Enteral Administration of Docosahexaenoic Acid to Prevent Necrotizing Enterocolitis in Preterm Neonates

Efficacy of Enteral Administration of the Docosahexaenoic Acid on Necrotizing Enterocolitis, Cytokines and Hospital Stay in Preterm Neonates

• The purpose of this study is to determine whether docosahexaenoic acid is effective in the prevention or reducing severity of necrotizing enterocolitis (NEC) in preterm neonates < 1500 g at birth who are starting enteral feeding.
• if NEC is prevented, this study will measure whether hospital stay is also reduced in neonates who receive Docosahexaenoic acid (DHA)

Study Overview

• Status: Completed
• Conditions: Necrotizing Enterocolitis
• Intervention / Treatment: Dietary supplement: Docosahexaenoic acid (DHA); Dietary supplement: Placebo

Detailed Description

• Preterm neonates with birth weight less than 1500 g are in higher risk to develop NEC.

• NEC is an inflammatory condition that:

  1. Is the medical urgency most frequent of gastrointestinal tube that requires neonatal intensive care
  2. may perforate infant´s bowel requiring surgery from 20% to 60% of the cases
  3. may cause infant's death in 20% to 42% of the cases.
  4. has no adequate treatment worldwide, therefore prevention is needed
• DHA by enteral feeding has been administrated by our research group to attenuate inflammatory response in septic and surgical neonates.

• Our results showed:

  1. lower Interleukin(IL)-1 beta in septic neonates, but in surgical neonates, they also showed less IL-6 and anti-inflammatory cytokines IL-10 and IL-1ra, after adjusting by confounders
  2. increased weight, length and fat mass gain in septic neonates
  3. decreased organic failures in surgical neonates, and
  4. lower stay at neonatal intensive care in surgical neonates

DHA has not been used as unique intervention at a high but physiological dose; in addition, our previous results found an anti-inflammatory effect in neonates.Therefore, we expect that preterm infants may have a reduced bowel inflammatory response and lower NEC events and or severity

• Study Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Mexico
  • Distrito Federal
    • Mexico City, Distrito Federal, Mexico, 06720
      • Unit of Medical Research in Nutrition, Pediatric Hospital, IMSS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 2 weeks (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Birth weight lower than 1500 g
• Adequate weight for gestational age
• Clinically stable to begin enteral feeding
• Written informed consent by both parents plus the sign of two witnesses

Exclusion Criteria:

• Clinical and biochemical data of inflammatory response such as body core temperature altered, cardiac and respiratory frequency -low or high according to age-, leucocytosis or leucopenia, taking into account the thresholds reported by Goldstein in Pediatric Critical Care Medicine 2005 Vol 6 N°1.
• Persistent bleeding at any level
• Mother taking n-3 supplements and planning to breastfed
• Parents who decline the authorization for participating in the study
• Early discharge to other hospital outside the metropolitan area
• Persistent vomiting
• Receiving medication to avoid coagulation
• Gastrointestinal malformations

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: DHA Group; DHA Group will receive 75 milligrams of docosahexaenoic acid (DHA) per kilogram of their baseline weight. They will receive one dose, administered by enteral feeding every 24 h during 14 days	Dietary supplement: Docosahexaenoic acid (DHA); Docosahexaenoic acid from algae source; Other Names: n-3 Fatty Acids
PLACEBO_COMPARATOR: Control Group (Placebo); Control group will receive sunflower oil which is the excipient of the DHA in this study. They will receive one dose every 24 h during 14 days.	Dietary supplement: Placebo; Placebo was designed to mimic the color and consistence of the oil that contains DHA; Other Names: Sunflower oil, Placebo for DHA intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Necrotizing enterocolitis (NEC)	Neonates will receive enteral DHA at beginning of their first enteral feeding and NEC will be diagnosed during hospital stay, measured as presence or absence, as well as severity of NEC by Bell's score.	Patients will be followed for the duration of hospital stay, an expected average of 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytokines Interleukin (IL)-1 beta, Tumoral necrosis factor (TNF)-alpha, IL-6, IL-10	Plasma cytokines will be determined before to the beginning of the enteral feeding (baseline) and if the infant develop confirmed or severe NEC. Cytokines will be measured by a multiplex kit in picograms/mL.	At baseline and a second measurement only if they develop confirmed or severe NEC according to Bell's criteria
Hospital stay	Hospital stay includes intensive stay care and preterm service (where clinically stable babies are attended) until they are discharged from the hospital to home, in days.	The duration of hospital stay, an expected average of 6 weeks
Growth velocity in weight	Gain of weight in g/kd/day, measured with an electronic scale every week until hospital discharge or 40 weeks of corrected gestational age	Throughout hospital stay as part of nutritional follow-up of the care unit, an expected average of 4 weeks
Growth velocity in length and head circumference	Gain of recumbent length and and head circumference in cm/week measured every 2 weeks until hospital discharge or 40 weeks of corrected gestational age. For measuring length we will use an infantometer and for head circumference we will use a glass fiber tape.	Throughout hospital stay as part of nutritional follow-up of the care unit, an expected average of 4 weeks
Growth velocity in skin folds	Gain of bicipital, tricipital, suprailiac and subscapular skin folds in mm/week measured every 2 weeks, until hospital discharge or 40 weeks of corrected gestational age. We will use a glass fiber tape to measure it.	Throughout hospital stay as part of nutritional follow-up of the care unit, an expected average of 4 weeks
Enteral tolerance	Registration of volume of the enteral intake every 24 h (ml/kg/day) until reach 150 ml/kg/day and being sustained or increased by enteral feeding with human milk or formula.	During their hospital stay until reach 150 ml/kg/day, in average 2 to 5 weeks
Enteral intolerance	Registration of number of patients with clinical signs of intolerance such as vomit, abnormal number of stool loss, abdominal distension, number of patients with medical indication to withdraw enteral feeding due clinical unstability and number of patients with use of medications related to enteral tolerance such as omeprazole, ranitidine, vitamins, iron, etc.	During their hospital stay until reach 150 ml/kg/day, in average 2 to 5 weeks

Collaborators and Investigators

• Sponsor: Coordinación de Investigación en Salud, Mexico
• Collaborators: National Council of Science and Technology, Mexico

Publications and helpful links

General Publications

• Lopez-Alarcon M, Bernabe-Garcia M, Del Prado M, Rivera D, Ruiz G, Maldonado J, Villegas R. Docosahexaenoic acid administered in the acute phase protects the nutritional status of septic neonates. Nutrition. 2006 Jul-Aug;22(7-8):731-7. doi: 10.1016/j.nut.2006.04.002. Epub 2006 Jun 5.
• Lopez-Alarcon M, Bernabe-Garcia M, del Valle O, Gonzalez-Moreno G, Martinez-Basilea A, Villegas R. Oral administration of docosahexaenoic acid attenuates interleukin-1beta response and clinical course of septic neonates. Nutrition. 2012 Apr;28(4):384-90. doi: 10.1016/j.nut.2011.07.016. Epub 2011 Nov 12.
• Bernabe-Garcia M, Lopez-Alarcon M, Villegas-Silva R, Mancilla-Ramirez J, Rodriguez-Cruz M, Maldonado-Hernandez J, Chavez-Rueda KA, Blanco-Favela F, Espinoza-Garcia L, Lagunes-Salazar S. Beneficial Effects of Enteral Docosahexaenoic Acid on the Markers of Inflammation and Clinical Outcomes of Neonates Undergoing Cardiovascular Surgery: An Intervention Study. Ann Nutr Metab. 2016;69(1):15-23. doi: 10.1159/000447498. Epub 2016 Jul 9.
• Bernabe-Garcia M, Calder PC, Villegas-Silva R, Rodriguez-Cruz M, Chavez-Sanchez L, Cruz-Reynoso L, Mateos-Sanchez L, Lara-Flores G, Aguilera-Joaquin AR, Sanchez-Garcia L. Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial. Nutrients. 2021 Feb 17;13(2):648. doi: 10.3390/nu13020648.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (ACTUAL): October 1, 2017
• Study Completion (ACTUAL): October 1, 2017

Study Registration Dates

• First Submitted: November 23, 2012
• First Submitted That Met QC Criteria: December 6, 2012
• First Posted (ESTIMATE): December 10, 2012

Study Record Updates

• Last Update Posted (ACTUAL): March 24, 2021
• Last Update Submitted That Met QC Criteria: March 22, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: n-3 fatty acids; preterm infants; necrotizing enterocolitis; docosahexaenoic acid
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Enterocolitis; Enterocolitis, Necrotizing
• Other Study ID Numbers: DHA-ECN; DHA, ECN and Preterm (OTHER_GRANT: CONACYT 161643)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This project has secondary outcomes that have not been analyzed; therefore, in this moment we decided not to share our database.