Necrotizing Enterocolitis and Bowel Perforation in Very Preterm Infants - Long-term Follow up (NOR-NEC)

Necrotizing enterocolitis (NEC) is a gastrointestinal syndrome characterized by transmural inflammation and necrosis of the large and/or small bowel and subsequent intramural gas-forming organisms into the intestinal wall. Some preterm infants also develop spontaneous intestinal perforations (SIP) without the classical bowel inflammation/necrosis seen in NEC. NEC and SIP can be challenging to differentiate. Severe cases of both conditions require surgery and often bowel resection, but mortality due to SIP seems lower.

Studies looking at "long-term prognosis" of infants with NEC and bowel perforation have mainly assessed outcome until 2-7 years of age. The primary school years is a vulnerable period for ex-preterm children. Disruption in learning and social integration is of great importance for their quality of life (QoL), but little data exist in this age group. Moreover, nutritional deficits (e.g. cobalamin- or iron-deficiency may impact cognitive development, but this has not been investigated in this "high-risk" population in school age. Authors of a recent systematic review on gastrointestinal sequel after NEC-surgery thus called for "more high-quality studies assessing long-term follow-up".

In this project we will study the long-term impact of surgery for NEC and bowel perforation in preterm infants, both with a quality of life (QoL) perspective and with a focus on development, growth, nutrition and persistent gastrointestinal problems.

Study Overview

• Status: Not yet recruiting
• Conditions: Necrotizing Enterocolitis; Intestinal Perforation; Premature Infant Disease

Detailed Description

INTRODUCTION

Necrotizing enterocolitis (NEC) is a gastrointestinal syndrome characterized by transmural inflammation and necrosis of the large and/or small bowel and subsequent intramural gas-forming organisms into the intestinal wall. The incidence of NEC is inversely related to birth weight and gestational age (GA), with the majority of affected being very preterm infants (GA < 32 weeks), and in particular extremely preterm infants (GA < 28 weeks). In Scandinavia, the rates of NEC in extremely preterm infants is 6-9% (1-3). NEC is a devastating condition and one of the four main causes of mortality in neonatal intensive care units (NICUs) (4). Some preterm infants also develop spontaneous intestinal perforations (SIP) without the classical bowel inflammation/necrosis seen in NEC. NEC and SIP can be challenging to differentiate. Severe cases of both conditions require surgery and often bowel resection, but mortality due to SIP seems lower (5).

The clinical onset of NEC is usually in the second or third week of life. Typical symptoms and signs are a distended abdomen, periumbilical erythema, bloody stools, feeding intolerance and a generally unstable infant. However, the signs are non-specific, and the diagnosis is usually based on radiographic findings such as intramural bowel gas (6, 17, 18). The severity is classified by modified Bells criteria (18, 19). Stage I refers to suspected, but unconfirmed NEC. Stage II is radiographically confirmed NEC requiring medical therapy including broad-spectrum antibiotics and supportive care. Stage III patients demonstrate clinical signs of bowel necrosis, peritonitis, and septic shock, or radiographic findings of bowel perforation. These patients often receive surgery in addition to intensive care. The mortality rate of NEC is between 20-40%; highest in immature infants and/or stage III disease (20, 21).

Survivors of severe NEC (stage III) require long and often very intensive medical therapy that cause suffering for both patients and their families (18, 20). Moreover, medical therapy of patients with NEC requires huge resources for the neonatal unit and the health care system (20). Those who survive NEC have an increased risk of later gut-associated problems (e.g. short bowel syndrome and strictures) (18, 22), and neurodevelopmental disability (20, 23). Similar results have been observed in follow-up studies after SIP, but less data is available for this condition (23).

Although significant progress has been made in our understanding of NEC/SIP over the last decade, many questions remain regarding the long-term prognosis and optimal follow-up.

Studies looking at "long-term prognosis" of infants with NEC and bowel perforation have mainly assessed outcome until 2-7 years of age (20, 24). The primary school years is a vulnerable period for ex-preterm children. Disruption in learning and social integration is of great importance for their quality of life (QoL), but little data exist in this age group (25). Moreover, nutritional deficits (e.g. cobalamin- or iron-deficiency (26, 27) may impact cognitive development, but this has not been investigated in this "high-risk" population in school age. Authors of a recent systematic review on gastrointestinal sequel after NEC-surgery thus called for "more high-quality studies assessing long-term follow-up" (28).

In this project we will study the long-term impact of surgery for NEC and bowel perforation in preterm infants, both with a quality of life (QoL) perspective and with a focus on development, growth, nutrition and persistent gastrointestinal problems.

AIM

to collect long-term follow-up data on QoL, growth, development, biochemical nutritional status and persistent gastrointestinal symptoms among survivors of surgical NEC or bowel perforation in the neonatal period, in order to identify areas where we can improve or optimize follow-up.

RESEARCH QUESTION

What is the long-term outcome of preterm infants surviving surgical NEC or bowel perforation in the neonatal period?

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Claus Klingenberg, MD, PhD; Phone Number: +47 91563167; Email: claus.klingenberg@unn.no
• Study Contact Backup: Name: Nina Hapnes, MD; Phone Number: +47 47448119; Email: nina.clare.hapnes@sus.no

Study Locations

• Norway
  • Tromsø, Norway, N-9038
    • University Hospital of North Norway

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Cases and Controls will be identified through the Norwegian Neonatal Network.

Description

Inclusion Criteria:

• Case: All Norwegian very preterm infants (gestational age (GA) < 32 weeks) born during the 6-year period 2008-2013, diagnosed with surgical NEC or bowel perforation and surviving up to one year of age will be invited to participate as cases.
• Controls: For each case we will invite two controls matched for important clinical characteristics (e.g. sex, GA, clinical illness score, intracranial pathology, need for oxygen at discharge etc.).

Exclusion Criteria:

• not signing informed consent scheme

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pediatric quality of life (PedsQL) questionnaire	modular approach measuring health-related QoL in children and adolescents (2-18 years) incl. children with acute and chronic health conditions. This questionnaire comprises of 4 essential core domains namely: Physical Functioning, Emotional Functioning, Social Functioning and School Functioning.	2020-2021

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pediatric quality of life (QoL) Gastrointestinal Symptoms	Validated questionnaire assessing gastrointestinal problems.The questionnaire reports data on gastrointestinal symptoms, within 10 scales. The final score goes from 0-100 and higher values indicates less symptoms and better QoL.	2025
5-15-R	a standardized questionnaire for parents covering development and behavior of children and adolescents in ages 5 to 17 years	2025
Blood samples	Hb, leukocytes with differential count, platelets, reticulocytes, mean corpuscular volume, Hb in reticulocytes, ferritin, 25-OH vitamin D, cobalamine, urea, creatinine, calcium, phosphorous, 9 essential trace elements, a broad panel of other fat and water soluble vitamins. Data will be reported in SI units, or other conventional measures. For this outcome we will report data on number of participants with 1, 2, 3 or 4 or more abnormal laboratory values	2025
Weight	in kilogram and one decimal (e.g. 24.8 kg)	2025
Height	in cm	2025
Head circumference	in cm and one decimal (e.g. 45.7 cm)	2025

Collaborators and Investigators

• Sponsor: University Hospital of North Norway
• Investigators: Study Director: Trond Flaegstad, MD, PhD, University Hospital of North Norway

Publications and helpful links

General Publications

• Hau EM, Meyer SC, Berger S, Goutaki M, Kordasz M, Kessler U. Gastrointestinal sequelae after surgery for necrotising enterocolitis: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2019 May;104(3):F265-F273. doi: 10.1136/archdischild-2017-314435. Epub 2018 Jun 26.
• Neu J. Necrotizing enterocolitis: the mystery goes on. Neonatology. 2014;106(4):289-95. doi: 10.1159/000365130. Epub 2014 Aug 20.

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: January 2, 2020
• First Submitted That Met QC Criteria: January 2, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 2, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: quality of life; long-term follow-up; necrotizing enterocolitis; preterm infant; bowel perforation
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Infant, Newborn, Diseases; Gastroenteritis; Infant, Premature, Diseases; Enterocolitis; Enterocolitis, Necrotizing; Intestinal Perforation
• Other Study ID Numbers: 2018/1976/REK nord

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: no plan to share IPD for this study which is not a RCT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No