Nutrition Fortification for Preterm Infants

(THRIVE Trial)

Recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the best way to boost nutrition for preterm infants using human milk. Researchers are comparing three fortification methods: the usual approach (standardized fortification), one that adjusts based on protein needs (adjustable fortification), and one that targets specific nutrient levels in the milk (targeted fortification). The goal is to determine which method best supports growth and development, including brain development, in these infants. It is ideal for parents of preterm babies born at 32 weeks or earlier who plan to provide human milk. As an unphased trial, this study offers parents a unique opportunity to contribute to groundbreaking research that could improve nutrition strategies for preterm infants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both adjustable and targeted methods of adding nutrients to breast milk are generally safe for premature babies. Studies have found that adjustable fortification, which involves checking protein levels in the baby's blood, is well-tolerated and does not raise major safety concerns. This method allows for protein intake adjustments based on the baby's needs.

In standardized fortification, a set amount of nutrients is added to breast milk. Evidence suggests this method does not increase the risk of serious conditions like necrotizing enterocolitis (a severe intestinal disease) or sepsis (a severe infection). However, some reports have raised concerns that standardized fortification might lead to excessive protein, potentially affecting brain development.

Overall, both adjustable and targeted fortification methods are considered safe options for supporting the early growth of premature babies. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it's exploring new ways to optimize nutrition for preterm infants using different fortification methods. Unlike traditional standardized fortification, the adjustable fortification approach tailors protein intake based on weekly blood tests, aiming for precise nutritional balance. The targeted fortification method goes even further, using advanced milk analysis to customize nutrient intake specifically to each infant's needs, ensuring they receive the exact macronutrients required for optimal growth. These innovative approaches could lead to more personalized and effective nutrition plans for preterm infants, potentially improving growth outcomes and overall health.

What evidence suggests that this trial's nutritional interventions could be effective for preterm infants?

This trial will compare different fortification methods for preterm infants. Research has shown that personalized approaches, such as adjustable and targeted fortification, can be more effective than standard methods. In this trial, participants in the adjustable fortification arm will have their protein intake adjusted based on blood tests, a method proven to safely support growth. Meanwhile, those in the targeted fortification arm will have nutrients in their milk adjusted to meet specific energy and protein needs, aiming for better weight gain. Studies have shown that these personalized methods can improve early physical growth and may also boost brain development, including thinking and movement skills. The standardized fortification arm, although widely used, might not meet the varied needs of preterm infants, potentially leading to growth and nutrition issues. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

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.

Birth gestational age (GA) of ≤32 weeks

Maternal plan to provide human milk to infant, and consent to providing donor human milk if insufficient maternal milk supply

Exclusion Criteria

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

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6439523/

Fortification of Human Milk for Preterm Infants: Update and ...

Human Milk as the Best Feeding Option for Preterm Infants. Evidence-based data show that HM is the best nutritional and normative standard for infant nutrition ...

2.

frontiersin.org

frontiersin.org/journals/pediatrics/articles/10.3389/fped.2024.1466528/full

Narrative review of methodological advances in human ...

Studies have demonstrated that either adjustable or targeted fortification is more effective than SF in promoting early physical growth in ...

3.

cochranelibrary.com

cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013465.pub2/full

Individualized versus standard diet fortification for growth ...

Human milk in preterm infants is also associated with improved neurodevelopmental outcomes, including mental, motor, and behavior skills (AAP ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04809350?tab=history&a=2

Human Milk Fortification With Adjustable Versus Targeted ...

Hypothesis: Targeted fortification of human milk results in better weight gain in infants with birth weight <1250 gr when compared to the adjustable ...

5.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0378378213002119

Adjustable protein fortification of human milk

Adjustable HM fortification method comprises of adding extra protein to fortified HM based on twice weekly blood urea measurements and was proven to be safe and ...