprofen in preterm infants also involves risks [5].

For several decades, clinical studies on DA have failed to establish a clear consensus on optimal management [9,10]. Many neonatal intensive care units (NICU) such as the CHU Amiens-Picardie (CHUAP) use ibuprofen as first line treatment when the DA is significant [5,7] on ultrasound [11–13] with respiratory failure symptoms [14]. Surgical treatment is used in case of contraindication to ibuprofen or after failure of 2 courses of ibuprofen. In some other care units, there is a preference for a conservative attitude, and surgical management is proposed only in case of severe respiratory failure [15–17].

In the absence of consensus, as there are side effects related to the use of this product, it seems important to estimate exposure to ibuprofen for the treatment of PDA in preterm infants born before the postconceptional age of 32 weeks and hospitalized at the CHU Amiens-Picardie NICU. This was the main objective of our current study. Secondary outcomes were to compare our practice to that of other equivalent neonatal centers and networks regarding exposure to a pharmacological medical treatment for PDA and the incidence of PDA with respect to gestational age and body weight at birth.
# Materials and methods

This study was retrospective, descriptive, observational and monocentric.

## 1. Study population

We reviewed the DXCare® electronic medical records of all the infants admitted to the NICU of CHUAP between January 1st 2018 and December 31st 2019. Preterm infants born <32 weeks of gestation were included in the study. Infants with congenital heart defect or major congenital malformations, infants who died within the first 48 hours of life, and infants transferred to CHUAP more than 7 days after birth were excluded from the analysis. The study protocol was approved by the local ethics committee (n° PI2020_843_0066).

Patients' demographics (gestational age, gender, birth weight/size/head circumference), perinatal and neonatal characteristics (chorioamnionitis, oligohydramnios, vascular or hemorrhagic placental pathology, singleton/twin pregnancy, antenatal steroids and magnesium sulfate administration, mode of delivery, inborn/outborn, occurrence of fetal heart rhythm abnormalities, Apgar score, CRIB, presence of PDA, treatment with ibuprofen or surgical ligation, pulmonary hemorrhage, chronic lung disease (CLD), treatment with antibiotics, support with respiratory care, surfactant administration, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), post-hemorrhage hydrocephalus and ventricular derivation, circulation support with vasopressor amines infusion, and inhaled nitric oxide within the first 72 hours of life) were recorded. Death and length of stay were also extracted from the electronic medical records. The significance of a PDA was defined after commonly and widely accepted criteria [12,13]; the National Institute for Child Health and Development (NICHD) criteria were used for the definition of CLD; the modified Bell criteria were used for the definition of NEC; the Papile cranial ultrasound classification was used for intraventricular hemorrhage (IVH), intrauterine growth restriction was defined according to AUDIPOG standards (<10th percentile).

In the current study, we also used data from the 2018 activity of the Canadian Neonatal Network in order to establish a comparison. This information from external hospitals was processed and analyzed using the same framework we applied for our own hospital so as to make the comparison easier.
## 2. Study design

The CHUAP in the north of France is a tertiary neonatal unit providing services for preterm infants from 23 weeks' gestational age.

In its NICU, the clinical and echocardiographic evaluation of the ductus arteriosus first took place at day 2 postnatal, then every 24 hours for infants < 28 weeks PCA and every 48 hours for infants >28 weeks PCA; all the paediatricians in our neonatal unit are trained to perform this evaluation. The assessment of ductus arteriosus with echography criteria [12,13] allowed classification into 3 categories: closed ductus, not significant or significant PDA. Infants were treated with ibuprofen when the DA showed signs of significance on echography associated with clinical symptoms and in the absence of contraindication to ibuprofen. In this study, all the evaluations were performed with the same ultrasound system CX 50 POC (Philips®, Amsterdam, Netherlands).

Population classification: in this study, patients were classified among sub-groups according to gestational age at birth (GA1: ≤ 26+6, GA2: from 27+0 to 28+6, GA3: from 29+0 to 30+6, GA4: from 31+0 to 31+6 weeks) and birth weight (BW1: <750, BW2: from 750 to 999, BW3: from 1000 to 1249, BW4: ≥ 1250 grams). The analyses were carried out for the whole population and then according to the gestational age and birth weight subgroups defined above. This made it possible to assess the incidence of PDA, the rate of exposure to a pharmacological treatment for PDA, perinatal characteristics, specific morbidity and outcomes during the initial neonatal period according to each gestational age category and each birth weight category. The same subgroups were also used as frameworks for the analysis of data from the CNN 2018 report [18].

The description of the quantitative variables was carried out by the mean and the standard deviation. We used t-test for the comparison of 2 groups and ANOVA when more than 2 groups were involved. Proportion and frequency were used for the description of qualitative variables; the chisquare test was used for comparison of groups for proportions. Kaplan-Meyer curve was applied for censured data. Non-parametric statistics and tests were applied when there were doubts about the Gaussian distribution for variables. The statistical significance was considered for 5% α-error (p <0.05). The statistical analyses were all performed using the R programming language's statistical libraries.
## Results

Two hundred and ninety-two preterm infants < 32 WG were admitted to the NICU at CHU Amiens-Picardie from January 1st 2018 to December 31st 2019, 21 of whom were not included in our study because of: congenital heart diseases (n=5), major congenital malformations (n=2), transfer to CHUAP after 7 days postnatal age (n=3), and death before 48 hours of life (n=11). Among these 11 dead infants: 4 were suffering from hemodynamic disorders, 3 from pulmonary hypertension, 2 from perinatal anoxia, 1 from septic shock and 1 from pulmonary hemorrhage. Thus, 271 preterm infants (129 F/142 M) were included in our study. Their gestational age was 28.27 ± 2.27 WG (minimum: 23.00; maximum: 31.86), and birth weight was 1078 ± 372 grams (g) (minimum: 490; maximum: 2600). The obstetrical characteristics of pregnancies, the clinical characteristics of infants and their management both at birth and during the stay in the intensive care unit, were in accordance with the data and current practices of care for preterm infants in industrialized countries (table 1). However, some of the perinatal characteristics such as the rate of antenatal corticosteroid therapy for fetal maturation (61.2%), administration of magnesium sulfate for fetal neuroprotection (64.2%), and the rate of caesarean sections (54.2%) should be further improved. The rate of chorioamnionitis was 24.3%, Apgar score was 6.8 ± 3, 8.2 ± 2.2 and 9 ± 1.6 at respectively 1, 5 and 10 minutes after birth, and clinical severity score (CRIB) was 8.7 ± 4.1. Details on clinical characteristics can be found in table 1, depending on gestational age at birth.

According to the classification defined in method section: 87 infants corresponded to the gestational age sub-group GA1, 61 to GA2, 85 to GA3, 38 to GA4. According to birth weight, 59 infants corresponded to the subgroup BW1, 65 to BW2, 60 to BW3 and 87 to BW4. Rate of exposure to ibuprofen for PDA (calculated as 100 x number of infants who received pharmacological treatment for PDA/ number of patient) was 35% (95/271), distributed as follows: 71.3% in GA1, 27.9% in GA2, 17.7% in GA3 and 2.6% in GA4 (figure 1, table 2). According to birth weight, specific rate of exposure to ibuprofen was 62.7% in BW1, 44.6% in BW2, 28.3% in BW3 and 13.8% in BW4 (table 2).

Incidence of PDA in the GA subgroups in CHUAP was 72.4% in GA1, 32.8% in GA2, 17.7% in GA3, and 2.6% in GA4. According to birth weight, results were 64.4% in BW1, 47.7% in BW2, 28.3% in BW3, 14.9% in BW4 (table 2). In the 2018 CNN report, this incidence was 65.7%, 44.7%, 17.0%, and 7.2% in subgroups ≤26<sup>+6</sup>, 27-28, 29-30 and 31-32 GW, respectively. According to birth weight, results were 63.9%, 55.2%, 32.6%, and 16.4% in subgroups <750, 750 to 999, 1000 to 1249, and ≥ 1250 grams, respectively [18] (table 2).
There was no difference between CHUAP and CNN for the specific rate of PDA in subgroups defined with respect to GA and BW (**table 2**). The crude rate of pharmacological treatment with (ibuprofen and / or indomethacin and / or paracetamol) in CNN (15%) was lower than in CHUAP (35%, p <0.05). Further analyses in subgroups showed that exposure to a specific pharmacological treatment in CHUAP was higher than in the CNN in GA1 (71.3% vs 41.6%, p<0.001), in GA3 (17.7% vs 3.9%, p<0.001), and in all birth weight subgroups (**table 2**). In BW2 the threshold was at the limit of significance. In our NICU, no infant was treated for PDA with a conservative approach, unlike in CNN hospitals where 670 (14.9%) infants benefited from it.

Twenty-two patients (8.1%) from our center were treated by surgical ligation, at 15 ± 5.1 postnatal days [7,31]. This represented 22.2% (22/99) of infants with PDA, all but two were born before 27 WG. According to data from the CNN report, this surgery was performed in 1.2% of infants born before 33WG, i.e. 4.1% (53/1303) of infants with PDA (**table 3**).

Treatment with infusion of vasopressor amines for circulatory disorders was observed in 65 patients, i.e. 24% (65/271) of infants included in our study and 65.6% (65/99) of infants with PDA. Inhaled nitric oxide (NOi) for the treatment of pulmonary hypertension was used in some patients at CHUAP during the few days just after birth. Intravenous antibiotic therapy lasting more than 3 days and antifungal therapy were prescribed respectively for 84.5% (229/271) and 25.5% (69/271) of infants in our study (**table 1**). Respiratory support with tracheal ventilation was necessary for 211 patients out of 271 (77.8%), exogenous surfactant was administrated to 252 patients out of 271 (93%) among whom 68 (25%) were treated by *Less Invasive Surfactant Administration* procedure (LISA). Weaning from respiratory support with tracheal ventilation was definitive within 48 hours postnatal in 37.2 % (n=100 patients), between 3 and 7 postnatal days in 10.8 % (n=29) and between 7 and 28 postnatal days in 30.5% (n=82). Rare cases of massive pulmonary hemorrhage (5%) occurred, especially in the smallest infants in subgroups GA1 (n=10) and GA2 (n=5), and in only 1 preterm infant born after 30 WG. Chronic lung disease (CLD) occurred in 79 patients (29.1%) and was more common in GA1 (41.1%, 41 patients out of 87) and GA2 (39.3%, 24 patients out of 61) than in GA3 (14.1%, 12 patients out of 85) and GA4 (5.3%, 2 patients out of 38). In the 2018 CNN report, CLD occurred in 28.3% preterm infants <33 WG; specific rate within subgroups was 54.6%, 40.6%, 22.6% and 9.9% in GA1, GA2, GA3 and GA4 subgroups, respectively (**table 3**). Sixty-eight infants out of 271 (25.1%) were transfused with red blood cells, platelets or plasma only once; and 62 (22.9%) needed two or more transfusions (**table 1**). Twenty-seven infants (10%) had necrotizing enterocolitis (NEC) ≥ grade 2 according to Bell's classification, 17 of whom in
GA1. In the CNN 2018 report, the incidence was 3.4% in all the infants <33 WG, and 10%, 3%, 2% and 1% in GA1, GA2, GA3 and GA4 subgroups, respectively (table 3). In CHUAP, 55 cases (20.3%) of intraventricular hemorrhages (IVH) grade 3-4 according to Papile classification occurred, among which 40 cases in GA1 (46%, 40 patients out of 87), 13 cases in GA2 (21.3%, 4 patients out of 61) and two in GA3 (2.3%, 1 patient out of 85). A ventricular derivation due to hydrocephalus was required for 2 infants (2.3%) in GA1, 4 (6.6%) in GA3, 1 (1.2%) in GA3. In the CNN report, 6.4% of infants < 33 WG developed a severe IVH, with proportions of 16.4%, 8.5%, 2.4% and 1.8% in the subgroups GA1, GA2, GA3 and GA4, respectively (table 3).

Death occurred in 56 preterm infants (20.7%) at postnatal age (median, extremes) of 25.2 days [2-147]; they were characterized by a birth weight of 747 ± 24 g [490-1500] and a gestational age at birth of 26.2 ± 2 WG [23-31.6]. In case of severe organic or functional damage, ethical considerations were taken into account to guide the decision whether to continue active child care or not. This probably influenced the characteristics of events recorded in medical files. In infants dead in context of neurologic damage, i.e. IVH 3-4 (53.6%, 30/56), average postnatal age was 19 days [2-99], gestational age was 25.4±1.4 WG and AUDIPOG growth score was normal at 44 ± 33 percentile. When severe IVH was not involved (46.4%, 26/56), gestational age was two weeks higher (27±2.2 weeks), AUDIPOG growth score was lower (23.5±26 percentile) and infants were older with 30.2 [3-147] postnatal days (table 4). Death in infants without severe IVH was associated with hemodynamic disorders (n=13), septic shock (n=4), enterocolitis (n=4), massive pulmonary hemorrhage (n=2), hemorrhagic shock (n=1), hepatic insufficiency (n=1), pneumothorax (n=1). In the CNN report, the death rate was 7.1% for all the infants <33 WG, details within subgroups can be found in table 3. There was an inverse association between the length of stay after admission to our NICU and the gestational age at birth: 50% of infants were released at 36 ± 22.9 days (d) in GA1, at 22.4 ± 14.9 d in GA2, at 12.8 ± 16.8 d in GA3, and at 8.8 ± 7.9 d in GA4; chi2 = 128, p <0.001 (Kaplan-Meyer) (figure 2).
## Limitations

Our main objective was to estimate exposure to ibuprofen for the treatment of PDA in preterm infants < 32 weeks in our neonatal level III unit: this crude rate was about 35% in this population. The exposure was all the higher as the gestational age and body weight were low at birth. The specific rates were 71.3% for ≤ 26<sup>+6</sup> WG and 62.7% <750g and as low as 2.6% in ≥ 31WG and 13.8% in ≥1250g subgroups of the infants. The rate of exposure was even higher in less than 25 WG preterm infants (78.3%). There was a marked difference before and after 27 WG regarding exposure to ibuprofen.

Physiologically the timing of spontaneous closure of the ductus arteriosus is determined by maturation in enzymatic reactions, endocrine functions (prostaglandins) and obeys genetic programing factors [3,19,20]. There are many other pharmacologic interventions that can affect the time of closure of DA; Cox-1 inhibitors like ibuprofen or indomethacin hasten closure, while others like prostine delay the closure of DA[5,7]. The spontaneous closure of ductus arteriosus continues to be common during the whole first week of life. To avoid overestimating the incidence of PDA, the diagnosis should be performed after 7 days postnatal, especially in very preterm infants, as shown by Se In Sung et al. [21]. Natural incidences of spontaneous closure of DA were measured in care units which have a conservative management strategy characterized by avoiding specific treatment [15,16,21].

Proper diagnosis of PDA is essential as it subsequently guides prescription. In fact, overdiagnosis could lead to overtreatment. In order to evaluate our practices regarding this diagnosis, we compared our results with those in literature. In comparison to the CNN 2018 report [18], there was no significant difference with our results about the rate of PDA diagnosis. In another study in 2015 in France at Antoine-Béclère Hospital [16], PDA was found for 89% preterm infants at 24-25 WG and 71% at 26-27 WG. In Korea [21] in 2019 the estimate was around 93% for infants born at 23-24WG, 64% at 25-26WG, and 21% at 27-28WG. In Italy [22] in 2019 it was 70% for infants born at 23-24 WG and 59% at 25 to 28WG. Finally, in a paper in 2017 in the United States [23] the incidence was around 61% PDA for infants at 23-26WG, 42% at 27-28WG and 20% at 29-30WG. Thus, our results for the presence of PDA seemed to be similar to those in literature, leading us to believe in the efficacy of the diagnosis of PDA in our center.

However, exposure to a medical treatment was higher in our population in comparison to the CNN 2018 report, probably due to the use of a conservative approach in their population. Indeed, the current trend in other centers is to use a less pharmacological closure and a more
conservative treatment approach. This conservative approach is justified by existence of side effects related to pharmacologic treatment [15,21]. It is difficult to establish the cause-effects relation between ibuprofen and adverse effects on preterm infants. Side effects attributed to ibuprofen may also be related to the hemodynamic consequences of PDA. Some inherent risks with ibuprofen are presented in literature [7,24–26]. Treatment with ibuprofen could lead to gastrointestinal effects (spontaneous intestinal perforation, necrotizing enterocolitis), transient renal insufficiency (oliguria, increased blood urea nitrogen and creatinine, renal failure), hyperbilirubinemia, alteration in cerebral perfusion [7]. Thus, despite more than 30 years of research, it seems difficult to establish a consensus on the optimal management of infants with PDA [9,23,27].

In centers using conservative management, surgical treatment is proposed in case of respiratory failure. Surgery is also performed in other centers in case of contraindication to medical treatment or failure. Several studies report adverse neonatal and neurodevelopmental outcomes following surgery [28]. However it seems difficult to establish a clear link, due to confounding factors in these mainly observational retrospective cohort studies of surgery of PDA [29,30]. These studies have led doctors to distrust surgical treatment, but it remains indicated for some infants [6]. An emerging therapeutic alternative that seems attractive is endovascular catheterization but the development of this technique for preterm infants remains challenging and requires more data [31,32].

Since the rate of pharmacological treatment was very high in our population, we compared the outcomes in our patients with those in the CNN patients, in order to define whether we had fewer adverse neonatal outcomes. Results found lower neonatal adverse outcome rates (IVH, NEC, Death) in CNN hospitals compared to our center. The odds ratio (OR) was 7.4 between CHUAP and CNN hospitals for the decision to treat PDA by surgery; the rate of NEC diagnosis (OR: 3.1) and the treatment of NEC by surgery (OR: 4.6) were higher for CHUAP than CNN. Severe IVH (OR: 3.7) and death (OR: 3.5) were also more likely to occur in CHUAP than in CNN. Death rates in preterm infants should be taken with great caution as ethical issues are often addressed in order to decide whether to continue active care or not. Given the lack of improvement in major outcomes despite a higher exposure to a pharmacological treatment, it seems legitimate to question the use of ibuprofen for preterm infants.

One of the limitations of this study is the retrospective nature of this monocentric study. However, our hospital is the only referral center for low-birth-weight infants throughout the Picardie region. Another limitation is that retinopathy, which is one of the main outcomes in
preterm infants was not analyzed in our study, nor was renal failure and increased in unbound
unconjugate bilirubin. We acknowledge that our sub-groups GA4 and BW4 were not quite
comparable to the CNN 2018 report since our GA4 subgroup only contained infants born
between 31<sup>+0</sup> to 31<sup>+6</sup> WG, whereas the CNN report had infants from 31<sup>+0</sup> to 32<sup>+6</sup>WG. In BW4
subgroup in CHUAP, there were no maximum limitation of weight, whereas in the CNN report
infants were included up to 1499g. These differences probably do not affect our results because
in these groups infants have higher birth weight and gestational age, i.e. have fewer medical
problems. Our GA1 group is comparable to theirs; however our BW1 contained only one child
under 500g, while the CNN report had 55 infants out of 4482. All other groups were
comparable. In comment, we note that different medical treatments were used in the CNN,
whereas in CHUAP only ibuprofen was given. Analyses were carried out combining all these
medical treatments.

This study provides a current state of knowledge of the exposure to a pharmacologic
treatment for PDA, with a view to improving professional practices. Comparison with data in
the literature was essential since it is a reliable method of studying our practices. For the first
time in our hospital, we have produced data both on exposure to ibuprofen and on the incidence
of PDA in our unit. The two years being consecutive, we assume consistency in treatment
techniques and especially in the composition of the medical and nursing staff.

Although the management of PDA remains controversial, new criteria have been defined
in literature to support a more individualized approach. In practice, therapeutic decisions are
currently and mainly guided by ultrasound criteria and signs of respiratory failure [9,11,14,23].
Some of these criteria are widely accepted, others are more questioned : gender, antenatal
steroids, chorioamnionitis, clinical signs (increased pulses, murmur, blood pressure), chest X-
ray radiology findings, phase photoplethysmography differences, platelets, nucleated red blood
cells, biochemical markers, C-reactive protein and inflammation, carbon monoxide and
inflammation, natriuretic peptides, troponin T, cerebral pulsed-wave Doppler assessment, near-
infrared spectroscopy, genetic predisposition and pharmacogenetics [11]. These new criteria
seem very interesting for an individualized management. Indeed, it is essential to treat infants
who really need it, and not to treat others, for whom the treatment would be harmful.
Conclusion

This study of practices estimated exposure to ibuprofen for the treatment of DA in preterm infants <32WG in our center in 2018 and 2019. This exposure was very high in CHUAP. There seems to be of interest to moderate prescription of ibuprofen in our center, since this study showed lower complication rates in centers with low exposure to pharmacological treatment, but also the side effects due to ibuprofen. Despite many studies in the last three decades, management of DA remains an enduring controversy, and no consensus has been reached. However, every study like this one will contribute for a better understanding of the DA, the main goal being to improve care so as to decrease adverse neonatal outcomes in preterm infants.
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<figure><img src="image_2.png" /><figcaption>**Figure 1:** Exposure to ibuprofen (%) according to gestational age at birth</figcaption></figure>
<figure><img src="image_3.png" /><figcaption>**Figure 2:** Length of stay in CHUAP NICU according to gestational age at birth</figcaption></figure>
<table><caption>**Table 1:** Perinatal characteristics n(%) according to gestational age at birth (WG)</caption><thead><tr><th></th><th>GA1 ≤ 26<sup>+6</sup><br>(N=87)</th><th>GA2 27 - 28<sup>+6</sup><br>(N=61)</th><th>GA3 29 - 30<sup>+6</sup><br>(N=85)</th><th>GA4 31 - 31<sup>+6</sup><br>(N=38)</th><th>Total<br>(N=271)</th></tr></thead><tbody><tr><td>Outborn</td><td>17 (19.5)</td><td>19 (31.2)</td><td>16 (18.8)</td><td>9 (23.7)</td><td>61</td></tr><tr><td>Female</td><td>47 (54.0)</td><td>25 (41.0)</td><td>39 (45.9)</td><td>18 (47.4)</td><td>129</td></tr><tr><td>PDA</td><td>48 (55.2)</td><td>32 (55.3)</td><td>61 (71.8)</td><td>25 (65.8)</td><td>166</td></tr><tr><td>Magnesium sulfate</td><td>57 (66.3)</td><td>40 (65.6)</td><td>54 (63.5)</td><td>23 (60.5)</td><td>174</td></tr><tr><td>LISA</td><td>7 (8.1)</td><td>18 (30.0)</td><td>29 (34.3)</td><td>14 (36.8)</td><td>68</td></tr><tr><td>Surfactant administration</td><td>82 (94.3)</td><td>57 (93.4)</td><td>79 (92.9)</td><td>34 (89.5)</td><td>252</td></tr><tr><td>Tracheal ventilation</td><td>85 (98.8)</td><td>53 (86.9)</td><td>52 (61.2)</td><td>21 (55.3)</td><td>211</td></tr><tr><td>Vascular plac. pathology</td><td>14 (16.3)</td><td>22 (36.1)</td><td>31 (36.5)</td><td>12 (31.6)</td><td>79</td></tr><tr><td>Hemorrhagic plac pathology</td><td>11 (12.6)</td><td>9 (14.8)</td><td>11 (12.9)</td><td>3 (7.9)</td><td>34</td></tr><tr><td>Chorioamnionitis</td><td>26 (29.9)</td><td>11 (18.0)</td><td>18 (21.2)</td><td>11 (29.0)</td><td>66</td></tr><tr><td>Oligoamnios</td><td>3 (3.5)</td><td>5 (8.2)</td><td>4 (4.7)</td><td>5 (13.2)</td><td>17</td></tr><tr><td>Hydramnios</td><td>2 (2.3)</td><td>1 (1.6)</td><td>2 (2.4)</td><td>3 (7.9)</td><td>8</td></tr><tr><td>Caesarean section</td><td>34 (39.1)</td><td>34 (55.7)</td><td>54 (63.5)</td><td>25 (65.8)</td><td>147</td></tr><tr><td>Twin pregnancy</td><td>19 (21.8)</td><td>12 (19.7)</td><td>18 (21.2)</td><td>9 (23.7)</td><td>58</td></tr><tr><td>Fetal arrhythmia</td><td>18 (20.7)</td><td>21 (35.0)</td><td>27 (32.1)</td><td>13 (34.2)</td><td>79</td></tr><tr><td>SGA &lt;3<sup>ème</sup></td><td>10 (11.5)</td><td>8 (13.1)</td><td>3 (3.1)</td><td>1 (2.6)</td><td>22</td></tr><tr><td>SGA &lt;10<sup>ème</sup></td><td>18 (20.7)</td><td>12 (19.7)</td><td>10 (11.8)</td><td>3 (7.9)</td><td>43</td></tr><tr><td>CRIB score</td><td>12.8±2.52</td><td>9.7±2.41</td><td>6.2±2.28</td><td>3.1±1.73</td><td>8.7±4.15</td></tr><tr><td>Vasopressor amines</td><td>36 (41.4)</td><td>13 (21.3)</td><td>11 (12.9)</td><td>5 (13.2)</td><td>65</td></tr><tr><td>NOi</td><td>18 (20.7)</td><td>7 (11.5)</td><td>6 (7.1)</td><td>2 (5.3)</td><td>33</td></tr><tr><td>ATB &gt;72h</td><td>87 (97.7)</td><td>54 (88.5)</td><td>62 (72.7)</td><td>28 (73.7)</td><td>229</td></tr><tr><td>Antifungal treatment</td><td>44 (50.7)</td><td>16 (26.2)</td><td>6 (7.1)</td><td>3 (7.9)</td><td>69</td></tr><tr><td>Blood transfusion</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>22 (25.4)</td><td>20 (32.8)</td><td>20 (23.5)</td><td>6 (15.8)</td><td>68</td></tr><tr><td>≥ 2</td><td>43 (50.0)</td><td>10 (16.4)</td><td>6 (7.1)</td><td>3 (7.9)</td><td>62</td></tr></tbody></table>

PDA: Patent ductus arteriosus; LISA: Less Invasive Surfactant Administration; Plac.: placental; SGA: small for gestational age; CRIB: Clinical Risk Index for Babies; NOi: inhaled nitric oxide; ATB: antibiotherapy
<table><caption>**Table 2:** Incidence of PDA and rate of exposure to a pharmacological medical treatment in the CNN population compared to our population according to gestational age at birth and birth weight, %(n)</caption><thead><tr><th rowspan="2">Subgroup</th><th colspan="3">CHUAP</th><th colspan="3">CNN</th><th colspan="2">p-Value</th></tr><tr><th>N</th><th>%PDA(n)</th><th>%Tmed(n)</th><th>N</th><th>%PDA(n)</th><th>%Tmed(n)</th><th>p-PDA</th><th>p-Tmed</th></tr></thead><tbody><tr><td><strong>Gest. age</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>GA1</td><td>87</td><td>72.4(63)</td><td>71.3(62)</td><td>977</td><td>65.7(642)</td><td>41.6(406)</td><td>0.21</td><td>&lt;0.001</td></tr><tr><td>GA2</td><td>61</td><td>32.8(20)</td><td>27.9(17)</td><td>804</td><td>44.7(359)</td><td>20.7(166)</td><td>0.07</td><td>0.28</td></tr><tr><td>GA3</td><td>85</td><td>17.7(15)</td><td>17.7(15)</td><td>1094</td><td>17(186)</td><td>3.9(37)</td><td>0.88</td><td>&lt;0.001</td></tr><tr><td>GA4</td><td>38</td><td>2.6(1)</td><td>2.6(1)</td><td>1607</td><td>7.2(116)</td><td>1.2(19)</td><td>0.28</td><td>0.42</td></tr><tr><td><strong>Total</strong></td><td><strong>271</strong></td><td><strong>36.5(99)</strong></td><td><strong>35.1(95)</strong></td><td><strong>4482</strong></td><td><strong>29.1(1303)</strong></td><td><strong>15(628)</strong></td><td></td><td></td></tr><tr><td><strong>Body Weight</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>BW1</td><td>59</td><td>64.4(38)</td><td>62.7(37)</td><td>563</td><td>63.9(360)</td><td>37.3(210)</td><td>0.94</td><td>0.01</td></tr><tr><td>BW2</td><td>65</td><td>47.7(31)</td><td>44.6(29)</td><td>739</td><td>55.2(408)</td><td>33.4(247)</td><td>0.28</td><td>0.05</td></tr><tr><td>BW3</td><td>60</td><td>28.3(17)</td><td>28.3(17)</td><td>807</td><td>32.6(263)</td><td>13.9(112)</td><td>0.43</td><td>0.01</td></tr><tr><td>BW4</td><td>87</td><td>14.9(13)</td><td>13.8(12)</td><td>977</td><td>16.4(160)</td><td>4.6(45)</td><td>0.81</td><td>&lt;0.001</td></tr><tr><td><strong>Total</strong></td><td><strong>271</strong></td><td><strong>36.5(99)</strong></td><td><strong>35.1(95)</strong></td><td><strong>3086</strong></td><td><strong>38.6(1191)</strong></td><td><strong>19.9(614)</strong></td><td></td><td></td></tr></tbody></table>

GA: gestational age subgroup: 1 (≤ 26+6), 2(27-28+6), 3(29-30+6), 4(31-32); BW: Body weight subgroup: 1 (≤749), 2 (750-999), 3 (1000-1249), 4 (>1250); CHUAP: CHU Amiens-Picardie; CNN: Canadian Neonatal Network; %Tmed: Medical (pharmacologic) treatment percentage rate. *Data from CNN 2018 report*
<table><caption>**Table 3:** Incidence of specific morbidity and outcomes in our population compared to the CNN population according to gestational age at birth</caption><thead><tr><th>Subgroup</th><th>N</th><th>PDA</th><th>PDAs</th><th>CLD</th><th>NEC</th><th>NECs</th><th>IVH ¾</th><th>DEATH</th></tr></thead><tbody><tr><td><strong>CHUAP</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>GA1</td><td>87</td><td>72.4% (63)</td><td>23.3%(20)<sup>†</sup></td><td>41.1% (41)</td><td>19.5% (17)<sup>†</sup></td><td>14.9% (13)<sup>†</sup></td><td>46% (40)<sup>†</sup></td><td>48.3% (42)<sup>†</sup></td></tr><tr><td>GA2</td><td>61</td><td>32.8% (20)</td><td>3.3% (2)<sup>†</sup></td><td>39.3%(24)</td><td>8.2% (5)<sup>Ω</sup></td><td>6.5% (4)<sup>†</sup></td><td>21.3% (13)<sup>†</sup></td><td>11.5% (7)</td></tr><tr><td>GA3</td><td>85</td><td>17.6% (15)</td><td>0% (0)</td><td>14.1%(12)</td><td>4.7% (4)<sup>†</sup></td><td>2.3% (2)</td><td>2.3% (2)</td><td>5.9% (5)</td></tr><tr><td>GA4</td><td>38</td><td>2.6% (1)</td><td>0% (0)</td><td>5.3% (2)</td><td>2.6% (1)</td><td>2.6% (1)<sup>†</sup></td><td>0% (0)</td><td>5.2% (2)<sup>Ω</sup></td></tr><tr><td><strong>Totals</strong></td><td><strong>271</strong></td><td><strong>36.5% (99)</strong></td><td><strong>8.1% (22)<sup>‡</sup></strong></td><td><strong>29.1% (79)</strong></td><td><strong>10% (27)<sup>‡</sup></strong></td><td><strong>7.4% (20)<sup>†</sup></strong></td><td><strong>20.3% (55)<sup>†</sup></strong></td><td><strong>20.7% (56)<sup>†</sup></strong></td></tr><tr><td><strong>CNN</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>GA1</td><td>977</td><td>65.7% (642)</td><td>4.7% (45)</td><td>54.6% (477)<sup>†</sup></td><td>10.4% (99)</td><td>5.4% (53)</td><td>16.4% (155)</td><td>21.5% (204)</td></tr><tr><td>GA2</td><td>804</td><td>44.7% (359)</td><td>0.4% (3)</td><td>40.6% (314)</td><td>3.4% (26)</td><td>1.6% (13)</td><td>8.5% (66)</td><td>6.3% (49)</td></tr><tr><td>GA3</td><td>1094</td><td>17% (186)</td><td>0.1% (1)</td><td>22.6% (240)</td><td>1.5% (16)</td><td>0.6% (7)</td><td>2.4% (26)</td><td>2.1% (22)</td></tr><tr><td>GA4</td><td>1607</td><td>7.2% (116)</td><td>0.2%(4)</td><td>9.9% (152)</td><td>0.7% (11)</td><td>0.1%(1)</td><td>1.8% (28)</td><td>1.4% (21)</td></tr><tr><td><strong>Totals</strong></td><td><strong>4482</strong></td><td><strong>29.1% (1303)</strong></td><td><strong>1.2%(53)</strong></td><td><strong>28.3% (1223)</strong></td><td><strong>3.4% (152)</strong></td><td><strong>1.6% (74)</strong></td><td><strong>6.4% (275)*</strong></td><td><strong>6.8% (296)*</strong></td></tr><tr><td><strong>Odds Ratio</strong></td><td></td><td><strong>1.4 (1.1 - 1.8)</strong></td><td><strong>7.4 (4.2 - 12)</strong></td><td><strong>1 (0.7 -1.4)</strong></td><td><strong>3.1 (1.8 - 4.9)</strong></td><td><strong>4.6 (2.6 -7.7)</strong></td><td><strong>3.7 (2.7 -5.2)</strong></td><td><strong>3.5 (2.5 -4.9)</strong></td></tr></tbody></table>

GAα: gestational age subgroup (weeks): α = 1 (≤26+⁶), 2 (27-28+⁶), 3 (29-30+⁶), 4 (31-32+⁰); CHUAP: CHU Amiens-Picardie; CNN: Canadian Neonatal Network; PDA: patent ductus arteriosus; PDAs: PDA treated by surgery; CLD: chronic lung disease; NEC: necrotizing enterocolitis; NECs: NEC treated by surgery; IVH¾: Intraventricular hemorrhage stage 3 or 4, or periventricular leukomalacia; N: groups and subgroups size. (*): For statistics' computations related to CLD, HIV¾ and DEATH in table 3, the subgroup size were GA1= 947, GA2=773, GA3=1061 et GA4=1540; (Ω): p< 0.05; (‡): p<0.001. *Data from CNN 2018 report*
<table><caption>**Table 4:** Observation of infants with and without severe neurologic damage among dead infants</caption><thead><tr><th></th><th>IVH ¾</th><th>No severe IVH</th><th>Total</th></tr></thead><tbody><tr><td>Death, n(%)</td><td>30(53.6%)</td><td>26(46.4%)</td><td>56</td></tr><tr><td>Birth Weight, g</td><td>707±165 [490-1110]</td><td>788±302 [520-1500]</td><td>747±24 [490-1500]</td></tr><tr><td>Gestational age, WG</td><td>25.4±1.39 [23-29.3]</td><td>27±2.21 [23-31.6]</td><td>26.2±1.98 [23-31.6]</td></tr><tr><td>Postnatal age, d</td><td>19 [2-99]</td><td>30.2 [3-147]</td><td>25.2 [2-147]</td></tr><tr><td>Growth, Audipog, perc</td><td>41.4±33.3 [0.03-94]</td><td>23.5±26.1 [0.09-80.5]</td><td>33.1 [0.03-94]</td></tr></tbody></table>

g: grams; WG: weeks of gestation; d: days; perc: percentile; IVH : Intraventricular hemorrhage; IHV¾: IVH stage 3 or 4
## Notes

Ce travail est destiné à une publication dans une revue internationale dont la soumission devrait être effective au moment de la soutenance de thèse.
## Etat des lieux de la prescription d'ibuprofène aux nouveau-nés prématurés d'âge gestationnel inférieur à 32 semaines d'aménorrhée pour le traitement du canal artériel. Données du CHU Amiens-Picardie de 2018 à 2019.

**Objectif:** La persistance du canal artériel (PCA) est un problème fréquent en néonatalogie. Malgré trois décennies de recherche, sa prise en charge reste controversée. Un traitement conservatif, pharmacologique, ou chirurgical peut être appliqué. L'ibuprofène est utilisé comme traitement de première ligne dans notre centre mais il peut entraîner des effets secondaires. Notre objectif principal était d'estimer le taux d'exposition à l'ibuprofène dans notre unité. L'objectif secondaire était de comparer notre pratique à celle d'autres centres équivalents.

**Méthode:** Nous avons étudié une cohorte rétrospective de 292 nouveau-nés prématurés <32 semaines d'aménorrhée (SA), admis dans le service de réanimation néonatale du CHU Amiens-Picardie entre le 1er janvier 2018 et le 31 décembre 2019. Les caractéristiques périnatales et néonatales ont été recueillies depuis les dossiers médicaux informatisés. L'exposition à l'ibuprofène et l'incidence du PCA ont été analysées en fonction de l'âge gestationnel et du poids de naissance. Ces données ont été comparées à celles du rapport de 2018 du Réseau Néonatal Canadien (CNN).

**Résultats:** 271 nouveau-nés prématurés ont été inclus dans l'étude. Le taux d'exposition à l'ibuprofène en fonction de l'âge gestationnel à la naissance (SA) était de 71.3% pour les $\leq 26^{+6}$, 27.9% pour les $27^{+0}$ à $28^{+6}$, 17.7% pour les $29^{+0}$ à $30^{+6}$, et 2.6% pour les $31^{+0}$ à $31^{+6}$. Selon le poids de naissance (grammes) les résultats étaient de 62.7% pour les moins de 750, 44.6% entre 750 à 999, 28.3% entre 1000 à 1249, et 13.8% chez les plus de 1250. En comparaison avec le rapport du CNN de 2018, l'exposition à un traitement pharmacologique était significativement plus élevée dans notre population, et l'incidence du diagnostic de PCA était identique.

**Conclusion:** L'exposition à l'ibuprofène était d'autant plus élevée que l'âge gestationnel et le poids à la naissance étaient faibles. Les effets secondaires et l'absence d'amélioration de la morbi-mortalité néonatale avec l'utilisation d'ibuprofène, mais également le taux élevé de fermeture spontanée du canal artériel dans les centres appliquant une prise en charge conservatrice, nous font nous questionner sur notre important taux d'exposition.

**Mots-clés:** canal artériel, PCA, nouveau-né prématuré, ibuprofène, Unités néonatales de soins intensifs

## Prescription status of ibuprofen for the treatment of patent ductus arteriosus in preterm infants born before 32 weeks of gestation. CHU Amiens-Picardie data from 2018 to 2019.

**Objectives:** Patent ductus arteriosus (PDA) is a common problem in neonatology. Despite three decades of research, its management remains an enduring controversy. Conservative, pharmacological, or surgical treatment can be used. Ibuprofen is used as first-line treatment in our center but it can lead to adverse effects. Our main objective was to estimate exposure to ibuprofen for the treatment of PDA in our center. Secondary outcome was to compare our practice to that of other equivalent centers.

**Method:** We studied a retrospective cohort of 292 preterm infants born <32 WG, admitted to the NICU of CHU Amiens-Picardie between January 1st 2018 and December 31st 2019. Perinatal and neonatal characteristics were reviewed from electronic medical records. Exposure to ibuprofen and incidence of PDA were analyzed with respect to gestational age and body weight at birth. Data were compared to those of the Canadian Neonatal Network (CNN) 2018 report.

**Results:** 271 preterm infants were included in our study. Rate of exposure to ibuprofen for PDA was analyzed according to gestational age at birth (WG) as follows: 71.3% in $\leq 26^{+6}$, 27.9% in $27^{+0}$ to $28^{+6}$, 17.7% in $29^{+0}$ to $30^{+6}$, and 2.6% in $31^{+0}$ to $31^{+6}$. According to birth weight (g) the rates of exposure were: 62.7% in <750, 44.6% in 750 to 999, 28.3% in 1000 to 1249, and 13.8% in $\geq 1250$. In comparison to the CNN 2018 report, exposure to a medical treatment was significantly higher in our population, and incidence of PDA diagnosis was not statistically different.

**Conclusion:** Exposure to ibuprofen was all the higher as gestational age and body weight were low at birth. Side effects and absence of benefits on major outcomes following a pharmacological treatment, but also high closure rate in centers using conservative management, lead us to question our elevated rate of exposure.

**Keywords:** ductus arteriosus, PDA, preterm infant, ibuprofen, NICU