Nutrition Fortification for Preterm Infants

(THRIVE Trial)

Overseen By Katherine M. Ottolini, M.D.

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Children's National Research Institute

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

150 Participants Needed

Trial Summary

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}

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.

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

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
• Standardized Fortification

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

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Findings from Research

Preterm infants typically receive less protein than needed when fed fortified human milk due to outdated assumptions, which can hinder their growth and neurocognitive development.

The Adjustable fortification regimen has been successfully implemented in several Italian NICUs, providing adequate protein intake and promoting appropriate growth in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update of adjustable fortification regimen for preterm infants: a new protocol. Arslanoglu, S., Bertino, E., Coscia, A., et al.[2022]

A study involving 32 healthy preterm infants showed that both bovine whey protein and ultrafiltrated human milk protein fortifiers were well tolerated and resulted in similar growth outcomes, indicating their efficacy in nutritional management.

The individualized fortification approach, based on protein content analysis of human milk, allows for tailored feeding strategies that can achieve equivalent protein intake and growth results in preterm infants.

NCBI (Pubmed)

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. Polberger, S., Räihä, NC., Juvonen, P., et al.[2022]

In a study of 67 preterm infants receiving human milk with two types of liquid human milk fortifiers (LHMF), those receiving acidified LHMF (ALHMF) had a significantly higher incidence of metabolic acidosis compared to those receiving heat-treated LHMF (HTLHMF).

Despite the differences in metabolic acidosis, there were no significant variations in other clinical, nutritional, or growth outcomes between the two groups, suggesting that while ALHMF may pose risks, it does not adversely affect overall growth and nutrition in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and nutritional outcomes of two liquid human milk fortifiers for premature infants. Lainwala, S., Kosyakova, N., Spizzoucco, AM., et al.[2018]

In a study involving 120 preterm neonates, individualized plus optimized nutrition did not lead to better weight gain or linear growth compared to optimized nutrition alone, with similar results in both groups.

Both groups showed equivalent weight-gain velocity and linear growth rates, indicating that the additional individualized approach may not provide significant benefits over standard optimized nutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing individual nutrition in preterm very low birth weight infants: double-blinded randomized controlled trial. Brion, LP., Rosenfeld, CR., Heyne, R., et al.[2021]

Human milk is essential for very preterm infants, providing significant short-term and long-term health benefits, but often requires fortification to meet their nutritional needs during hospitalization.

Individually targeted fortification, using point-of-care analysis of human milk composition, shows promise in addressing nutrient delivery gaps and improving growth outcomes for these infants.

NCBI (Pubmed)

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. Talebiyan, S., Belfort, MB.[2023]

This observational study aims to compare a new target fortification method for human milk (HM) in very preterm infants with the standard method, assessing its impact on energy and macronutrient intake as well as growth quality.

The contemporary cohort will use a multi-nutrient fortifier and modular protein and fat supplements, with growth measured through weight, length, and head circumference, potentially leading to improved nutritional outcomes for very preterm infants.

NCBI (Pubmed)

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. Cardoso, M., Virella, D., Macedo, I., et al.[2021]

Targeted fortification of human milk significantly improved growth rates in very low birth weight preterm infants, with weekly weight gain averaging 205.5 g compared to 155 g in those receiving standard fortification.

The study found no gastrointestinal or metabolic intolerance in infants receiving targeted fortification, indicating it is a safe method for enhancing nutrition in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is targeted fortification of human breast milk an optimal nutrition strategy for preterm infants? An interventional study. Morlacchi, L., Mallardi, D., Giannì, ML., et al.[2022]

Multicomponent fortification of human milk is essential for promoting short-term growth in preterm infants, but there is no agreement on the best timing or methods for fortification.

Both bovine and human milk-based fortifiers are considered safe, but higher levels of fortification may be necessary to ensure adequate growth, highlighting the need for further research on new products and strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Milk Fortification Strategies in the Neonatal Intensive Care Unit. Fu, TT., Poindexter, BB.[2023]

Individualized fortification of breast milk for preterm infants, either through targeted or adjustable methods, likely leads to increased weight gain, length gain, and head circumference gain compared to standard non-individualized fortification, based on a review of 7 randomized controlled trials involving 521 participants.

However, there is low certainty regarding the impact of individualized fortification on important clinical outcomes such as mortality and major health complications, indicating that while growth may improve, the long-term safety and benefits of these strategies need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk. Fabrizio, V., Trzaski, JM., Brownell, EA., et al.[2022]

Fortifying human milk is essential for preterm infants to meet their specific nutritional needs and support growth rates similar to those of fetuses at the same gestational age.

Individualized fortification methods, such as targeted/tailored and adjustable fortification, are recommended to optimize nutrient delivery and ensure adequate growth in premature infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fortification of maternal milk for preterm infants. Di Natale, C., Coclite, E., Di Ventura, L., et al.[2018]

In a trial involving 39 preterm infants, tailored fortification of human milk did not significantly improve weight gain compared to standard fortification, with average gains of 27.01 g/d and 25.84 g/d respectively.

The study highlighted challenges in implementing targeted fortification in neonatal intensive care units, suggesting that while it is a promising approach, its feasibility may be limited in practice.

NCBI (Pubmed)

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. Seliga-Siwecka, J., Fiałkowska, J., Chmielewska, A.[2023]

References

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

Update of adjustable fortification regimen for preterm infants: a new protocol. [2022]

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]

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

Clinical and nutritional outcomes of two liquid human milk fortifiers for premature infants. [2018]

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

Optimizing individual nutrition in preterm very low birth weight infants: double-blinded randomized controlled trial. [2021]

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]

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]

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]

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

Human Milk Fortification Strategies in the Neonatal Intensive Care Unit. [2023]

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

Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk. [2022]

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

Fortification of maternal milk for preterm infants. [2018]

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]