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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how different formulas affect newborns with Neonatal Abstinence Syndrome (NAS), a condition in babies born to mothers who used certain drugs during pregnancy. The study compares a high-calorie formula with a standard-calorie formula to determine which better helps these babies maintain a healthy weight in their first two weeks. Eligible infants should have been exposed to methadone during pregnancy and be delivered at Yale New Haven Hospital, with plans for regular follow-up visits. As an unphased trial, this study provides a unique opportunity to enhance understanding of the best nutritional support for newborns with NAS.

Will I have to stop taking my current medications?

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

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

Studies have shown that high-calorie formula can help babies exposed to methadone before birth gain weight more effectively. This is crucial because these babies often struggle with weight gain due to neonatal abstinence syndrome (NAS), where newborns experience withdrawal symptoms. Research indicates that starting high-calorie formula early is generally well-tolerated by these infants.

Although specific safety details about the high-calorie formula are not provided, its use in clinical settings suggests it is considered safe enough for testing with infants. So far, studies have not reported any major negative effects from using high-calorie formula in these situations, indicating it is relatively safe for babies with NAS. Always consult a healthcare provider to understand more about any potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using a high-calorie formula for treating Neonatal Abstinence Syndrome (NAS) because it offers a new way to support infants going through withdrawal. Unlike standard formulas, this approach provides more calories, which might help these newborns grow better and recover faster. By potentially speeding up weight gain and reducing withdrawal symptoms, this method could improve overall outcomes for affected infants.

What evidence suggests that the high-calorie formula is effective for neonatal abstinence syndrome?

Research has shown that high-calorie formula, which participants in this trial may receive, can help babies with neonatal abstinence syndrome (NAS) gain weight more effectively. One study found that babies exposed to methadone before birth gained weight better with high-calorie formula. Another study demonstrated that this formula was beneficial even without lactose. High-calorie formula also reduced weight loss and shortened hospital stays for babies with NAS. These findings suggest that high-calorie formula can be a good option for helping newborns going through withdrawal manage their weight. ^{1 2 3 6 7}

Who Is on the Research Team?

Matthew Grossman, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12020722/

Evaluating Nutritional Selection and Outcomes in Neonatal ... Infants with severe NAS required more elemental feeds. All formula selections supported favorable growth. Keywords: neonatal abstinence syndrome ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5744267/

Versus High-Calorie Formula for Methadone-Exposed ... Study findings suggest that early initiation of high-calorie formula for infants with prenatal methadone exposure may be beneficial for weight gain.

3. childrensmercy.org childrensmercy.org/siteassets/media-documents-for-depts-section/documents-for-health-care-providers/evidence-based-practice/critically-appraised-topics/low-lactose-formula-in-neonatal-abstinence-syndrome.pdf

Critically Appraised Topic (CAT): Neonatal Abstinence ... In fact, one study (Kaplan et al., 2020) found that high calorie formula was most beneficial regardless of lactose content.

4. publications.aap.org publications.aap.org/pediatrics/article/146/4/e20190914/79690/Orchestrated-Testing-of-Formula-Type-to-Reduce

Orchestrated Testing of Formula Type to Reduce Length ... We used orchestrated testing (OT) to learn from this variation and improve nonpharmacologic care of infants with neonatal abstinence syndrome (NAS)

5. researchgate.net researchgate.net/publication/344232505_Orchestrated_Testing_of_Formula_Type_to_Reduce_Length_of_Stay_in_Neonatal_Abstinence_Syndrome

Orchestrated Testing of Formula Type to Reduce Length ... Response plots revealed the benefit of high-calorie formula (HCF) on weight loss, treatment failure, and LOS. The nonpharmacologic treatment ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02178189

RCT of High- vs. Standard-Calorie Formula for Methadone ... Neonatal abstinence syndrome (NAS) symptoms contribute to poor infant weight gain. Early caloric enhancement for infants exposed to methadone is ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10827648/

Advances in the Care of Infants With Prenatal Opioid ... The objective of this state-of-the-art review is to highlight recent advances in the identification, diagnosis, assessment, and management of infants with POE