High-Calorie Formula for Neonatal Abstinence Syndrome

Overseen By Lisa Palmieri, BA

Age: Any Age

Sex: Any

Trial Phase: Academic

Sponsor: Yale University

Must be taking: Methadone

Disqualifiers: Major congenital malformations, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

A randomized clinical study in NAS infants managed via the Eat, Sleep, Console (ESC) approach comparing early weight loss on a standard-caloric density versus high-caloric density feeding regimen.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What data supports the effectiveness of the treatment High-calorie formula for Neonatal Abstinence Syndrome?

Research shows that high-energy formulas can help infants with growth issues gain weight effectively, as seen in cases of growth faltering and critical illnesses. These formulas provide extra calories and nutrients, which can be beneficial for infants needing additional nutrition, like those with Neonatal Abstinence Syndrome. ^{1 2 3 4 5}

Is high-calorie formula safe for infants?

Research suggests that high-energy infant formulas are generally safe for infants, with studies showing they can be used without major side effects. However, more data is needed to fully understand their long-term safety and effects on growth and metabolism. ^{1 2 6 7 8}

How is the high-calorie formula treatment different for neonatal abstinence syndrome?

The high-calorie formula is unique because it provides more energy per volume compared to standard formulas, which may help infants with neonatal abstinence syndrome (NAS) who have increased energy needs. This approach is different from other treatments that focus on reducing symptoms or using medications, as it aims to support growth and energy intake directly through nutrition. ^{1 2 8 9 10}

Research Team

Matthew Grossman, MD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for NAS infants born to mothers aged 18-45 who used methadone during pregnancy. The babies must be at least 36 weeks gestational, over 2200 grams, and not placed for adoption. They should be delivered at Yale New Haven Hospital with plans to attend follow-up visits.

Inclusion Criteria

Delivered at: Yale New Haven Hospital

Confirm that mothers are planning to deliver their infant(s) at Yale New Haven Hospital

My baby was born at or after 36 weeks of pregnancy.

Exclusion Criteria

My infant was in the NICU for more than a day for reasons other than NAS treatment within their first 3 days.

Newborns with serious birth defects.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Infants are randomly assigned to either high-calorie or standard-calorie formula for 14 days

2 weeks

Daily weight measurements

Follow-up

Participants are monitored for weight gain and return to birthweight after treatment

2 weeks

Daily weight measurements at home

Extended Follow-up

Participants are monitored for days to return to birthweight and overall weight change

1 month

Treatment Details

Interventions

• High-calorie formula

Trial Overview The study tests if a high-calorie formula can help NAS infants gain weight better than standard formula. Infants are randomly assigned to one of the two feeding regimens while being managed via the Eat, Sleep, Console approach.

Participant Groups

Group I: High-calorie formula Experimental Treatment 1 Intervention

Infant randomly assigned to high-calorie formula for 14 days

Group II: Standard calorie formula Active Control 1 Intervention

Infant randomly assigned to standard-calorie formula for 14 days

High-calorie formula is already approved in United States, European Union for the following indications:

Approved in United States as High-calorie formula for:

• Failure to thrive (FTT)
• Low birth weight infants
• Premature infants needing extra calories

Approved in European Union as High-calorie formula for:

• Preterm infants requiring higher caloric intake
• Infants with feeding difficulties needing extra calories

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

A study involving 30 infants with faltering growth showed that a high-energy infant formula (1 kcal/mL) can be safely administered at full strength from day 1, with no significant differences in growth or vomiting between full strength and stepwise introduction groups.

Younger infants (under 12 weeks) experienced more frequent bowel actions when given the formula at full strength, suggesting that a gradual introduction may be beneficial for this age group to minimize gastrointestinal discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Should high-energy infant formula be given at full strength from its first day of usage? Evans, S., Twaissi, H., Daly, A., et al.[2008]

Infants who received a high-energy formula (HF) after cardiac surgery experienced less weight loss compared to those on a standard formula, indicating that HF may support better weight maintenance in this vulnerable population.

While the HF group had some gastrointestinal intolerance symptoms, such as abdominal distension and gastric retention, these issues were manageable with medication and did not hinder the overall feeding process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-energy nutrition in paediatric cardiac critical care patients: a randomized controlled trial. Zhang, H., Gu, Y., Mi, Y., et al.[2020]

Infants hospitalized for critical illnesses are at high risk of undernutrition, which can lead to growth faltering, making appropriate nutritional management crucial.

The use of energy- and nutrient-dense formula (ENDF) in two infants with severe upper airway obstruction resulted in satisfactory weight gain and facilitated catch-up growth, demonstrating its effectiveness without notable adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Energy- and Nutrient-Dense Formula for Growth Faltering: A Report of Two Cases From India. Kareem, ZU., Panuganti, SK., Bhatia, S.[2021]

A study involving 49 infants with faltering growth found that a nutrient-dense formula (NDF) provided significantly more protein and essential vitamins and minerals compared to an energy-supplemented formula (ESF), without compromising tolerance or feed intake.

The NDF group maintained normal blood urea levels and did not experience a decline in growth, while the ESF group showed a significant drop in length z-score and a 50% reduction in blood urea, indicating a suboptimal protein-to-energy ratio.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized comparison of a nutrient-dense formula with an energy-supplemented formula for infants with faltering growth. Clarke, SE., Evans, S., Macdonald, A., et al.[2008]

Human milk is the best source of nutrition for newborns, especially in the first 6 months, but preterm infants in the NICU often require additional nutritional support due to their unique health challenges.

Multinutrient human milk fortifiers (HMFs) are commonly used to meet the higher nutritional needs of preterm infants, and they come in various forms, each with specific benefits and risks, highlighting the importance of tailored nutrition strategies in the NICU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human milk fortification and use of infant formulas to support growth in the neonatal intensive care unit. Moreira, DH., Gregory, SB., Younge, NE.[2023]

Partially hydrolyzed formulas (pHFs) appear to be safe for healthy term infants in terms of growth, as limited data suggest they are not harmful when breastfeeding is not possible.

However, there is a significant lack of data on the long-term effects of pHFs, particularly regarding immune, metabolic, and hormonal outcomes, indicating a need for further research before recommending them universally for all infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Should Partial Hydrolysates Be Used as Starter Infant Formula? A Working Group Consensus. Vandenplas, Y., Alarcon, P., Fleischer, D., et al.[2022]

In a study involving 402 formula-fed infants, lower protein hydrolyzed formulas (1.9 g protein/100 kcal) were found to support normal weight gain comparable to regular protein formulas (2.3 g protein/100 kcal) during the first 4 months of life, indicating their safety and efficacy.

The study confirmed that all tested low-protein hydrolyzed formulas provided balanced nutrition and allowed for adequate growth without compromising weight gain, making them a viable option for infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydrolyzed Formula With Reduced Protein Content Supports Adequate Growth: A Randomized Controlled Noninferiority Trial. Ahrens, B., Hellmuth, C., Haiden, N., et al.[2019]

In a study of 692 preterm infants, those fed extensively hydrolyzed formula (EHF) experienced significantly lower rates of feeding intolerance, intestinal infections, and necrotizing enterocolitis (NEC) compared to those fed standard preterm formula (SPF).

EHF also led to quicker establishment of full enteral feeding, shorter duration of jaundice, and higher serum albumin levels by week 3, indicating its overall safety and efficacy in improving health outcomes for preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical effect of extensively hydrolyzed formula in preterm infants: an analysis of 327 cases]. He, W., Pan, JH.[2020]

A systematic review of 4 studies, including 1 randomized controlled trial, found no significant benefits of using low lactose formula (LLF) in infants with neonatal abstinence syndrome (NAS) regarding short-term outcomes like length of hospital stay and need for medication.

The evidence quality was assessed as low, indicating that more research is needed to determine the efficacy of LLF in this population, as current studies did not show improvements compared to standard formula.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Low Lactose Formula on the Short-Term Outcomes of Neonatal Abstinence Syndrome: A Systematic Review. Alsaleem, M., Dusin, J., Akangire, G.[2021]

In a study of 110 infants born to opioid-dependent mothers, the use of partially hydrolyzed formula (PHF) did not show any significant benefits over standard formula (SF) in treating neonatal abstinence syndrome (NAS), as measured by morphine treatment requirements and hospital stay duration.

Both PHF and SF groups had similar outcomes regarding the need for morphine therapy and the maximum dose used, suggesting that changing the type of formula may not improve short-term recovery from NAS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Partially Hydrolyzed Formula on Severity and Outcomes of Neonatal Abstinence Syndrome. Alsaleem, M., Berkelhamer, SK., Wilding, GE., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Should high-energy infant formula be given at full strength from its first day of usage? [2008]

2. England pubmed.ncbi.nlm.nih.gov

High-energy nutrition in paediatric cardiac critical care patients: a randomized controlled trial. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Energy- and Nutrient-Dense Formula for Growth Faltering: A Report of Two Cases From India. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Randomized comparison of a nutrient-dense formula with an energy-supplemented formula for infants with faltering growth. [2008]

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

Human milk fortification and use of infant formulas to support growth in the neonatal intensive care unit. [2023]

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

Should Partial Hydrolysates Be Used as Starter Infant Formula? A Working Group Consensus. [2022]

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

Hydrolyzed Formula With Reduced Protein Content Supports Adequate Growth: A Randomized Controlled Noninferiority Trial. [2019]

8. China pubmed.ncbi.nlm.nih.gov

[Clinical effect of extensively hydrolyzed formula in preterm infants: an analysis of 327 cases]. [2020]

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

Effect of Low Lactose Formula on the Short-Term Outcomes of Neonatal Abstinence Syndrome: A Systematic Review. [2021]

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

Effects of Partially Hydrolyzed Formula on Severity and Outcomes of Neonatal Abstinence Syndrome. [2021]