<figure><img src="image_1.png" /></figure>

Liver, Pancreas and Biliary Tract

Incidence and risk factors for thromboembolic events in pediatric-onset inflammatory bowel disease: A French population-based study

Nicolas Richard<sup>a,*</sup>, Ariane Leroyer<sup>b,c</sup>, Delphine Ley<sup>c,d</sup>, Claire Dupont<sup>e</sup>, Valérie Bertrand<sup>f</sup>, Pauline Wils<sup>c,g</sup>, Corine Gower-Rousseau<sup>h</sup>, Dominique Turck<sup>c,d</sup>, Nathalie Guillon<sup>b</sup>, Hélène Sarter<sup>b,c</sup>, Guillaume Savoye<sup>a</sup>, Mathurin Fumery<sup>i</sup>, “EPIMAD study group”<sup>l</sup>

ARTICLE INFO

Article history:

Received 26 June 2024

Accepted 4 September 2024

Available online xxx

Keywords:

Arterial thromboembolism

Venous thromboembolism

Inflammatory bowel disease

Pediatric IBD

A B S T R A C T

**Introduction:** Patients with inflammatory bowel disease (IBD) are at higher risk of thromboembolic events (TE). In pediatric-onset IBD, more data on incidence and risk factors of venous (VTE) and arterial events (ATE) at the population level are needed to guide thromboprophylaxis.

**Methods:** All patients aged ≤ 16 years diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) between 1988 and 2011 in the prospective EPIMAD population-based registry were followed until 2013. Every TE occurring during the follow-up period was included.

**Results:** A total of 1,344 patients were included: 1,007 with CD and 337 with UC, and a median diagnosis age of 14.3 years. After a median follow-up of 8.3 years, 2 (0.15 %) ATE and 15 (1.1 %) VTE occurred at median age of 20.4 years. The global incidence rate of thromboembolic events was 1.32 per 1000 person-years. Periods of active disease (HR=8.4, *p* = 0.0002), the 3-month-period following surgery (HR=16.4, *p* = 0.0002) and hospitalization (HR=21.7, *p* < 0.0001) were found to be associated with an increased risk of VTE. A lower rate of VTE was found in patients treated with 5-aminosalicylates (HR=0.1, *p* = 0.002).

**Conclusion:** The risk of TE was low in this population. VTE were strongly associated with active disease, surgery and hospitalization.

© 2024 The Author(s). Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

1. Introduction

In adults, inflammatory bowel disease (IBD) is associated with an increased risk of thromboembolism (TE) and particularly of venous TE (VTE), despite significant variability in findings across dif-

ferent publications [1–9]. A meta-analysis enrolling >200 000 IBD patients, revealed that the risk of VTE in IBD patients was approximately double that of the general population [1]. Similarly a modest increase of the risk of arterial TE (ATE) was reported, especially in women and young patients [10]. Despite a growing body of literature on this subject and the development of guidelines for thromboprophylaxis in IBD, the incidence of VTE has been decreasing only slowly in the United States. In the meantime, hospitalizations related to VTE in IBD patients have been on the rise [11,12].

Compared to the general population, the relative risk of TE is higher in younger patients with a six-fold increase before 20 years

<footnote><sup>a</sup> Univ Rouen Normandie, INSERM, ADEN UMR1073, "Nutrition, Inflammation and microbiota-gut-brain axis", CHU Rouen, Department of Gastroenterology, F-76000 Rouen, France</footnote>

<footnote><sup>b</sup> Department of Public Health, Epidemiology, and Economic Health, EPIMAD Registry, Regional House of Clinical Research, Lille University Hospital, Lille, France</footnote>

<footnote><sup>c</sup> Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research, in Inflammation, F-59000 Lille, France</footnote>

<footnote><sup>d</sup> Department of Paediatrics, Lille University Hospital, F-59000 Lille, France</footnote>

<footnote><sup>e</sup> Gastroenterology Unit, Caen University Hospital, Caen, France</footnote>

<footnote><sup>f</sup> Department of Paediatrics, Le Havre Hospital, Le Havre, France</footnote>

<footnote><sup>g</sup> Lille University Hospital, Gastroenterology, Lille, France</footnote>

<footnote><sup>h</sup> Research and Public Health Unit, Reims University Hospital, Reims, France</footnote>

<footnote><sup>i</sup> Gastroenterology Unit, Amiens university Hospital, Amiens, France</footnote>

<footnote>* Corresponding author at: CHU de Rouen, Service d'Hépato-Gastroentérologie, 37 boulevard Gambetta, 76031 Rouen, France.</footnote>

<footnote>E-mail address: nicolas.richard1@etu.univ-rouen.fr (N. Richard).</footnote>

<footnote n="1">¹ "EPIMAD study group": full names and affiliations of each member of this study group are listed in APPENDIX A.</footnote>
old [2]. Nevertheless, none of the existing cohort studies have re-
ported on ATE, and the only available data in this regard is derived
from the adult population of IBD patients [1,13–15]. Moreover, in
pediatric-onset IBD patients, data on VTE incidence and risk fac-
tors are limited and primarily based on small observational retro-
spective cohorts [16,17]. As a result, the application of thrombopro-
phylaxis in this population is inconsistent [18]. Current guidelines
from ECCO recommend thromboprophylaxis only for children with
severe acute colitis who have at least one additional risk factor
[19]. In 2022, a RAND panel emphasized the need to re-evaluate of
the role of thromboprophylaxis in future guidelines [18]. Therefore,
gaining a better understanding of VTE risk factors in pediatric-
onset IBD patients is essential.

In 2023, a meta-analysis comprising 107 studies involving 216 cases of VTE in pediatric IBD found associations with ulcerative colitis, steroid use, central venous catheters, and the first year of IBD diagnosis [16]. Recently, a large international study involving 129 centers reported, based on a questionnaire, that the incidence of venous thromboembolism (VTE) in pediatric inflammatory bowel disease (IBD) was 3.72 per 10,000 person-years, with cerebral sinus venous thrombosis occurring in half of these cases [20]. Nevertheless, this non-population-based study is a likely to present selection bias. Population-based observational cohort studies evaluate an entire population in a defined geographic area during an extended period of time. They avoid selection biases associated with referral center studies and are ideal to inform on natural history of disease. The largest population-based studies relied on administrative data, which are susceptible to information bias, yielding to heterogeneous results with a seven-fold difference in incidence rates of VTE among them [21–23]. Parallelly, administrative data or non-dedicated data bases do not provide a precise description of the IBD phenotype, location or activity. In addition, these studies primarily focused on the increased risk of VTE caused by IBD itself, rather than delving into the risk factors for VTE in pediatric IBD.

Consequently, there is a pressing need for high-quality cohort
studies to expand our understanding of TE in pediatric IBD [17].
Hence, our objective was to investigate the risk of TE in pediatric-
onset IBD through a population-based study.

## 2. Methods

2.1. Study population

All patients from the prospective EPIMAD registry with a diag-
nosis of IBD between January 1988 and December 2011 younger
than 17 years at diagnosis were included. The EPIMAD registry
covers a large area of Northern France with almost 6 million in-
habitants representing 9.3 % of the entire French population. The
methodology of the EPIMAD registry has been previously described
in detail [24]. Briefly, all patients consulting for the first time for
symptoms compatible with IBD are reported since 1988 by adult
(n = 250) and pediatric (n = 12) gastroenterologists, regardless
of their type of practice (hospital [n = 94] or private [n = 168]).
Only patients who are residents in Northern France at the time of
diagnosis are included. Interviewing practitioners collect data for
each new case from medical records using a standardized ques-
tionnaire including age, sex, year of diagnosis, clinical, radiological,
endoscopic, and histologic findings at the time of diagnosis. A fi-
nal diagnosis of CD, UC, or IBD—unclassified is made by 2 expert
gastroenterologists according to previously defined criteria.

## 2.2. Study design and data collection

This study was part of the INSPIRED (impact of therapeutic
strategies on the natural history of pediatric IBD) project whose

methodology has already been presented in detail [25]. Briefly, ad-
ditional data were collected from the medical charts by trained
research assistants, and each file was further audited by 2 in-
dependent expert gastroenterologists. Baseline characteristics col-
lected were type of IBD, age at diagnosis, gender, IBD phenotype
and location according to Paris classification [26], smoking status
at baseline, and extraintestinal manifestations. During follow-up,
smoking status was updated, and intercurrent medical events were
collected. At each visit, the location and behavior of IBD as well
as the smoking status were recorded. Dates of initiation, with-
drawal, dosage and reason for withdrawal of the following medi-
cations were recorded for each patient: oral 5-aminosalicylic acid
(5-ASA), oral and intravenous corticosteroids, immunosuppressants
(IS) (azathioprine, 6-mercaptopurine, and methotrexate) and anti-
tumor necrosis factor (TNF) agents (infliximab, adalimumab, goli-
mumab, and certolizumab). Patients were followed from diagnosis
to December 31, 2013, date of loss to follow-up, or date of death.

2.3. Definitions and outcomes

Every thromboembolic event, both venous and arterial, occur-
ring during the follow-up period were included. A VTE was defined
as a radiologically confirmed thromboembolism and categorized as
deep venous thrombosis (DVT), pulmonary embolism, and other lo-
cation according to the Clinical-Etiology-Anatomy-Pathophysiology
(CEAP) classification [27]. Arterial thrombosis consisted of the fol-
lowing: ischemic heart disease, myocardial infarction, stroke, pe-
ripheral artery disease and mesenteric ischemia. For each case the
following additional information was collected: thrombosis type
and location, history of thrombosis, presence of thrombophilia and
thrombosis risk factors, and outcome.

Active disease was defined by the presence of at least one
of the following criteria: (1) clinical flare defined by a Harvey-
Bradshaw index ≥ to 4 in CD patients or by partial Mayo Score ≥
3 in UC, and/or (2) active luminal inflammation in endoscopy de-
fined by a Mayo endoscopic subscore greater than or equal to 2 in
UC or by the presence of ulcerations in CD, and/or (3) radiological
features related to disease activity. Inflammation was considered as
present on CT or MRI if the radiologist's report described ileitis or
colitis.

2.4. Statistics

Quantitative data were described with their median and in-
terquartile range (Q1-Q3) and categorical data by frequencies and
percentages. Incidence rates were calculated by dividing the num-
ber of events by the person-time of follow-up, and 95 % confi-
dence intervals (95 % CI) were calculated using a Poisson distribu-
tion. Cumulative incidence rates and cumulative incidence curves
were estimated by the Kaplan-Meier method. Univariable Cox pro-
portional hazard models with hazard ratio (HR) and 95 % CI were
used to analyze impact of different patient and disease character-
istics on VTE occurrence: patient's characteristics at diagnosis (sex,
age, type of IBD, extraintestinal manifestations and period of diag-
nosis), tobacco smoking, disease activity, drug therapy (IS, anti-TNF,
systemic steroids and systemic 5-ASA), and some events within the
last 3 months (surgery, hospitalization and hospitalization without
surgery). All variables studied were treated as time dependent [28]
(Supplementary Table 1) except for patient's characteristics at di-
agnosis. In order to take into account only immobilization of at
least 72 h, only hospitalizations ≥ 3 days were considered in this
analysis. In addition, a sensitivity analysis was done for hospitaliza-
tion, considering all these events, except scheduled hospitalization
for check-up. At last, bivariable Cox proportional hazard model was
used to analyze joint impact of disease activity and 5-ASA use on
VTE occurrence. The threshold for statistical significance was set
<table><caption>**Table 1**

Characteristics of the population.</caption><thead><tr><th></th><th>CD<br>N = 1007</th><th>UC<br>N = 337</th><th>Total<br>N = 1344</th></tr></thead><tbody><tr><td><strong>Gender [n (%)]</strong></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>556 (55.2)</td><td>144 (42.7)</td><td>700 (52.1)</td></tr><tr><td>Female</td><td>451 (44.8)</td><td>193 (57.3)</td><td>644 (47.9)</td></tr><tr><td><strong>Age at diagnosis (years) [median [IQR]]</strong></td><td>14.5 [12.0, 16.1]</td><td>14.0 [11.2, 15.8]</td><td>14.3 [11.7, 16.0]</td></tr><tr><td><strong>Year of IBD diagnosis [n (%)]</strong></td><td></td><td></td><td></td></tr><tr><td>1988-1993</td><td>167 (16.6)</td><td>58 (17.2)</td><td>225 (16.7)</td></tr><tr><td>1994-2000</td><td>260 (25.8)</td><td>87 (25.8)</td><td>347 (25.8)</td></tr><tr><td>2001-2011</td><td>580 (57.6)</td><td>192 (57.0)</td><td>772 (57.4)</td></tr><tr><td><strong>Follow-up (years) [median [IQR]]</strong></td><td>8.8 [4.6-14.2]</td><td>7.2 [3.8-13.0]</td><td>8.3 [4.3, 13.9]</td></tr><tr><td><strong>CD location [n (%)] - 12 missing</strong></td><td></td><td></td><td></td></tr><tr><td>L1</td><td>215 (21.6)</td><td>-</td><td>-</td></tr><tr><td>L2</td><td>234 (23.5)</td><td>-</td><td>-</td></tr><tr><td>L3</td><td>546 (54.9)</td><td>-</td><td>-</td></tr><tr><td><strong>CD behavior [n (%)] - 3 missing</strong></td><td></td><td></td><td></td></tr><tr><td>B1</td><td>827 (82.4)</td><td>-</td><td>-</td></tr><tr><td>B2</td><td>145 (14.4)</td><td>-</td><td>-</td></tr><tr><td>B3</td><td>32 (3.2)</td><td>-</td><td>-</td></tr><tr><td><strong>UC location [n (%)] - 4 missing</strong></td><td></td><td></td><td></td></tr><tr><td>E1</td><td>-</td><td>79 (23.7)</td><td>-</td></tr><tr><td>E2</td><td>-</td><td>107 (32.1)</td><td>-</td></tr><tr><td>E3</td><td>-</td><td>40 (12.0)</td><td>-</td></tr><tr><td>E4</td><td>-</td><td>107 (32.1)</td><td>-</td></tr><tr><td><strong>Smoking [n (%)]</strong></td><td>92 (9.1)</td><td>19 (5.6)</td><td>111 (8.3)</td></tr><tr><td><strong>Hypertension</strong></td><td>3 (0.3)</td><td>1 (0.3)</td><td>4 (0.3)</td></tr><tr><td><strong>(at any point during the follow-up period) [n (%)]</strong></td><td></td><td></td><td></td></tr><tr><td>Obesity</td><td>24 (2.4)</td><td>7 (2.1)</td><td>31 (2.3)</td></tr><tr><td><strong>(at any point during the follow-up period) [n (%)]</strong></td><td></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>2 (0.2)</td><td>1 (0.3)</td><td>3 (0.2)</td></tr><tr><td><strong>(at any point during the follow-up period) [n (%)]</strong></td><td></td><td></td><td></td></tr><tr><td>Thrombophilia [n (%)]</td><td>3 (0.3)</td><td>1 (0.3)</td><td>4 (0.3)</td></tr><tr><td><strong>Surgery during follow-up [n (%)]</strong></td><td>470 (46.7)</td><td>61 (18.1)</td><td>531 (39.5)</td></tr><tr><td><strong>Therapeutics during follow-up</strong></td><td></td><td></td><td></td></tr><tr><td>5-ASA [n (%)]</td><td>887 (88.1)</td><td>316 (93.8)</td><td>1203 (89.5)</td></tr><tr><td>Steroids [n (%)]</td><td>718 (71.3)</td><td>237 (70.3)</td><td>955 (71.1)</td></tr><tr><td>Immunosuppressant [n (%)]</td><td>711 (70.6)</td><td>155 (46.0)</td><td>866 (64.4)</td></tr><tr><td>Biologics [n (%)]</td><td>482 (47.9)</td><td>83 (24.6)</td><td>565 (42.0)</td></tr><tr><td>None [n (%)]</td><td>12 (1.2)</td><td>18 (5.3)</td><td>30 (2.2)</td></tr></tbody></table>

Location is given at diagnosis according to Paris classification. 5-ASA, 5-aminosalicylates; CD, Crohn's disease; IBD, inflammatory bowel disease; IQR, interquartile range; UC, ulcerative colitis.

to P value < 0.05 in all tests. Data were analyzed with R v4.0.3, using the 'survival' and 'mstate' packages. The study protocol was approved by the French Ministry of Health according to the regulation of the registries in general population (Number n°14.519 for CCTIRS and 915,476 for the CNIL). Authors vouch for the accuracy of reported data. The data of this article cannot be shared publicly to ensure the privacy of patients.

## 3. Results

### 3.1. Population

Among the 1344 patients diagnosed with IBD between 1988 and 2011, 1007 (74.9 %) patients were diagnosed with CD and 337 (25.1 %) with UC. Demographic and clinical characteristics of this population are depicted in Table 1. The follow-up stopped in 2013 and overall median of follow-up was 8.3 IQR[4.3, 13.9] years. The median age at diagnosis was 14.3 [11.7, 16.0] years. One hundred eleven patients (8.3 %) were smoker at diagnosis. Thrombophilia was known in 4 (0.3 %) patients and 37 (2.8 %) had cardiovascular risk factor including hypertension, diabetes mellitus or obesity. During follow-up 1069 IBD-related surgery were performed in 531 (39.5 %) patients and 837 (62.3 %) were hospitalized during at least 3 days.

### 3.2. Incidence rate of thromboembolic events

During follow-up, 17 thromboembolic events, 15 venous and 2 arterial events, were observed among 1344 patients. No patients were excluded from the analysis. The cumulative incidence of TE was 0.2 % 95 %CI [0.0 %, 0.5 %] at one year, 0.7 % [0.2 %, 1.2 %] at five years and 1.5 % [0.6 %, 2.4 %] at ten years (Fig. 1A). The global incidence rate of thromboembolic event was 1.32 per 1000 person-years, [0.77 - 2.11]. The median age at the thromboembolic event was 21.3 [16.7, 26.8] years (Fig. 2).

The incidence rate of VTE was 1.16 per 1000 person-years, [0.65 - 1.92]. The cumulative incidence of VTE was 0.2 % [0.0 %, 0.5 %] at one year and 0.7 % [0.2 %, 1.2 %] at five years (Fig. 1B). In patients with CD, the incidence of VTE was 1.41 per 1000 person-years, [0.77 - 2.37], whereas it stood at 0.33 per 1000 person-years, [0.01 - 1.85], in those with UC. No cases of death linked to thromboembolic event was reported.

The incidence rate of ATE was 0.15 cases per 1000 person-years, [0.19-0.56]. Two ATE occurred 18.1 and 20.8 years after the diagnosis of IBD.

### 3.3. Clinical characteristics of venous thromboembolic events

During follow-up, 15 venous thromboembolisms were observed (Table 2) with a median age at diagnosis of 20.4 [16.6 - 24.5] years. The minimal age of occurrence was 14.8 years. Specifically, 5 of
A

<figure><img src="image_2.png" /></figure>

B

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Global cumulative incidence rate of thromboembolic event [A] and cumulative incidence rates of venous and arterial thromboembolic events, separately [B] in the 1344 patients population-based cohort (Kaplan-Meier curves).</figcaption></figure>

these cases were classified as deep vein thrombosis according to the CEAP classification [27], one was a pulmonary embolism, 2 were cerebral venous sinus thrombosis. All these patients had undergone surgery (n = 4) or have been hospitalized (n = 8) within 3 months prior to VTE occurrence or had active disease (n = 13) at the time of VTE. The median delay between clinical flare diagnosis and thromboembolism was 31.0 [8.0 - 50.8] days. Five patients (33 %) received systemic steroid within the last 30 days. A median delay of 23.5 [5.8 - 41.0] days between hospital discharge and VTE occurrence was observed, as well as a median delay of 8.5

[6.8 - 23.5] days between surgery and VTE occurrence. None of the patients with thromboembolism were found to have either thrombophilia or cancer. Lastly, there were no cases of pulmonary hypertension, or postphlebitic syndrome reported at the end of follow-up.

### 3.4. Clinical characteristics of arterial thromboembolic events

Two arterial thromboembolic events were observed, occurring at the age of 31 and 35 years, including one myocardial infarction
<table><caption>**Table 2**

Characteristics of venous thromboembolic events.</caption><thead><tr><th></th><th>Total<br>n = 15</th></tr></thead><tbody><tr><td><strong>Age at thrombo-embolic event</strong> [years] [median [IQR]]</td><td>20.4 [16.6, 24.5]</td></tr><tr><td><strong>Time since IBD diagnosis</strong> [years] [median [IQR]]</td><td>4.4 [3.2, 9.8]</td></tr><tr><td><strong>Anatomical location</strong> [n (%)]</td><td></td></tr><tr><td>Deep vein thrombosis</td><td>5 (33)</td></tr><tr><td>Cerebral venous sinus</td><td>2 (13)</td></tr><tr><td>Splanchnic vein</td><td>2 (13)</td></tr><tr><td>Pulmonary embolism</td><td>1 (6.7)</td></tr><tr><td>Right atrial</td><td>1 (6.7)</td></tr><tr><td>Basilic vein</td><td>1 (6.7)</td></tr><tr><td>Superior vena cava</td><td>1 (6.7)</td></tr><tr><td>Internal jugular vein</td><td>1 (6.7)</td></tr><tr><td>Unknown</td><td>1 (6.7)</td></tr><tr><td><strong>Catheter-related thrombosis</strong> [n (%)]</td><td>4 (26.7)</td></tr><tr><td><strong>HBI</strong> ≥ 4 or pMS ≥ 3 [n (%)]</td><td>9 (60.0)</td></tr><tr><td><strong>C-reactive protein before VTE</strong> [mg/L] [median [IQR]], n = 4</td><td>63.4 (62.0, 82.0)</td></tr><tr><td><strong>Biological, endoscopic or radiological signs of IBD activity within 6 months</strong> [n (%)]</td><td></td></tr><tr><td>Yes</td><td>10 (66.7)</td></tr><tr><td>No</td><td>4 (26.7)</td></tr><tr><td>Unknown</td><td>1 (6.7)</td></tr><tr><td><strong>Type of IBD</strong> [n (%)]</td><td></td></tr><tr><td>UC</td><td>1 (6.7)</td></tr><tr><td>CD</td><td>14 (93.3)</td></tr><tr><td>pMS ≥ 3 [n (%)], n = 1</td><td>1 (100)</td></tr><tr><td><strong>HBI</strong> ≥ 4 [n (%)], n = 14</td><td>8 (57)</td></tr><tr><td><strong>Hospitalisation within 3 months</strong> [n (%)]</td><td>8 (53.3)</td></tr><tr><td>Admission for IBD</td><td>8 (100)</td></tr><tr><td><strong>Surgery within 3 months</strong> [n (%)]</td><td></td></tr><tr><td>IBD surgery</td><td>4 (26.7)</td></tr><tr><td><strong>History of smoking</strong> [n (%)]</td><td>4 (26.7)</td></tr><tr><td><strong>Therapeutics at VTE</strong> [n (%)]</td><td></td></tr><tr><td>Systemic steroid within the last 30 days</td><td>5 (33)</td></tr><tr><td>5-ASA</td><td>1 (6.7)</td></tr><tr><td>Immunosuppressant</td><td>7 (46.7)</td></tr><tr><td>Biologics</td><td>3 (20.0)</td></tr></tbody></table>

5-ASA, 5-aminosalicylates; CD, Crohn's disease; HBI, Harvey-Bradshaw Index; IBD, inflammatory bowel disease; IQR, interquartile range; pMS: partial Mayo Score; UC, ulcerative colitis; VTE, venous thromboembolic event.

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Number of thromboembolic events according to the age at occurrence.</figcaption></figure>

and one stroke. Notably, there were no biological, radiological, or endoscopic signs of disease activity within the six months preceding the arterial thromboembolic event.

### 3.5. Factors associated with venous thromboembolism

Periods of active disease were found to be associated with an increased risk of VTE (HR 8.4 [2.3–30.5], *p* = 0.0002) (Table 3). Similarly, the 3-month-period following surgery or hospitalization exhibited a higher rate of VTE (HR 16.4 [5.2–52.3], *p* = 0.0002 and HR 21.7 [7.5–62.9], *p* < 0.0001, respectively) (Table 3). The periods of hospitalization remained at higher risk of VTE, even when excluding the period in which hospitalization coincides with surgery (HR 10.1 [2.5–40.4], *p* = 0.007) (Table 3). The sensitivity analysis using all hospitalization of any duration (except hospitalization for check-up) provide a similar result. A trend towards a lower rate of thromboembolism in patients with UC was observed (HR 0.2 [0.0–1.8], *p* = 0.08). A lower rate of VTE was found in patients treated with 5-ASA (HR 0.1 [0.0–0.7], *p* = 0.002). Considering both the use of 5-ASA and the disease activity in bivariate analysis, the HR observed remained similar to those observed in univariate analysis (HR 0.1 [0.0–0.7], *p* = 0.001, for the use of 5-ASA and HR 8.8 [2.4–31.9], *p* = 0.02, for disease activity). The risk of thromboembolism did not vary throughout the study period (Table 3). Among patients with VTE, no cases of lupus, cancer, or pregnancy were found. According to the low number of events, no multivariable analysis could be performed [29].
<table><caption>**Table 3**
Factors associated with venous thromboembolic events.</caption><thead><tr><th></th><th>Person-years</th><th>Number of events</th><th>Hazard Ratio [95 %CI]</th><th>p value</th></tr></thead><tbody><tr><td><strong>Gender</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>6499</td><td>7</td><td>1.0 [ref]</td><td>0.77</td></tr><tr><td>Female</td><td>6418</td><td>8</td><td>1.2 [0.4-3.2]</td><td></td></tr><tr><td><strong>Age at diagnosis</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; age of puberty</td><td>6303</td><td>7</td><td>1.0 [ref]</td><td>0.38</td></tr><tr><td>≥ age of puberty</td><td>6614</td><td>8</td><td>1.1 [0.4-3.0]</td><td></td></tr><tr><td><strong>Type of IBD</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>CD</td><td>9907</td><td>14</td><td>1.0 [ref]</td><td>0.08</td></tr><tr><td>UC</td><td>3010</td><td>1</td><td>0.2 [0-1.8]</td><td></td></tr><tr><td><strong>Period of diagnosis</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>1988-1993</td><td>3903</td><td>5</td><td>1.0 [ref]</td><td>0.84</td></tr><tr><td>1994-2000</td><td>4534</td><td>4</td><td>0.7 [0.2-2.9]</td><td></td></tr><tr><td>2001-2011</td><td>4480</td><td>6</td><td>1 [0.3-4.1]</td><td></td></tr><tr><td><strong>Active tobacco smoking<sup>**</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>10,703</td><td>11</td><td>1.0 [ref]</td><td>0.34</td></tr><tr><td>Yes</td><td>2214</td><td>4</td><td>1.8 [0.6-5.9]</td><td></td></tr><tr><td><strong>Active disease<sup>**</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>8898</td><td>3</td><td>1.0 [ref]</td><td>0.0002</td></tr><tr><td>Yes</td><td>4020</td><td>12</td><td>8.4 [2.3-30.5]</td><td></td></tr><tr><td><strong>Treatment<sup>**</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>5-ASA</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>7701</td><td>14</td><td>1.0 [ref]</td><td>0.002</td></tr><tr><td>Yes</td><td>5217</td><td>1</td><td>0.1 [0.0-0.7]</td><td></td></tr><tr><td>Immunosuppressant</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>9225</td><td>8</td><td>1.0 [ref]</td><td>0.08</td></tr><tr><td>Yes</td><td>3693</td><td>7</td><td>2.6 [0.9-7.4]</td><td></td></tr><tr><td>Biologics</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>11,028</td><td>12</td><td>1.0 [ref]</td><td>0.52</td></tr><tr><td>Yes</td><td>1890</td><td>3</td><td>1.6 [0.4-5.7]</td><td></td></tr><tr><td>Systemic steroids</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>11,730</td><td>11</td><td>1.0 [ref]</td><td>0.08</td></tr><tr><td>Yes</td><td>1187</td><td>4</td><td>3.3 [1.0-10.8]</td><td></td></tr><tr><td><strong>Surgery (within 3 months)<sup>**</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>12,674</td><td>11</td><td>1.0 [ref]</td><td>0.0002</td></tr><tr><td>Yes</td><td>244</td><td>4</td><td>16.4 [5.2-52.3]</td><td></td></tr><tr><td><strong>Hospitalisation<sup>**</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Up to 3 months after hospitalization</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>12,390</td><td>8</td><td>1.0 [ref]</td><td>&lt;0.0001</td></tr><tr><td>Yes</td><td>528</td><td>7</td><td>21.7 [7.5-62.9]</td><td></td></tr><tr><td>Up to 3 months after hospitalization (excluding surgery related hospitalization)</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>12,593</td><td>12</td><td>1.0 [ref]</td><td>0.007</td></tr><tr><td>Yes</td><td>325</td><td>3</td><td>10.1 [2.5-40.4]</td><td></td></tr></tbody></table>

## 4. Discussion

In this population-based study involving patients with pediatric-onset IBD, the risk of VTE was relatively low, occurring in young adults with a median age of 20 years, and showing a cumulative incidence of 0.7% over five years. The main lesson from these findings is the importance of thrombotic prophylaxis for postpubertal children hospitalized either due to a flare or for digestive surgery.

These data are consistent with a Canadian study that reported a cumulative VTE incidence in children with IBD of 1.69% after an 11-year follow-up [21]. A non-population-based retrospective study in Germany and Austria recorded a VTE incidence rate of 1.41 per 1000 person-years, close to the incidence rate reported in this study [22]. Likewise, a Danish population-based study found an incidence rate of 0.89 per 1000 person-years in IBD patients within the age group 0-20 years [2]. An international prospective non-population-based study conducted across 129 IBD centers, involving younger patients (10 years at diagnosis in median), reported a lower incidence rate of 0.37 per 1000 person-years [20]. Inversely a Canadian population-based study reported a much higher incidence rate of 3.12 per 1000 person-years

five years after the diagnosis of pediatric-onset IBD [23]. These discrepancies in the literature may be explained by various factors. First, some non-population-based studies might be susceptible to recall and selection biases due to their study design. Second, differences in the age of the studied population play a role, as younger age is associated with a decreased absolute risk of TE [16]. Thus, in two studies, the population studied was younger [2,20], leading to a lower rate of VTE. Accordingly, in the Germano-Austrian study, the age of the population and the incident rate were similar [22]. Nevertheless, the Canadian study, which had the highest incidence, was based on a younger population compared to our study [23]. Third, methodological considerations must be addressed regarding the differentiation between incident and prevalent cases. Hence, administrative data are more likely to discriminate between incident and prevalent cases than studies based on remote questionnaires. Fourth, the diagnosis method used for VTE in the Canadian administrative study with the highest incidence rate may explain part of this difference. Indeed, concerns have been raised regarding to the reliability of the ICD codes for the diagnosis of VTE [30,31]. This has led some authors to consider the ICD codes as a preliminary identification tool for TVE before confirming through chart review [31].

<footnote>* the average age of puberty in France is 13 for female and 15 for male⁴¹.</footnote>

<footnote>** time-dependant variables</footnote>

<footnote>5-ASA, 5-aminosalicylates; IQR, interquartile range; IBD, inflammatory bowel disease; CD, Crohn's disease; UC, ulcerative colitis.</footnote>
Over the study period (1988–2011), the rate of TE remained sta-
ble. This observation aligns with data available for the adult pop-
ulation with IBD [11,12]. To our knowledge, this is the first data
regarding the evolution of the incidence of TE in pediatric-onset
IBD. This stagnation of the incidence rate of TE may result from
either the study's insufficient power or a failure to adhere to pedi-
iatric IBD guidelines on thromboprophylaxis, with thromboprophy-
laxis prescriptions being absent in as many as 20 % of pediatric IBD
cases [20].

The clinical presentation of VTE was similar to previously pub-
lished data. In this study, the median age at the diagnosis of VTE
was 20.4 years. Previous studies and a scoping review reported a
younger age of occurrence (between 13 and 14 years) [16,20,22].
Even though pubertal status was not recorded, the minimum age
of VTE occurrence (14.8 years) suggests that these events occurred
after puberty. In this study, deep vein thrombosis was the most
frequent VTE as previously reported in the Canadian and Danish
studies [2,21,23]. Cerebral venous sinus thrombosis was the sec-
ond most observed type of VTE. In two prior studies, cerebral ve-
nous sinus thrombus was the most common VTE type, represent-
ing about one third to one half of all VTE cases [16,20,22].

The investigation of risk factors for VTE in pediatric IBD has re-
ceived limited attention. In this study, VTE occurrence has been
associated with at least one risk factor, which was consistent with
a prior study [20]. Moreover, a combination of risk factors is likely
to amplify the risk of VTE, as established in adults with IBD [32].
Three risk factors linked with VTE were identified in this study:
disease activity, recent hospitalization and surgery. Notably, disease
activity has not yet been documented as a VTE-associated factor
in pediatric IBD, although a population-based study has reported
this risk factor in adults with IBD [3]. Recent hospitalization is al-
ready a well-established risk factor of VTE in pediatric IBD, albeit
with a substantially higher risk ratio (560 versus 21.7 in this study)
[22,23]. Similarly, surgery has already been identified as a risk fac-
tor for VTE [20] with a VTE rate reaching as high as 4.3 % in pe-
diatric IBD two weeks after colorectal resection [33]. Conversely, a
treatment with 5-ASA was associated with a reduction of the risk
of VTE. In our study, if disease activity did not seem to impact this
association, the low number of thromboembolism events observed
necessitates interpreting this result with extreme caution. More-
over, 5-ASA are likely to be prescribed to young patients who are
also at low risk of VTE. The effect of 5-ASA on VTE risk is rarely
studied, and data are conflicting. One study found a similar re-
sult in a nationwide IBD cohort [34], while two other works did
not observe any effect of 5-ASA on VTE [35,36]. Recently, a meta-
analysis found the risk of VTE to be equivalent in patients with 5-
ASA or anti-TNF [37]. Conclusions about the impact of coagulopa-
thy in pediatric IBD cannot be drawn, as this predisposing condi-
tion is rarely tested in this young population [16]. Lastly, catheter
related thrombosis was frequent in our study, accounting for ap-
proximately one-quarter of VTE cases. A similar trend was noted
in prior studies [23,33]. On the whole, the risk-increasing factors
for VTE in pediatric IBD appeared to align with those described in
adults with IBD [3,32,38].

Prior studies indicated a higher prevalence of VTE in patients
with pediatric-onset UC, although the association was no longer
significant when adjusting of demographic characteristics [21-23].
Although our study did not observe this trend, our results are
likely to be biased and underpowered due to residual confound-
ing. The extension of the disease, specifically pancolitis, has been
suggested to be closely linked to the risk of VTE [22]. In our
study, pancolitis represented one-third of UC patients, while in one
pediatric-onset UC cohort study, this proportion was over one-half
[22] and unknown in a second one [23]. Thus, a lack of power and
confounding bias are likely to explain our result as no multivari-
ate analysis has been performed. Indeed, CD patients were three

times more likely to undergo digestive surgery during the follow-
up period than UC patients, and the presence of a catheter was not
documented in the entire cohort. In adults with IBD, the relation-
ship between IBD subtype and VTE is debated. In a large Ameri-
can study involving hospitalized IBD patients, adults with UC were
found to have a heightened risk of VTE [8] whereas two other
population-based studies demonstrated a similar risk of VTE be-
tween UC and CD [4,7]. Lastly, it should be noted that data re-
garding obesity status were unavailable for the majority of pa-
tients, which represents a limitation of our study. Similarly, while
estrogen-based contraceptives are commonly used among young
women and are associated with an increased risk of VTE [39],
these medications were not included in our study. Currently, ECCO
guidelines advocate for thrombotic prophylaxis in adolescent with
severe acute colitis associated with at least one other risk factor
[19]. These results support the use of thrombotic prophylaxis in
postpubertal children aged 14 or older and hospitalized either in
context of a flare or digestive surgery. In younger patients with risk
factors, we advise a case-by-case discussion.

This study was the first to report the occurrence of ATE in a
pediatric-onset IBD population. During the follow-up period, only
one case of myocardial infarction was documented. As expected,
the incidence of arterial thromboembolic events in this study was
considerably lower than the reported myocardial infarction rate in
adults with UC (cumulative incidence of about 1.1 % at 5 years)
[40] or the prevalence of chronic coronary heart disease (2.2 %)
reported in an IBD adult population in Finland [41]. Similarly, only
one case of stroke was reported during follow-up, while a Swedish
population-based study in adults reported an incidence rate of 3.2
strokes per 1000 person-years [14]. Further case-control studies
specifically focused on the pediatric IBD population are necessary
to better understand the risk of arterial thromboembolic events in
comparison to their peers.

Despite the population-based nature of this work, it is impor-
tant to acknowledge certain limitations when interpreting our find-
ings. Although we followed >1300 patients with pediatric-onset
IBD for 8 years, we observed only 17 cases of TE. This low in-
cidence rate necessitates caution when considering the risk fac-
tors we have presented, as (1) some additional risk factors may
have been neglected due to limited statistical power and (2) some
risk factors, including obesity, cancer, pregnancy, and use of throm-
boprophylaxis or estrogen-based contraceptives, are missing from
analysis. To that extent, the limited number of ATE cases do not
allow to draw any conclusion regarding the putative predisposing
conditions. Last, while the likelihood of an information bias re-
garding TE occurrence is low, it remains a possibility. Neverthe-
less, given the seriousness of such events, it is improbable that
they have been missed. Moreover, these results are certainly more
applicable to a European population than to an American one, as
the obesity rate is higher in the United States and has worsened
over the last decade [42]. Likewise, the low number of pancolic
UC cases limits the applicability to this specific population. The
study time period, which included the last incident cases of IBD
in 2011, may introduce bias as standards of care and thrombopro-
phylaxis protocols may have improved in the meantime. However,
the follow-up of patients stopped in 2013, and the stable rate of
TE advocates for a similar result currently. Moreover, despite the
time period of the study, 48 % of CD patients and 24 % of UC pa-
tients in our population-based cohort were exposed to anti-TNFs.
The major strengths of our study are the use of a large, unselected
cohort of pediatric IBD patients included prospectively and con-
secutively in a population-based registry, and highly detailed data
retrieved from patient records by experts rather than from admin-
istrative databases.

To conclude, the risk of both arterial and venous thromboembolism was relatively low in this population-based study of
pediatric-onset IBD patients. This data highlights the importance of thromboprophylaxis in hospitalized post-pubertal children with IBD flare or undergoing surgery.

## Funding

EPIMAD is organized under an agreement between the Institut National de la Santé Et de la Recherche Médicale (INSERM) and Santé Publique France and also received financial support from the François Aupetit Association, Lille, Amiens, and Rouen University Hospitals. This work was supported by the Programme Hospitalier de Recherche Clinique interrégional and the Conseil Régional du Nord-Pas-de-Calais.

## Conflict of interest

The authors declare the following conflict of interest: M.F. has received lecture/consultant fees from AbbVie, Ferring, Tillotts, MSD, Biogen, Amgen, Fresenius, Hospira, Sandoz, Pfizer, Celgene, Gilead, Boehringer, Galapagos, Janssen, and Takeda. C.D. has received consultant fees from AbbVie. N.R. has received lecture/consultant fees from AbbVie and Takeda. The other authors state that they have no competing interests regarding this work to disclose.

## Acknowledgements

The authors wish to thank the interviewing practitioners who collected data: N. Guillon, I. Rousseau, A. Pétillon, B. Turck, H. Penkel, L. Damageux, S. Auzou, C. Le Gallo, D. Rime, and B. David. The authors thank all patients and all gastroenterologists and pediatric gastroenterologists who participated in this study and the European Charity Foundation DigestScience.

## APPENDIX A. EPIMAD study group

AL GHOSSAINI Najib, CH Region De Saint Omer, Saint-Omer, AL HAMEEDI Raied, Clinique Mathilde, Rouen, AL TURK Saria, Clinique Anne d'Artois, Béthune, AGOUTE Eric, Hôpital Privé de l'estuaire, Le Havre, ANTOINE Matthieu, CHU de Lille, Lille, ANTONIETTI Michel, Clinique de l'Europe, Rouen, AOUAKLI Amar, Centre Hospitalier de l'Arrondissement de Montreuil, Rang-du-Fliers, ARMENGOL-DEBEIR Laura, Clinique du Cèdre, Bois-Guillaume, AROICHANE Ibrahim, Clinique des Ormeaux, Le Havre, ASSI Fadi, CH d'Abbevile, Abbeville, AUXENFANTS Eric, Hopital Victor Provo, Roubaix, AZZOUZI Kassem, Polyclinique du Val de Sambre, Maubeuge, BANKOVSKI Damyan, Clinique tous vents, Lillebonne, BARBRY Bernard, SCI du 15 quai de Cherbourg, Tourcoing, BARDOUX Nicolas, Clinique Saint-Hilaire, Rouen, BARON Philippe, Clinique de Flandre, Coudekerque-Branche, BAUDET Agnès, Hôpital privé Arras Les Bonnettes, Arras, BAYART Pauline, Hôpital privé Le Bois, Lille, BAZIN Brice, Clinique Victoire, Tourcoing, BEBAHANI Arash, Polyclinique Jean Villar, Bruges, BECQWORT Jean-Pierre, Cabinet Mondor, Dunkerque, BELLATI Sara, Hôpital privé de Villeneuve d'Ascq, Villeneuve d'Ascq, BENET Vincent, Clinique Mathilde, Rouen, BEN ALI Houssem, Hôpital Privé de Bois-Bernard, Bois-Bernard, BENARD Coralie, Clinique Saint-Hilaire, Rouen, BENGUIGUI Corinne, Clinique Mathilde, Rouen, BEN SOUSSAN Emmanuel, Centre Alfred Kastler, Sarcelles, BENTAL Abdeslam, CH d'Abbeville, Abbeville, BERNET Jacques, CHU de Rouen, Rouen, BERNOU Karine, CH de Boulogne-sur-Mer, Boulogne-sur-Mer, BERTOT Pauline, Clinique de l'Europe, Rouen, BERTIAUX-VANDAËLE Nathalie, Hôpital Privé de l'Estuaire, Le Havre, BERTRAND Valérie, CH du Havre, Le Havre, BILLOUD Emilie, CH du Havre, Le Havre, BIRON Nathalie, CH de Grasse, Grasse, BISMUTH Benjamin, Hôpital Privé Le Bois, Lille, BLANCHARD Cyril, Hôpital Privé de l'Estuaire, Le Havre, BLONDEL Fabienne, Hôpitaux Privés du Hainaut, Valenciennes,

BLONDIN Valérie, CH d'Elbeuf, Elbeuf, BOBULA Marius, Clinique Mégival, Dieppe, BOHON Philippe, Polyclinique de la Thérache, Lille, BOIVIN Eléonore, Clinique Mathilde, Rouen, BON DJEMAH Vanessa, Polyclinique de Hénin-Beaumont, Hénin-Beaumont, BONIFACE Eric, Cabinet du Dr Boniface, Lens, BANKOVSKI Damyan, Clinique tous Vents Lillebonne, BONNIÈRE Philippe, Cabinet du Dr Bonnière, Dunkerque, BORUCHOWICZ Arnaud, CH de Valenciennes, Valenciennes, BOUALIT Médina, Hôpitaux Privés du Hainaut, Valenciennes, BOUAZZA Ahlem, Hôpital Saint Vincent de Paul et Saint Philibert, Lille, BOUCHE Bruno, Hôpital Privé les Bonnettes, Arras, BOURGEAUX Claude, Hôpital Clinique du Val de Seine, Lillebonne, BOURGEOIS-FUMERY Morgane, Clinique Victor Pauchet, Amiens, BOURGUET Arnaud, Hôpital Privé Le Bois, Lille, BOUTALEB Hamza, Polyclinique de la Clarence, Divion, BOUTHORS Alexis, Hôpital Privé les Bonnettes, Arras, BRANCHE Julien, CHRU Lille, Lille, BRAZIER Frank, CHU d'Amiens, Amiens, BRIDENNE Marie, CH de Dunkerque, Dunkerque, BRIHIER Hélène, Hôpital Privé de l'Estuaire, Le Havre, BRIL Laura, Clinique Saint-Hilaire, Rouen, BRUNG-LEFEBVRE Maud, Hôpital des Feugrais, St Aubin les Elbeuf, BULOIS Philippe, Hôpital Privé La Louvière, Lille, BURGIERE Pierre, Cabinet du Dr Burgière, Le Havre, BUTEL Joël, CH d'Abbeville, Abbevile, CANVA-DELCAMBRE Valérie, CHU de Lille, Lille, CARDOT Florence, CH de Dieppe, Dieppe, CARETTE Sandrine, CH de Lens, Lens, CARPENTIER Pierre, Cabinet du Dr Carpentier, Dunkerque, CASSAR Jean-François, Cabinet du Dr Cassar, Fécamp, CASSAGNOU Michel, Hôpital Privé de Villeneuve d'Ascq, Villeneuve d'Ascq, CASTEX François, Hôpital privé de Villeneuve d'Ascq, Villeneuve d'Ascq, CATALA Pascale, Hôpital public de Béthune Beuvry, Beuvry, CATTAN Stéphane, CHRU de Lille, Lille, CATTEAU Sylviane, CH de Boulogne-sur-Mer, Boulogne-sur-Mer, CAUJOLLE Bernard, Hôpital Privé de l'Estuaire, Le Havre, CHARPENTIER Cloé, CHU de Rouen, Rouen, CHAVANCE-THELU Marthe, Clinique Victor Pauchet, Amiens, CHENY Agathe, CHBA Site de Vannes, Vannes, CHOTEAU Antoire, Clinique des Aca-cias, Cucq, CLERGUE Pierre-Yves, Cabinet du Dr Clergue, Harfleur, COEVOET Hugues, Hôpital Privé les Bonnettes, Arras, COHEN Gil, Polyclinique de Picardie, Amiens, COLLET Régis, Centre Médical Spécialisé du Littoral, Saint-Martin-Boulogne, COLIN Marie, Polyclinique de la Louvière, Lille, COLOMBEL Jean-Frederic, Mount Sinai Hospital, New York City, COOPMAN Stéphanie, CHU de Lille, Lille, CORDIEZ Lucie, Groupe Hospitalier Seclin Carvin, Seclin, CORVIS-ART Jean, Cabinet du Dr Corvisart, Lille, CORTOT Antoine, CHRU de Lille, Lille, COUTTENIER Frédéric, Cabinet du Dr Couttenier, Attiches, CROMBE Valérie, Hôpital Privé Le Bois, Lille, DAOUDI Abdelhakim, Polyclinique de Grande-Synthe, Grande-Synthe, DAPVRIL Vincent, Clinique des Hêtres, Le Cateau-Cambrésis, DAVION Thierry, CH de Lens, Lens, DECOSTER Sébastien, Groupement des Hôpitaux de l'Institut Catholique de Lille, Lille, DEJAEGER Aurélien, CHU d'Amiens, Amiens, DELCENSERIE Richard, CHU d'Amiens, Amiens, DELEPLANQUE Marine, CH de Lens, Lens, DELESALLE Dorothée, Cabinet du Dr Delesalle, Lambersart, DELETTE Olivier, Cabinet du Dr. Delete, Lille, DELGRANGE Thierry, CH Doullens, Doullens, DELHOUSTAL Laurence, CH de Dunkerque, Dunkerque, DELMOTTE Jean-Stéphane, Cabinet du Dr Delmotte, Lille, DEMANe Sabri, Clinique Hemera Pays de Caux, Yvetot, DEREIGNAUCOURT Guy, Centre Futura Medica, Béthune, DESECHALLIERS Jean Pierre, CHI d'Elbeuf, Elbeuf, DESMET Patrick, Cabinet du Dr Desmet, Villeneuve d'Ascq, DESREUMAUX Pierre, CHRU de Lille, Lille, DESSEAUX Gérard, Cabinet du Dr Desseaux, Roubaix, DESURMONT Philippe, Centre Médical Pasteur, Marcq en Baroeul, DEVIENNE Alain, Hôpital Privé des Bonnettes, Arras, DEVOUGE Eve, CH d'Arras, Arras, DEVROUX Alex, CH de Cambrai, Cambrai, DEWAILLY Arnaud, Centre Hospitalier de l'Artois, Lens, DHARANCY Sébastien, CHRU de Lille, Lille, DI FIORE Aude, Clinique du Cèdre, Bois-Guillaume, DJEDDI Djamal-Dine, CHU Amiens, Amiens, DJEDIR Rachid, Centre Hospitalier de l'Artois, Lens, DOLEH Wissam, Centre Côte d'Opale, Saint-Martin-Boulogne, DREHER-DUWAT Marie Laure,
Hôpital Privé des Bonnettes, Arras, DUBURQUE Clotilde, Groupe-
ment des Hôpitaux de l'Institut Catholique de Lille, Lille, DUCROT
Frédéric, Clinique des Ormeaux, Le Havre, DUCROTTE Philippe, CHU
de Rouen, Rouen, DUFILHO André, Polyclinique de la Thérache,
Wignehies, DUHAMEL Christian, CSAPA Pont-Audemer CH La Risle,
Pont-audemer, DUMANT-FOREST Caroline, CHU de Rouen, Rouen,
DUPAS Jean Louis, CHU d'Amiens, Amiens, DUPONT Frédéric, Cabi-
net du Dr Dupont, Anzin-les-Valenciennes, DURANTON Yves, Clin-
ique Mathilde, Rouen, DURIEZ Arnaud, Hôpital privé de Villeneuve
d'Ascq, Villeneuve d'Ascq, DUVEAU Nicolas, CHU de Roubaix,
Roubaix, EL ACHKAR Khalil, CH de Péronne, Péronne, EL FARISI Mo-
hammadi, Clinique de Villeneuve-Saint-Georges, Villeneuve-Saint-
Georges, ELIE Caroline, CHI d'Elbeuf, Elbeuf, DESMET Patrick, Cab-
inet du Dr Desmet, Villeneuve-d'Ascq, ELIE-LEGRAND Marie-Claire,
Hôpital Privé de l'Estuaire, Le Havre, EOCHE Matthieu, Clinique
Sainte Isabelle, Abbeville, ESSMAEEL Essmaeel, Hôpital privé de
Villeneuve d'Ascq, Villeneuve d'Ascq, EVRARD Dominique, CH de
Boulogne, Boulogne, EVRARD Jean-Paul, Hôpital privé de Bois-
Bernard, Bois-Bernard, FATOME Armelle, CH du Havre, Le Havre,
FINET Laurent, Clinique de Flandre, Coudekerque-Branche. FLA-
HAUT Mathilde, CH de Dunkerque, Dunkerque, FLAMME Camille,
Cabinet du Dr Flamme, Tourcoing, FOISSEY David, Clinique
Saint Amé, Lambres-lez-Douai, FOURNIER Peggy, Hôpital privé Le
Bois, Lille, FOUTREIN-COMES Marie-Christine, CH d'Arras, Arras,
FOUTREIN Philippe, Clinique Ambroise Paré, Beuvry, FRERE Thierry,
Clinique Sainte Marie, Cambrai, FUMERY Mathurin CHU Amiens,
Amiens, GALAND Julie, CH d'Arras, Arras, GALLAIS Philippe, CH
de Cambrai, Cambrai, GAMBLIN Claudine, CH de Valenciennes, Va-
lenciennes, GANGA Serge, CH de Roubaix, Roubaix, GERARD Ro-
main, CHRU de Lille, Lille, GHRIB Salah, CH de Cambrai, Cam-
brai, GILBERT Thierry, Clinique Mathilde, Rouen, GODART Denis,
Clinique Sainte Marie, Cambrai, GODCHAUX Jean-Michel, Hôpital
privé de Villeneuve d'Ascq, Villeneuve d'Ascq, GOEGEBEUR Guetty,
Cabinet du Dr Goegebeur, La Roche-sur-Yon, GORIA Odile, CHU
de Rouen, Rouen, GOTTRAND Frederic, CHRU de Lille, Lille, GRA-
DOS Lucien, CHU Amiens, Amiens, GRANDMAISON Brigitte, Cab-
inet du Dr Grandmaison, Calais, GROUX Marion, Clinique Victor
Pauchet, Amiens, GUEDON Claire, CHU de Rouen, Rouen, GUER-
BEAU Loïc, Clinique Saint Amé, Lambres-lez-Douai, GUEROULT-
DERO Mathilde, Hôpital Privé de l'Estuaire, Le Havre, GUILLEM
Laurence, CHI d'Elbeuf, Elbeuf, GUILLEMOT François, Cabinet du
Dr Guillemot, Lille, GUIMBER Dominique, CHU Lille, Lille, HAD-
DOUCHE Baya, Clinique Hemera Pays de Caux, Yvetot, HAUTE-
FEUILLE Vincent, CHU d'Amiens, Amiens, HECQUET Geneviève,
Cabinet du Dr Hecquet, Gondecourt, HEDDE Jean-Pierre, Groupe-
ment des Hôpitaux de l'Institut Catholique de Lille, Lille, HEN-
NERESSE Pierre-Emmanuel, CH Jacques Monod, Flers, HEYMAN
Bruno, Centre de gastro-entérologie de la Vallée des Vignes,
Amiens, HERAUD Michel, Cabinet du Dr Heraud, Lille, HERVE So-
phie, Polyclinique du Parc, Caen, HOCHAIN Patrick, Clinique du Cè-
dre, Bois-Guillaume, HOUSSIN-BAILLY Lucie, Polyclinique Vauban,
Valenciennes, HOUCKE Philippe, Clinique Ambroise Paré, Beuvry,
HUGUENIN Bruno, Hôpital Privé des Bonnettes, Arras, IOBAGIU Sil-
viu, Clinique du Plateau, Bezons, ISTANBOLI Shata, CH d'Abbeville,
Abbeville, IVANOVIC Alexsandar, Clinique des Ormeaux, Le Havre,
IWANICKI-CARON Isabelle, Clinique Saint-Hilaire, Rouen, JANICKI
Eric, CH d'Arras, Arras, JARRY Marine, Cabinet du Dr Jarry, Tour-
coing, JEAN BART Charlotte, CH de Roubaix, Roubaix, CH du Ter-
nois, Saint-Pol-sur-Ternoise, JOUVENET Anne, CH de Douai, Douai,
KATHERIN Fadi, Centre Côte d'Opale, Saint-Martin-Boulogne, KER-
LEVEO André, Cabinet du Dr Kerleveo, Etaples, KHACHFE Ali,
CH de Calais, Calais, KIRIAKOS Jean, CHI d'Elbeuf, Elbeuf, KLEIN
Olivier, Polyclinique Vauban, Valenciennes, KOHUT Matthieu, Clin-
ique Sainte Isabelle, Abbeville, KORNHAUSER Richard, Hôpital Privé
des Bonnettes, Arras, LABERENNE Jean-Eric, Groupement Hospi-
talier Seclin Carvin, Seclin, LACOTTE Eric, CHU de Caen, Caen,

LAFFINEUR Guy, CH de Calais, Calais, LAGARDE Marine, Clinique
Victor Pauchet, Amiens, LAHAYE Anouck, CHU d'Amiens, Amiens,
LALANNE Arnaud, Cabinet du Dr Lalanne, Lambresart, LALIEU Am-
broise, CH de Valenciennes, Valenciennes, LANNoy Pierre, Poly-
clinique de la Clarence, Divion, LAPRAND Michel, Centre de santé
Filieris, Oignies, LAUDE Denis, Clinique Sainte Isabelle, Abbeville,
LEBLANC Rachida, CH de Valenciennes, Valenciennes, LECLEIRE
Stéphane, Clinique du Cèdre, Bois-Guillaume, LECLERC Nathalie,
Clinique Ambroise Paré, Beuvry, LE COUTEULX Christian, Cabi-
net du Dr Lecouteulx, Yvetot, LEFILLIATRE Pascale, CH du Havre,
Le Havre, LEGRAND Céline, CH de Béthune, Béthune, LEMAITRE
Caroline, CH du Havre, Le Havre, LE MOUEL Jean Philippe, CHU
d'Amiens, Amiens, LEPEUT Gabriel, Hôpital Victor Provo, Roubaix,
LEPIEUR Lucie, Hôpital Privé de l'Estuaire, Le Havre, , LEPOUTRE-
DUJARDIN Elodie, Hôpital privé Le Bois, Lille, LEROI Henri, Polyclin-
ique du Parc, Maubeuge, LEROY Maryvonne, CH Région De Saint
Omer, Saint-Omer, LE ROY Pauline, Hôpital privé de Villeneuve
d'Ascq, Villeneuve d'Ascq, LESAGE Benoit, Hôpital privé Le Bois,
Lille, LESAGE Xavier, Hôpital privé Le Bois, Lille, LESAGE Jocelyn,
Centre Côte d'Opale, Saint-Martin-Boulogne, LESCANNE-DARCHIS
Isabelle, Cabinet du Dr Lescanne-Darchis, Aire-sur-la-Lys, LES-
CUT Dominique, Hôpitaux Privé du Hainaut-Vauban, Valenciennes,
LEURENT Bruno, Cabinet du Dr Laurent, Saint-Omer, LEY Delphine,
CHRU de Lille, Lille, LIBIER Louise, Hôpital privé Le Bois, Lille,
LOREAU Julien, Clinique de l'Europe, Amiens, LOUVET Alexandre,
CHRU de Lille, Lille, LOZINGUEZ Joséphine, CHU d'Amiens, Amiens,
LUBRET Henri, CH de Boulogne, Boulogne-sur-Mer, LUCIDARME
Damien, Groupement des Hôpitaux de l'Institut Catholique de Lille,
Lille, LUGAND Jean-Jacques, Cabinet du Dr Lugand, Auchel, MAETZ
Denis, Cabinet du Dr Maetz, Lille, MANOLACHE Olivia, Clinique
Saint Amé, Lambres-lez-Douai, MARKS-BRUNEL Anne-Bérangère,
Hôpitaux Privés du Hainaut-Vauban, Valenciennes, MARRE Char-
line, CH du Havre, Le Havre, MARZLOFF Eric, Clinique de Flandre,
Coudekerque-Branche, MATHURIN Philippe, CHRU de Lille, Lille,
MAUILLON Jacques, CH du Havre, Le Havre, MAUNOURY Vincent,
CHRU de Lille, Lille, MEDAM DJOMO Michèle-Ange, Polyclinique de
Grande-Synthe, Grande-Synthe, MELCHIOR Chloé, CHU de Rouen,
Rouen, MELKI Ziad, Hôpital Privé des Bonnettes, Arras, METHARI
Lofti, Polyclinique d'Aubervilliers, Aubervilliers, MEURISSE Franck,
Polyclinique Vauban, Valenciennes, MICHAUD Laurent, CHRU de
Lille, Lille, MODAINE Patricia, Polyclinique de la Clarence, Di-
vion, MONTHE Angélique, CH de Boulogne, Boulogne-sur-Mer,
MOREL Loïk, Clinique Saint Omer, Saint-Omer, MORIN Mathilde,
Clinique Mathilde, Rouen, MORTIER Pierre Eugene, Institut Calot,
Berck Sur mer, MOUTERDE Olivier, CHU de Rouen, Rouen, MOZZI-
CONACI Nicolas, CH de Tourcoing, Tourcoing, MUDRY Jean, Ca-
bient du Dr Mudry, Lambres-lez-Douai, NACHURY Maria, CHRU
de Lille, Lille, NGO Minh Dung, CH de Dieppe, Dieppe, N'GUYEN
KHAC Eric, CHU d'Amiens, Amiens, NOTTEGHEM Bertrand, Hôpi-
tal privé de Villeneuve d'Ascq, Villeneuve d'Ascq, OLLEVIER Vin-
cent, Hôpital de Mons, Mons, OURAGHI Atika, CH d'Arras, Arras,
OUSSADOU Barriza, Centre Hospitalier d'Armentières, Armentières,
PAINCHART Claire, Clinique Saint Amé, Lambres-lez-Douai, PARENT
Bruno, Clinique de l'Europe, Rouen, Lille, PATRIER Philippe, Clinique
Mathilde, Rouen, PAUPARD Thierry, CH de Dunkerque, Dunkerque,
PAUWELS Mathieu, Clinique Victor Pauchet, Amiens, PETIT Richard,
CH de Dieppe, Dieppe, PIAT Muriel, CHU de Rouen, Rouen, PIOTTE
Sandrine, Polyclinique Vauban, Valenciennes, PLANE Christophe,
Centre Germon Gauthier, Beuvry, PLOUVIER Bernard, Cabinet du
Dr Plouvier, Marcq-en-Barœul, POMMELET Pierre, Hôpital Privé
La Louvière, Lille, POP Daniela, CH de Dieppe, Dieppe, PORDES
Charlotte, CH de Calais, Calais, POUCHAIN Gérard, CH Région
De Saint Omer, Saint-Omer, PRADES Philippe, Clinique de Flan-
dre, Coudekerque-Branche, PREVOST Jean Christophe, Clinique de
l'Europe, Amiens, QUARTIER Gilles, CH de Dunkerque, Dunkerque,
QUEUNIET Anne-Marie, CHI d'Elbeuf, Elbeuf, QUINTON Jean-
François, Polyclinique Vauban, Valenciennes, RABACHE Alain, Hôpital privé Le Bois, Lille, RATAJCZYK Sébastien, Clinique Saint Amé, Lambres-lez-Douai, REIX Nicole, Clinique Victor Pauchet, Amiens, RENAUT-VANTROYS Thibaud, Hôpital Victor Provo, Roubaix, REVILLION Marine, Centre Médipôle, Lens, RIACHI Ghassan, CHU de Rouen, Rouen, RIAULT Clémentine, Clinique de l'Europe, Amiens, RICHARD Nicolas, CHU de Rouen, Rouen, RICHEZ Cécile, Polyclinique de Grande-Synthe, Grande-Synthe, RIMBERT Benoit, Clinique Saint-Hilaire, Rouen, RODRIGUEZ Juan Daniel, Clinique Ambroise Paré, Beuvry, ROUX Jean-Marc, Clinique des 2 Caps, Coquelles, RUDELLI Alain, Polyclinique de Picardie, Amiens, SAINGIER Clémence, CHU de Lille, Lille, SAVOYE Guillaume, CHU de Rouen, Rouen, SCHLOSSBERG Patrick, Cabinet du Dr Schlossberg, Lens, SEFRIQUIO David, CHU de Rouen, Rouen, SEGUY David, CHRU de Lille, Lille, SEMINUR Celik, Clinique Mathilde, Rouen, SPYCKERELLE Claire, Hôpital Saint Vincent - Saint Antoine, Lille, TALBODEC Nathalie, Hôpital privé Le Bois, Lille, TAVERNIER Noémie, Hôpital privé de Villeneuve d'Ascq, Villeneuve d'Ascq, TCHANDEU Henriette, Clinique les Fontaines, Melun, TECHY Aurore, Hôpital privé de Villeneuve d'Ascq, Villeneuve d'Ascq, THIEBAULT Henri, Clinique de l'Europe, Amiens, THOREL Jean-Marie, Clinique du Cèdre, Bois-Guillaume, THUILLIER Christophe, Hôpital privé de Villeneuve d'Ascq, Villeneuve d'Ascq, TIELMAN Guillaume, Hôpital privé de Villeneuve d'Ascq, Villeneuve d'Ascq, TODE Manuela, Polyclinique Vauban, Valenciennes, TOUCHAIS Jean-Yves, Clinique Saint-Hilaire, Rouen, TOUMELIN Pierre, Hôpital Victor Provo, Roubaix, TUZEYvan, Centre Hospitalier de l'Artois, Lens, TRAN Léa, CHU de Lille, Lille, TRANVOUEZ Jean-Luc, CH du Havre, Le Havre, TRIKI Nadia, CH région de Saint Omer, Saint-Omer, TURCK Dominique, CHU de Lille, Lille, TURPIN Justine, Clinique Victor Pauchet, Amiens, UHLEN Stéphanie, Cabinet du Dr Hulen, Lille, VAILLANT Eric, Hôpital privé Le Bois, Lille, VALMAGE Claude, Cabinet du Dr Valimage, Hénin-Beaumont, VANCO Dominique, Clinique Saint Amé, Lambres-lez-Douai, VANDAELE-BERTIAUX Nathalie, Hôpital Privé de l'Estuaire, VANDAMME Hélène, CH de Béthune, Béthune, VANDERBECQ Etienne, CH de Cambrai, Cambrai, VANDER EECKEN Elise, Clinique Saint-Hilaire, Rouen, VANDERMOLEN Philipe, Centre Hospitalier de l'arrondissement de Montreuil, Montreuil-sur-Mer, VANDEVENNE Philippe, Cabinet du Dr Vandevenne, Villeneuve-d'Ascq, VANDEVILLE Lionel, Hôpital privé Le Bois, Lille, VANDEWALLE Alain, Clinique des 2 Caps, Coquelles, VANHOOVE Jean-Pierre, Cabinet du Dr Vanhooove, Hénin-Beaumont, VANRENTERGHEM Audrey, CHU d'Amiens, Amiens, VANVEUREN Charlotte, CH de Boulogne, Boulogne-sur-Mer, VASIES Iona, CHU de Rouen, Rouen, VERBIESE Guy, Clinique Ambroise Paré, Beuvry, VERLYNDE Juliette, CH de Dunkerque, Dunkerque, VERNIER-MASSOUILLE Gwenola Clinique des Acacias, Cucq, VERMELLE Philippe, Cabinet du Dr Vermelles, Villeneuve d'Ascq, VERNE Christine, Polyclinique Vauban, Valenciennes, VEZILIER-COCQ Perrine, Groupement des Hôpitaux de l'Institut Catholique de Lille, Lille, VIART Juliette, CH de Tourcoing, Tourcoing, VIGNERON Benoit, Hôpital Privé de Bois-Bernard, Bois-Bernard, VINCENDET Marc, Cabinet du Dr Vincendet, Saint Martin Boulogne, WALLEZ Jean-Yves, Cabinet du Dr Wallez, Lille, WANTIEZ Michel, Polyclinique de Picardie, Amiens, WARTEL Faustine, CH de Valenciennes, Valenciennes, WEBER Jean-Christian, Centre Hospitalier de l'arrondissement de Montreuil, Rang-du-Fliers, WILLOQUET Jean-Louis, CH de Denain, Denain, WIZLA Nathalie, CHRU de Lille, Lille, WOLSCHIES Eric, CH de Morlaix, Morlaix, ZAHARIA Oana, CH de Dunkerque, Dunkerque, ZAOUI Sonia, Hôpital Victor Provo, Roubaix, ZALAR Alberto, Clinique de l'Europe, Rouen, ZELLWEGER Anne, Hôpital privé Le Bois, Lille.

Supplementary materials

Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.dld.2024.09.005.

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