Nutrition Fortification for Preterm Infants

(THRIVE Trial)

Recruiting in Palo Alto (17 mi)

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Children's National Research Institute

Disqualifiers: Formula feeding, Genetic syndrome, Brain lesions, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

Human milk has several well-established benefits but does not adequately meet the increased nutritional demands of the growing preterm infant, necessitating additional nutrient supplementation in a process known as fortification. In U.S. neonatal intensive care units (NICUs), human milk is primarily supplemented using standardized fortification, in which a multicomponent fortifier is added to human milk to achieve assumed nutrient content based on standard milk reference values. However, this method does not account for the significant variability in human milk composition or in preterm infant metabolism, and up to half of all very premature infants experience poor growth and malnutrition using current nutritional practices. Poor postnatal growth has adverse implications for the developing preterm brain and long-term neurodevelopment. Recent advances allow for individualized methods of human milk fortification, including adjustable and targeted fortification. Adjustable fortification uses laboratory markers of protein metabolism (BUN level) to estimate an infant's protein requirements. In targeted fortification, a milk sample is analyzed to determine its specific macronutrient and energy content, with additional macronutrient supplementation provided as needed to achieve goal values. Emerging data suggest that both methods are safe and effective for improving growth, however information on their comparable efficacy and neurodevelopmental implications are lacking, particularly using advanced quantitative brain MRI (qMRI) techniques. Through this prospective, randomized-controlled trial, the investigators will compare the impact of individualized human milk fortification on somatic growth and neurodevelopment in preterm infants. Infants will be randomized to receive one of three nutritional interventions: standardized (control group), adjustable, or targeted human milk fortification. Infants will undergo their assigned nutritional intervention until term-equivalent age or discharge home, whichever is achieved first. Brain qMRI will be performed at term-corrected age, and neurodevelopmental follow-up will be performed through 5 years of age.

Do I need to stop my current medications for the trial?

The trial information does not specify whether participants need to stop taking their current medications. It focuses on nutritional interventions for preterm infants.

What data supports the effectiveness of the treatment Nutrition Fortification for Preterm Infants?

Research shows that adjustable fortification of human milk, which involves tailoring nutrient levels to individual needs, is effective in providing adequate protein and supporting growth in preterm infants. This approach has been successfully implemented in neonatal intensive care units, improving growth outcomes by ensuring infants receive the necessary nutrients. ^{1 2 3 4 5}

Is human milk fortification safe for preterm infants?

Both bovine milk-based and human milk-based fortifiers are considered safe for preterm infants, though more research is needed to evaluate newer fortification strategies. ^{5 6 7 8 9}

How does the Adjustable Fortification treatment for preterm infants differ from other treatments?

Adjustable Fortification is unique because it customizes the nutrient content of human milk based on individual needs, using point-of-care analysis to address the variability in milk composition, unlike standard fixed-dose fortification which does not account for these differences. ^{1 5 8 10 11}

Eligibility Criteria

This trial is for preterm infants with low birth weight, including those born very prematurely. It aims to optimize their growth and brain development by testing different ways of fortifying the milk they receive.

Inclusion Criteria

My baby is 4 weeks old or younger.

I am over 18 years old.

Birth gestational age (GA) of ≤32 weeks

Exclusion Criteria

I have physical features or birth defects that suggest a genetic condition.

My baby was formula-fed before 36 weeks due to choice or medical need.

Dysgenetic or major destructive brain lesions detected by head ultrasound before enrollment

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Nutritional Intervention

Infants are randomized to receive standardized, adjustable, or targeted human milk fortification until term-equivalent age or discharge home.

Up to 40 weeks postmenstrual age or discharge

Weekly monitoring

Neurodevelopmental Assessment

Brain qMRI performed at term-corrected age to assess total and regional brain volumes.

Term-equivalent age (38 to 41 weeks postmenstrual age)

Follow-up

Neurodevelopmental follow-up performed through 5 years of age to assess growth and cognitive development.

5 years

Treatment Details

Interventions

• Adjustable Fortification (Dietary Supplement)
• Standardized Fortification (Dietary Supplement)

Trial Overview The study compares three methods of human milk fortification: standardized (the usual way), adjustable (based on protein needs), and targeted (customized to the milk's nutrients). Infants will be randomly assigned to one method until they reach term age or go home.

Participant Groups

Group I: Targeted Experimental Treatment 2 Interventions

Targeted fortification will begin 1 week after tolerating goal feeds of standardized fortification. Additional supplementation with liquid protein and/or MCT oil will be provided based on twice weekly milk analysis using a mid-infrared human milk analyzer in order to meet macronutrient (carbohydrate, protein, lipid) and energy intake goals per pediatric nutrition guidelines (protein 4-4.5g/kg/day, fat 6-8g/kg/day, energy 120-130kcal/kg/day). Growth failure is defined as a decline in weight-for-age z-score by \>1 SD beginning 1 week after receiving macronutrient and energy intake within goal range from targeted fortification. For infants with growth failure, total energy intake will be increased with additional protein and/or MCT oil supplementation. Energy intake may be increased weekly as needed.

Group II: Adjustable Experimental Treatment 2 Interventions

Adjustable fortification will begin 1 week after tolerating goal feeds of standardized fortification. Blood urea nitrogen (BUN) level as a marker of protein metabolism will be measured weekly, and supplementation with liquid protein will be adjusted as necessary to maintain a goal BUN level between 9-14mmol/dL, up to a maximum assumed protein intake of 4.5 g/kg/day. Liquid protein supplementation will be modified as follows: * BUN Level \<9 mmol/dL: Increase by 0.5g/kg/day * BUN Level 9-14 mmol/dL: No change * BUN Level \>14 mmol/dL: Decrease by 0.25g/kg/day * BUN Level \>20 mmol/dL: Hold for 1 week and re-assess Growth failure is defined as a decline in weight-for-age z-score by \>1 SD beginning 1 week after achieving BUN within goal range from adjustable fortification. For infants who demonstrate growth failure, MCT oil will be added and increased weekly as needed.

Group III: Standardized Fortification Active Control 1 Intervention

All study participants will undergo feed advancement and fortification with liquid, bovine-based human milk fortifier (HMF) to an assumed human milk content of 24kcal/oz per the Children's National Hospital NICU standardized clinical feeding protocol. The same milk fortification recipes are utilized for mother's own milk (MOM) and donor human milk (DHM). Each infant's growth trajectory is monitored (weight, length, and head circumference) with dietary modifications performed as needed based on growth parameters. Growth failure is defined as a decline in weight-for-age z-score by greater than 1 standard deviation (\>1 SD) beginning 1 week after reaching goal fortified feeds. For infants who demonstrate growth failure, Step 1 will be to add medium chain triglyceride (MCT) oil. If growth remains sub-optimal, Step 2 will be to add liquid protein.

Adjustable Fortification is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as Human Milk Fortification for:

• Preterm infant nutrition
• Neonatal nutrition support

🇪🇺 Approved in European Union as Human Milk Fortification for:

• Preterm infant nutrition
• Neonatal nutrition support

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Children's National Hospital Washington, United States

Who Is Running the Clinical Trial?

Children's National Research Institute Lead Sponsor

References

1. Italy pubmed.ncbi.nlm.nih.gov

Update of adjustable fortification regimen for preterm infants: a new protocol. [2022] Preterm infants fed fortified human milk in standard fashion receive less protein than they need due to customary assumptions. Protein is limiting for growth and neurocognitive development,and shortfalls of protein are not acceptable. Adjustable fortification regimen has been proven as an effective way to provide adequate protein intakes and appropriate growth in this group of infants. Italian Association of Human Milk Banks (AIBLUD) has promoted and implemented this Adjustable fortification regimen in neonatal intensive care units (NICUs) with success. This paper presents an update of Adjustable fortification regimen; a new protocol already utilized in several italian NICUs.

2. United States pubmed.ncbi.nlm.nih.gov

Individualized protein fortification of human milk for preterm infants: comparison of ultrafiltrated human milk protein and a bovine whey fortifier. [2022] To improve the nutritional management of pre-term infants, a new individualized human milk fortification system based on presupplementation milk protein analyses was evaluated.

3. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical and nutritional outcomes of two liquid human milk fortifiers for premature infants. [2018] In preterm infants fortification of human milk with human milk fortifiers (HMF) to optimize nutrition and growth is standard practice. We compared clinical, nutrition and growth outcomes in infants receiving two types of liquid HMF (LHMF).

4. United States pubmed.ncbi.nlm.nih.gov

Optimizing individual nutrition in preterm very low birth weight infants: double-blinded randomized controlled trial. [2021] In preterm neonates fed human milk, fortification may be adjusted by (1) optimization, based on growth rate and serum nutrient analyses, or (2) individualization, based on serial milk nutrient analyses. The primary aim was to determine whether individualized plus optimized nutrition (experimental) improves velocity of weight gain and linear growth from birth to endpoint (36 weeks postmenstrual age or discharge) when compared with optimized nutrition alone (controls).

5. United States pubmed.ncbi.nlm.nih.gov

Human Milk Fortification for Very Preterm Infants: Toward Optimal Nutrient Delivery, Neonatal Intensive Care Unit Growth, and Long-Term Outcomes. [2023] Human milk is the preferred diet for very preterm infants due to short-term and long-term benefits for health and neurodevelopment. Fortification of human milk is required to deliver sufficient nutrients to attain recommended growth targets during the neonatal hospitalization. Intrinsic variability in human milk composition poses a challenge in clinical practice because some infants fail to meet recommended nutrient intakes even with existing approaches of standard (fixed-dose) and adjustable fortification. Individually targeted fortification is an emerging strategy to minimize nutrition delivery gaps through application of point-of-care human milk analysis and has potential to improve growth and related outcomes.

6. Switzerland pubmed.ncbi.nlm.nih.gov

Customized Human Milk Fortification Based on Measured Human Milk Composition to Improve the Quality of Growth in Very Preterm Infants: A Mixed-Cohort Study Protocol. [2021] Adequate nutrition of very preterm infants comprises fortification of human milk (HM), which helps to improve their nutrition and health. Standard HM fortification involves a fixed dose of a multi-nutrient HM fortifier, regardless of the composition of HM. This fortification method requires regular measurements of HM composition and has been suggested to be a more accurate fortification method. This observational study protocol is designed to assess whether the target HM fortification method (contemporary cohort) improves the energy and macronutrient intakes and the quality of growth of very preterm infants, compared with the previously used standard HM fortification (historical cohorts). In the contemporary cohort, a HM multi-nutrient fortifier and modular supplements of protein and fat are used for HM fortification, and the enteral nutrition recommendations of the European Society for Paediatric Gastroenterology Hepatology and Nutrition for preterm infants will be considered. For both cohorts, the composition of HM is assessed using the Miris Human Milk analyzer (Uppsala, Sweden). The quality of growth will be assessed by in-hospital weight, length, and head circumference growth velocities and a single measurement of adiposity (fat mass percentage and fat mass index) performed just after discharge, using the air displacement plethysmography method (Pea Pod, Cosmed, Italy). ClinicalTrials.gov registration number: NCT04400396.

7. England pubmed.ncbi.nlm.nih.gov

Is targeted fortification of human breast milk an optimal nutrition strategy for preterm infants? An interventional study. [2022] Fortifying human milk contributes to the prevention of postnatal growth failure in preterm infants. Because of the natural variability of human milk, targeted fortification of human milk has been advocated. However, data regarding the efficacy and safety of prolonged targeted fortification are scarce. We aimed to assess the safety of targeted fortification of human milk in preterm infants compared with standard fortification, as well as the effects on infant growth.

8. United States pubmed.ncbi.nlm.nih.gov

Human Milk Fortification Strategies in the Neonatal Intensive Care Unit. [2023] Multicomponent fortification is the standard of care to support short-term growth in preterm infants receiving human milk. There is no consensus regarding the optimal timing, method, or products used to fortify human milk. Both bovine milk-based and human milk-based human milk fortifiers are safe options, though increased fortification and enrichment may be needed to achieve adequate growth. Additional studies are needed to evaluate newer fortifier products and fortification strategies.

9. England pubmed.ncbi.nlm.nih.gov

Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk. [2022] Human milk as compared to formula reduces morbidity in preterm infants but requires fortification to meet their nutritional needs and to reduce the risk of extrauterine growth failure. Standard fortification methods are not individualized to the infant and assume that breast milk is uniform in nutritional content. Strategies for individualizing fortification are available; however it is not known whether these are safe, or if they improve outcomes in preterm infants.

10. England pubmed.ncbi.nlm.nih.gov

Fortification of maternal milk for preterm infants. [2018] During the last few decades, neonatal survival rates for preterm infants have markedly been improved. The American Academy of Pediatrics recommended that preterm neonates should receive sufficient nutrients to enable them to grow at a rate similar to that of fetuses of the same gestational age. Although human milk is the recommended nutritional source for newborn infants for at least the first six months of postnatal life, unfortified human breast milk may not meet the recommended nutritional needs of growing preterm infants. Human milk must therefore be supplemented (fortified) with the nutrients in short supply. The fortification of human milk can be implemented in two different forms: standard and individualized. The new concepts and recommendations for optimization of human milk fortification is the "individualized fortification". Actually, two methods have been proposed for individualization: the "targeted/tailored fortification" and the "adjustable fortification". In summary, the use of fortified human milk produces adequate growth in premature infants and satisfies the specific nutritional requirements of these infants. The use of individualized fortification is recommended.

11. Switzerland pubmed.ncbi.nlm.nih.gov

Effect of Targeted vs. Standard Fortification of Breast Milk on Growth and Development of Preterm Infants (≤32 Weeks): Results from an Interrupted Randomized Controlled Trial. [2023] Human milk is recommended for very low birth weight infants. Their nutritional needs are high, and the fortification of human milk is a standard procedure to optimize growth. Targeted fortification accounts for the variability in human milk composition. It has been a promising alternative to standard fixed-dose fortification, potentially improving short-term growth. In this trial, preterm infants (&#8804;32 weeks of gestation) were randomized to receive human milk after standard fortification (HMF, Nutricia) or tailored fortification with modular components of proteins (Bebilon Bialko, Nutricia), carbohydrates (Polycal, Nutricia), and lipids (Calogen, Nutricia). The intervention started when preterms reached 80 mL/kg/day enteral feeds. Of the target number of 220 newborns, 39 were randomized. The trial was interrupted due to serious intolerance in five cases. There was no significant difference in velocity of weight gain during the supplementation period (primary outcome) in the tailored vs. standard fortification group: 27.01 &#177; 10.19 g/d vs. 25.84 &#177; 13.45 g/d, p = 0.0776. Length and head circumference were not significantly different between the groups. We found the feasibility of targeted fortification to be limited in neonatal intensive care unit practice. The trial was registered at clinicaltrials.gov NCT:03775785.