Sodium and Milk Fortification Evaluation of Body Composition Among Very Preterm Infants (SAFE)

The goal of the trial is to learn if targeted sodium supplementation (including blood and urine sodium testing) versus standard milk fortification (including blood sodium testing) improves growth and body composition in very preterm infants?

Study Overview

• Status: Recruiting
• Conditions: Very Preterm and Extremely Preterm Birth
• Intervention / Treatment: Diagnostic test: Urine sodium testing; Diagnostic test: Serum sodium testing; Dietary supplement: Milk fortification

Detailed Description

Very preterm infants (born <32 weeks gestational age) are at high risk for postnatal growth faltering, which is associated with adverse neurodevelopmental outcomes. Despite routine use of enriched human milk fortification in the NICU, many infants fail to achieve adequate somatic and lean mass growth. Sodium depletion has been identified as a potentially modifiable contributor to this problem: renal tubular immaturity in preterm infants results in obligate urinary sodium wasting. Total body sodium depletion has been associated with poor growth in infants and poor muscle mass development in animal studies.

Current NICU practice relies primarily on serum sodium to guide supplementation; however, serum sodium is a late and insensitive marker of total body sodium depletion. Urine sodium is a more sensitive indicator of sodium balance and may identify depletion before serum levels fall. Gestational-age-specific urine sodium thresholds to guide supplementation have recently been proposed (Stalter et al., 2025), but have evaluated body composition in a prospective randomized trial.

This trial tests whether a structured, urine sodium-guided supplementation protocol based on every other week urine and serum sodium monitoring improves anthropometric growth and lean mass accrual compared to standard enriched fortification alone. The intervention runs from day of life 14 through 36 weeks postmenstrual age, with tapering through 38 weeks PMA.

Body composition assessment incorporates two complementary modalities: serial point-of-care ultrasound (POCUS) of the biceps, rectus femoris, and subcutaneous fat for longitudinal lean and fat mass tracking, and Air Displacement Plethysmography (PeaPod) at 36 weeks postmenstrual age or discharge for criterion-standard whole-body composition. Fat mass, fat-free mass, and body fat percentage will be referenced against the Norris et al. preterm normative curves.

The trial uses an open-label design with block randomization stratified by gestational age. A Data Safety and Monitoring Board will conduct oversight and interim safety reviews.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Debbie Ng, MPH; Email: ngdm@uw.edu
• Study Contact Backup: Name: John Feltner, MS; Phone Number: (206) 543-3200; Email: jfeltner@uw.edu

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45221
      • Not yet recruiting
      • University of Cincinnati
      • Contact: Ting Ting Fu, MD; Phone Number: 513-636-4200; Email: futn@ucmail.uc.edu
  • Oregon
    • Portland, Oregon, United States, 97239
      • Not yet recruiting
      • Oregon Health & Science University
      • Contact: Brian Scottoline, MD, PhD; Phone Number: (503) 494-8122; Email: scottoli@ohsu.edu
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington
      • Contact: Katie M Strobel, MD, MSCR; Phone Number: (206) 543-3200; Email: kmstrob@uw.edu
      • Sub-Investigator: D Taylor Hendrixson, MD, MPH

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Admitted to the University of Washington, Oregon Health and Sciences, or University of Cincinnati NICU at 14 days of age
• Born between 24w0days and 31w6d
• Achieved full enteral feeding

Exclusion Criteria:

• Congenital or chromosomal anomalies affecting growth
• Acute renal insufficiency (KDIGO stage 1 or higher)
• Necrotizing enterocolitis (modified Bell's stage IIA or higher)
• Anticipated NICU stay less than 30 days
• Enrollment in a concurrent interventional study that may confound study outcomes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Targeted sodium supplementation; Every two weeks serum sodium and urine sodium testing with sodium supplementation if indicated by algorithm. Milk fortification per growth metrics.	Diagnostic test: Urine sodium testing; The investigators will utilize urine sodium testing every two weeks in conjunction with serum sodium testing to determine if sodium supplementation is indicated.; Diagnostic test: Serum sodium testing; The investigators will use serum sodium testing to determine if sodium supplementation or adjustments to sodium supplementation need to be made.; Dietary supplement: Milk fortification; The investigators will provide milk fortification using either a bovine-based or a human-milk-based fortifier (per unit protocol), based on growth trajectories.
Active Comparator: Enriched Milk Fortification; Serum sodium testing every two weeks with sodium supplementation if indicated by clinical team. Milk fortification per growth metrics.	Diagnostic test: Serum sodium testing; The investigators will use serum sodium testing to determine if sodium supplementation or adjustments to sodium supplementation need to be made.; Dietary supplement: Milk fortification; The investigators will provide milk fortification using either a bovine-based or a human-milk-based fortifier (per unit protocol), based on growth trajectories.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body composition by point-of-care ultrasound	Evaluate muscle and subcutaneous fat accretion from enrollment to 36 weeks posmtnestrual age. The study team will perform biceps and rectus femoris cross-sectional area measurements using point-of-care ultrasound every 2 weeks. We will perform arm and mid-thigh subcutaneous fat measurements using point-of-care ultrasound every 2 weeks.	Enrollment to study completion, on average 4-10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body composition using air-displacement plethysmography	We will conduct air-displacement plethysmography when the infant is off of oxygen at 36 weeks postmenstrual age or prior to discharge, whichever comes earlier.	At study completion, on average 4-10 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anthropometric growth	The clinical team measures weight, length, and head circumference z-scores weekly during hospitalization. The investigators will evaluate the change in z-score from birth to 36 weeks postmenstrual age	Enrollment to study completion, on average 4-10 weeks
Adverse outcomes	The study team will evaluate adverse outcome rates such as bronchopulmonary dysplasia, necrotizing enterocolitis, and all-cause mortality.	Enrollment to hospital discharge, on average between 4 to 16 weeks

Collaborators and Investigators

• Sponsor: University of Washington
• Investigators: Principal Investigator: Katie Strobel, MD, MSCR, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): October 31, 2029

Study Registration Dates

• First Submitted: March 31, 2026
• First Submitted That Met QC Criteria: April 28, 2026
• First Posted (Actual): May 1, 2026

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 23, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: growth; body composition; sodium monitoring
• Other Study ID Numbers: STUDY00023657

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Once the study and planned analyses are complete, we will submit de-identified participant data to a public database such as Zenodo.
• IPD Sharing Time Frame: We anticipate this data would be available October 2030 and would be available untl 2040.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes