Saline Enema Administration in Meconium Obstruction of Prematurity and Impact on the Resolution, Feeds, Microbiome, and Gut-brain Axis.

May 20, 2025 updated by: Thowfique Kadavukarayil Ibrahim, KK Women's and Children's Hospital

The Administration of Saline Enema Versus Glycerin Suppository as a Treatment Intervention for Meconium Obstruction of Prematurity (MOP) and to Study the Impact on the Resolution of MOP, Time to Reach Full Enteral Feeds, Gut Microbiome, and Gut-brain Axis, a Randomised Control Trial.

The goal of this clinical trial is to study the effect of twice-daily saline enema (SE) in the treatment obstruction of prematurity (MOP) in infants with the birth weight ≤1.25kg. The main questions, the trial aims to answer are

  1. To validate the finding of our pilot study which had shown that twice-daily SE reduces the time to reach full enteral feeds in premature infant as compared to premature infant treated with Glycerine Suppository (GS), in a larger cohort. Infant with MOP fails to pass meconium in the first 48 hours of life and develop symptoms and signs like abdominal distension and feed intolerance.

  2. The other aims of this study are to test whether the intervention is

    1. Effective treatment for MOP
    2. Reduce the duration of ICU stay
    3. Reduce the rate of necrotizing enterocolitis, sepsis, Total Parenteral Nutrition (TPN) days and number of intravenous catheter days
  3. The study also wants to explore the impact of this intervention on the gut microbiome, gut-brain interaction and immune response of the new-born.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Very low birth weight infants (VLBW ≤ 1.5 kg) constitute more than 60% of bed occupancy in level III neonatal units. They face the risk of 10-50% long-term disability, and their initial healthcare cost ranges from S$50,000 to 1 million, an important healthcare issue.

The incidence of meconium obstruction of prematurity (MOP) is 20-30% in extremely low birth weight (ELBW ≤ 1 kg) infants. The intervention based on the current standard of care increase the risk of laparotomy necrotizing enterocolitis, intestinal perforation, and neurodevelopmental risks posed by general anaesthesia. Our published pilot RCT demonstrated that saline enema (SE) is an effective, feasible, and safe intervention to reduce the time to reach full enteral feeds and is a potentially effective treatment for MOP in ELBW (< 1 kg) infants.

Our primary hypothesis is that Infants with Twice-daily high-volume SE (20-40 ml/kg/day) intervention will result in reduced time to reach full enteral feeds compared to infants treated with conventional management with Glycerin suppository (GS) in (≤1.25kg) infants with MOP. Our exploratory hypothesis is that SE will have a protective effect on the gut microbiome, inflammatory and immune response in preterm infants.

Ninety-five infants born over three years in KK Hospital (KKH) and Singapore General Hospital (SGH) will be enrolled and randomized at 48 hours or later to receive SE or GS. The standardized protocol will be used for the accreditation and administration of SE. Primary, secondary, and exploratory outcomes data, including treatment failure data, will be recorded. Infants will be followed up to 36 weeks of gestation or discharge, whichever is earlier. Maternal and infant characteristics, inflammatory and immune response, and safety outcome data will be collected.

If the findings of our pilot trial are confirmed, the protocol can become the standard of care in preterm infants with MOP. Additionally, significant healthcare cost savings will be realized alongside an improved understanding of the Microbiome, immune and inflammatory response pertaining to the gut.

Study Type

Interventional

Enrollment (Estimated)

95

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Criteria A: For infant presenting with early onset of MOP

    1. Birth weight 500 - 1250 gram
    2. ≥ 23 weeks gestation
    3. No BO for 48 hours
    4. BO present but with a small amount or stain of meconium
    5. Feeds intolerance or abdominal X-ray showing dilated loops of bowel

  • Criteria B: For infant presenting with Late onset of MOP

    1. Birth weight 500 - 1250 gram
    2. ≥ 23 weeks gestation
    3. Infants who passed meconium initially and develop evidence of meconium obstruction at a later age (feed intolerance or vomiting and abnormal abdominal X-ray with or without abdominal distension)

Exclusion Criteria:

Infants that:

  1. Neuromuscular disorder
  2. Moderate or severe asphyxia
  3. Inability to start enteral feeding, which continued for 3 consecutive days before 2 weeks of post-natal age for reasons unrelated to meconium inspissation or its complication
  4. Without parental consent
  5. Aggravated medical instability
  6. Single mothers < 21 years

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention Arm (Saline Enema Arm)

After randomisation, infant who allocated with intervention group will proceed with SE with normal saline (20-40ml/kg twice daily) earliest at 48 to 72 hours of age. Then continue until 2 days of yellow stools/ 110ml/kg/day of oral feeds; whichever is earlier.

SE are recommended if baby do not do bowel opening (BO) for 2 days before reaching full feeds
Procedure: Saline Enema (SE)

infant who allocated with intervention group will proceed with SE with normal saline (20-40ml/kg twice daily) at 48 hours of age. Then continue until 2 days of yellow stools/ 110ml/kg/day of oral feeds; whichever is earlier.

SE are recommended if baby do not do bowel opening (BO) for 2 days before reaching full feeds

Failure to resolve the MOP with SE will be designated as treatment failure and managed with contrast enema or Laparotomy by paediatric surgeons, following a formal referral.GS is not allowed in intervention arm
Active Comparator: Control Arm (Glycerin Suppository Arm)

Infants randomized to GS received the standard management protocol for meconium retention in the unit. GS (2,000 mg, a quarter unit, four doses 12 h apart) were administered to infants earliest at 48 hour to 72 hours of birth, with subsequent once-daily GS being administered at the discretion of the managing team. Infants who were diagnosed with meconium obstruction later in the first 2 weeks of life were also treated with glycerin suppositories for 48 hrs, with subsequent once-daily GS being administered at the discretion of the managing team.

Infants who failed to respond to glycerin suppositories were referred to the surgical team by the managing team The subsequent management of meconium retention was at the surgeon's discretion and included continued GS by the surgical team, contrast enema or surgical interventions performed in escalating order as mentioned.
Drug: Glycerin Suppository

Infants randomized to GS received the standard management protocol for meconium retention in the unit. GS (2,000 mg, a quarter unit, four doses 12 h apart) were administered to infants earliest at 48 hour to 72 hours of birth, with subsequent once-daily GS being administered at the discretion of the managing team. Infants who were diagnosed with meconium obstruction later in the first 2 weeks of life were also treated with glycerin suppositories for 48 hrs, with subsequent once-daily GS being administered at the discretion of the managing team.

Infants who failed to respond to glycerin suppositories were referred to the surgical team by the managing team The subsequent management of meconium retention was at the surgeon's discretion and included continued GS by the surgical team, contrast enema or surgical interventions performed in escalating order as mentioned.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to reach full enteral feeds in days
Time Frame: Before 36 weeks of corrected age of discharge of the infant

Time to reach full enteral feeds is measured from birth to the time infant reaches full oral milk feeds.

Full oral milk feed is defined as milk volume of 110ml/kg/day. The total parenteral nutrition is discontinued when infant reaches milk feed volume of 110ml/kg/day.

Rationale:

SE loosens the thick and sticky meconium by saline absorption and triggers effective and strong peristaltic contractions, thereby leading to the evacuation of meconium from the gut. The evacuation of meconium leads to the resolution of the gut obstruction, thereby enhancing feed tolerance in premature infants with meconium obstruction of prematurity.
Before 36 weeks of corrected age of discharge of the infant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of treatment failure
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Treatment failure is defined as the need to use additional treatment measures, apart from the study intervention to resolve MOP in the study cohort.
Before 36 weeks of corrected age of discharge of the infant
Rate of (a) Culture positive sepsis (b) Necrotising enterocolitis.
Time Frame: Before 36 weeks of corrected age of discharge of the infant

Rationale:

If twice daily SE leads to the shortening of time to reach full enteral feeds, resolution of MOP, and promote friendly bacteria microbiome, then it has the potential to reduce NICU stay, risk of necrotising enterocolitis, risk of sepsis, duration of total parenteral nutrition, duration of PICC and overall cost of care.
Before 36 weeks of corrected age of discharge of the infant
Duration in days of (a) ICU stay (b) Total parenteral nutrition (c) PICC days.
Time Frame: Before 36 weeks of corrected age of discharge of the infant

Rationale:

If twice daily SE leads to the shortening of time to reach full enteral feeds, resolution of MOP, and promote friendly bacteria microbiome, then it has the potential to reduce NICU stay, risk of necrotising enterocolitis, risk of sepsis, duration of total parenteral nutrition, duration of PICC and overall cost of care.
Before 36 weeks of corrected age of discharge of the infant
Overall cost of care calculated in SGD at the time of discharge
Time Frame: Before 36 weeks of corrected age of discharge of the infant

Rationale:

If twice daily SE leads to the shortening of time to reach full enteral feeds, resolution of MOP, and promote friendly bacteria microbiome, then it has the potential to reduce NICU stay, risk of necrotising enterocolitis, risk of sepsis, duration of total parenteral nutrition, duration of PICC and overall cost of care.
Before 36 weeks of corrected age of discharge of the infant

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Identification and quantification of bacteria from meconium/stool samples by DNA sequencing and analysis of top 50 bacteria Genus
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Bacteria are identified from meconium/stools samples, collected at birth and weekly interval till discharge or 36 weeks of gestation
Before 36 weeks of corrected age of discharge of the infant
To measure the serum level of IL 6 in pg/ml
Time Frame: Before 36 weeks of corrected age of discharge of the infant

Use Olink Target 48 platform to measure

Rationale:

To explore the relationship between gut microbiome and gut-brain axis
Before 36 weeks of corrected age of discharge of the infant
To measure the serum level of neurotransmitters noradrenaline in pg/L
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Use Norepinephrine ELISA Kit from abcam to measure
Before 36 weeks of corrected age of discharge of the infant
Measure serum levels of dopamine in arbitrary units (peak area of analyte divided by peak area of an internal standard)
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Use Norepinephrine ELISA Kit from abcam to measure
Before 36 weeks of corrected age of discharge of the infant
Measure serum levels of serotonin in arbitrary units (peak area of analyte divided by peak area of an internal standard)
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Use Norepinephrine ELISA Kit from abcam to measure
Before 36 weeks of corrected age of discharge of the infant
Measure serum levels of GABA in arbitrary units (peak area of analyte divided by peak area of an internal standard)
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Use Norepinephrine ELISA Kit from abcam to measure
Before 36 weeks of corrected age of discharge of the infant
Measure level of Propionate in µM
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Use Short Chain Fatty Acid Panel to measure
Before 36 weeks of corrected age of discharge of the infant
Measure level of Butyrate in µM
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Use Short Chain Fatty Acid Panel to measure
Before 36 weeks of corrected age of discharge of the infant
Measure level of Acetate in µM
Time Frame: Before 36 weeks of corrected age of discharge of the infant
Use Short Chain Fatty Acid Panel to measure
Before 36 weeks of corrected age of discharge of the infant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

KK Women's and Children's Hospital

Collaborators

Singapore General Hospital
Duke-NUS Graduate Medical School
Genome Institute of Singapore
Translational Immunology Institute

Investigators

  • Principal Investigator: Thowfique Ibrahim, FRCPCH, FAMS, Singhealth Duke-NUS Medical School, NUS and LKC Medical School

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 2, 2024

Primary Completion (Estimated)

August 31, 2027

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

August 3, 2023

First Submitted That Met QC Criteria

September 14, 2023

First Posted (Actual)

September 21, 2023

Study Record Updates

Last Update Posted (Actual)

May 23, 2025

Last Update Submitted That Met QC Criteria

May 20, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2023/2270

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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