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Formula-Based Nutrition for Infants With Growth Failure

  • Authors: Praveen S. Goday, MD
  • CME / ABIM MOC Released: 8/30/2022
  • Valid for credit through: 8/30/2023, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for pediatricians and pediatric specialists such as pediatric gastroenterologists, pediatric cardiologists, pediatric endocrinologists, pediatric dieticians, neonatologists, and critical care specialists.

The goal of this activity is that learners will be better able to identify formula-based nutritional options that can be given to infants who have growth failure.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Identification of infants whose nutritional requirements are not being met by traditional formula or breast milk
    • Data on formula options for infants with growth failure


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  • Praveen S. Goday, MD

    Director of Nutrition
    Nationwide Children's Hospital
    Columbus, Ohio


    Praveen S. Goday, MD, has the following relevant financial relationships:
    Consultant or advisor for: Takeda Pharmaceuticals


  • Briana Betz, PhD

    Medical Education Director, WebMD Global, LLC


    Briana Betz, PhD, has no relevant financial relationships.

  • Jason Luis Quiñones, PhD

    Scientific Content Manager, Medscape, LLC


    Jason Luis Quiñones, PhD, has no relevant financial relationships.

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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

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Formula-Based Nutrition for Infants With Growth Failure

Authors: Praveen S. Goday, MDFaculty and Disclosures

CME / ABIM MOC Released: 8/30/2022

Valid for credit through: 8/30/2023, 11:59 PM EST


Medscape sat down with Praveen S. Goday, MD, Nationwide Children's Hospital, Columbus, Ohio, to discuss conventional and emerging formula-based nutrition for managing infants with growth failure.

Medscape: How prevalent is growth failure, how is it defined in the clinic, and what are the main causes of growth failure among full-term infants in the United States?

Praveen S. Goday, MD: In the United States, ~5% to 13% of children meet criteria for malnutrition in the primary care setting. This is particularly problematic among children who have chronic diseases, such as congenital heart disease (CHD) and chronic kidney disease.[1-4] Other high-risk children include those with respiratory conditions, cancers, gastrointestinal disorders, and those who have undergone prior major surgery -- in this setting, it is estimated that ~42% to 45% of children with chronic disease have moderate to high nutrition risk.[5,6] The most common cause of poor growth observed among children with or without chronic disease is insufficient energy consumption. Other causes in children living with chronic disease include inability to meet the increased energy needs of underlying disease, problems with nutrient usage, malabsorption, and issues with nutrient losses due to vomiting or diarrhea.[7] Additional contributing factors include social and economic considerations, such as poverty and poor parent education on appropriate dietary needs for their child.[8] Inadequate nutrition is an issue that requires prompt medical attention because malnutrition can lead to additional complications, such as growth failure later in life, and can have negative effects on cognitive development and health outcomes.[1] 

Growth failure (also known as failure to thrive) is a term used to describe inadequate weight gain among the pediatric population. Children with a weight-for-length z-score less than -2 generally meet the criteria for growth failure, though children whose z score is less than -1 should have their growth assessed more carefully.[2,9] Various criteria for growth failure and malnutrition have attempted to provide objective cutoffs for normal and below normal weight gain. However, because growth is highly dynamic during the first 2 years of life, these criteria are either unable to capture all children with growth failure or include children with normal growth. Hence, a universal consensus on how to define growth failure is lacking.[2,9] Therefore, weight gain should be evaluated by clinicians using some of the nuances of expected growth, but clinicians should be aware that weight loss which is inexplicable and/or persistent is always likely to be abnormal in children.

When assessing growth, birth weight is an important factor. Children born large for gestational age (LGA) tend to exhibit catch-down growth in the first few months following birth. Children who were LGA and show catch-down growth are less likely to be obese as they get older.[10] Conversely, ~80% of children who are born small for gestational age (SGA) demonstrate catch-up weight gain during the first 2 years of life. While preterm infants born SGA experience significant benefits in cognitive development from catch-up growth, this is not true of children born SGA after 32 weeks of gestation. All children born SGA with catch-up growth have an elevated risk of metabolic syndrome in the long term.[10-15]

Medscape: Are there different nutritional needs among infants with growth failure?

Dr Goday: Yes -- If you're talking about infants in the first year of life, there is a general decrease in the amount of energy (per kilogram body weight) that a baby needs. In the first 3 months, the baby’s weight significantly increases and thereafter it slows down; hence, older babies in general require less energy. When there is disease-related malnutrition, babies oftentimes can have higher energy needs.[3-7, 16] Below is a summary (Table 1) of available guidance from the World Health Organization on energy and protein intake requirements for optimal catch-up growth.[16] Here, it is important to note that a protein-energy ratio between 8.9% to 11.5% is ideal in order to establish a body lean mass of 70% and fat mass of 30%, respectively.[17] Accordingly, 105 kcal/kg per day to 126 kcal/kg per day is commonly recommended as a target range of energy intake to promote catch-up growth in infants.[17]

Table 1. Guidance From WHO on Energy and Protein Intake for Catch-Up Growth[16]

Rate of gain (g/kg per day)

Protein (g/kg per day)

Energy (kcal/kg per day)

Protein energy ratio (PE %)









PE, protein energy ratio; WHO, world health organization.

Medscape: What nutritional options are available for infants with growth failure and what is the goal of treatment?

Dr Goday: Traditional strategies include providing infants with feeds that are concentrated (eg, increasing ratio of powder to water) or richer in nutrients and energy, involving the use of high-energy fortifiers such as lipids, carbohydrates, or protein-based preparations. In patients with severe growth failure, temporary tube feeding may be considered. In addition to this, other medical factors that may be contributing to undernourishment should be addressed and managed appropriately.[18-22] Therefore, when managing patients with growth failure it is critical for clinicians to keep the overall goal of treatment in mind, which is to implement strategies that will provide enough energy intake and supportive care measures that will aid in promoting catch-up growth of the child.[21,22]

Medscape: What data are available to support the use of energy- and protein-enriched formula (EPEF) in infants with growth failure and what are the implications for clinical practice?

Dr Goday: The strategies listed above of increasing energy provision by concentrating and/or fortifying infant formula come with some issues, including increased risk of errors during formula preparation, intolerance due to increases in the osmolality of the formula, and suboptimal energy distribution from macronutrients (decreased energy available from protein).[1] To begin addressing these deficits, researchers have conducted several clinical studies evaluating the utility of ready-to-feed EPEF (also known as energy- and nutrient-dense formula) as an alternative way to help infants meet energetic requirements for growth (see Table 2).[23-25] So far, these studies have shown that EPEF is well tolerated, enhances energy and nutrient intake, and promotes the growth of infants over time.

Table 2. Key Selected Randomized Controlled Trials Investigating EPEF[23-25]

Clarke SE, et al.[23]

Nutrient-dense formula vs energy-supplemented formula in infants with growth failure

N = 49

Eveleens RD, et al.[24]

Protein and EE formula in the PICU setting

N = 70

Scheeffer VA, et al.[25]

EE formula compared with normocaloric formula in infants after CHD surgery

N = 59

Duration of study: 6 weeks

Duration of study: ≥ 14 days

Duration of study: 30 days

Tolerance/safety: no difference in stool frequency, vomiting, etc.

Tolerance/safety: constipation observed in 5/70 infants; 47 infants experienced vomiting at least once

Tolerance/safety: similar rate of GI AEs observed; diarrhea occurred more in the EPEF arm

Growth endpoint: +0.29 median WAZ; P = .007

Growth endpoint: +0.48 mean WAZ; P < .001

Growth endpoint: higher completion WAZ; P = .042

AE, adverse event; CHD, chronic heart disease; EE, energy-enriched; EPEF, energy- and protein-enriched formula; GI, gastrointestinal; PICU, pediatric intensive care unit; WAZ, weight-for-age z-score.

More recently, the GROW-in study, led by my colleagues and me, evaluated the safety, tolerability, and improvement in weight gain with EPEF among infants with growth failure.[1] The GROW-IN study was a prospective, open-label, single-arm study conducted at 6 sites across the United States; 30 infants were enrolled, with 24 going on to complete the 16-week study. The study population included patients with either growth failure-related to CHD (58%) or other organic causes (35%) and nonorganic causes (8%)[1] and showed that EPEF nutritional intervention can support improvements in infant growth with various etiologies of malnutrition while being well tolerated and safe.[1] The primary endpoint of the study, obtaining an adequate rate of weight to achieve catch-up growth, was met. Importantly, all infants who completed the study gained weight and also gained in body length and head circumference, with significant improvements in z-scores from baseline to week 16.[1] Most adverse events were mild/moderate and considered not related or unlikely to be related to the nutritional intervention used in the study -- this is consistent with previous studies investigating EPEF that have reported this type of formula to be safe and well tolerated, with very few side effects.[1] Table 3A and 3B below present a summary of the key endpoints in growth and weight measures, tolerance, and safety data from the GROW-in trial.

Table 3A. Key Growth and Weight Endpoint Results From the GROW-IN Trial[1]

Key Growth and Weight Endpoints

WAZ, mean (SD), change from baseline to week 16:

  • 0.86 (0.74); P = .0001

HAZ, mean (SD), change from baseline to week 16:

  • 0.25 (0.61); P = .003

WHZ, mean (SD), change from baseline to week 16:

  • 0.77 (0.81); P = .0001

HCZ, mean (SD), change from baseline to week 16:

  • 0.54 (0.68); P = .0001

Weight gain velocity*: 

  • 83% achieved ≥ median weight gain velocity for age

Total energy intake:

  • 123 ± 32 mL EPEF/kg per day

Energy from EPEF intake alone:

  • 116 ± 32 mL EPEF/kg per day
*On at least 1 visit interval during the study.
EPEF, energy- and protein-enriched formula; HAZ, height-for-age z-score; HCZ, head circumference-for-age z-score; WAZ, weight-for-age z-score; WHZ, weight-for-length z-score; SD, standard deviation.

Table 3B. Key Tolerance and Safety Endpoint Results From the GROW-IN Trial[1]

Key Tolerance and Safety Results


  • Gassiness, flatulence, fussiness, and crying were all observed at a similar or lower rate vs baseline
    1. Gassiness and crying for some visits vs baseline: significantly lower, < .05
  • No changes in the mean number of stools
  • More watery stools during study, 57.1% to 69.6% vs first visit, 13.6%
  • Fewer soft stools at first visit, 68.2% vs during study, 13% to 30%
  • Stool consistency at visits 2 and 3 vs baseline: statistically different, P < .03

Total AEs:

  • At least 1 reported for 93% of all infants on study
  • 60% of AEs were classified as unrelated to the nutritional intervention

Most common AEs:

  • Mild to moderate gastrointestinal events, 77%, which included vomiting, 53%, increased spit-ups, 20%, and diarrhea, 30%
  • Infections were the second most frequent AE reported: 53%

AEs probably related to the study intervention:

  • 13 out of 15 were gastrointestinal in nature (vomiting, diarrhea, and increased spit-ups)
  • 1 out of 15 was dermatologic (perioral skin rash)
  • 1 out of 15 was hepatic, lymphatic/hematologic (increase in aspartate aminotransferase, alanine aminotransferase, and platelet levels)


  • 6 reported in 5 infants with CHD (16.6%) during the study
  • 4 classified as unrelated to the nutritional intervention
AE, adverse event; CHD, chronic heart disease.

Based on these data and supporting clinical findings from several other important trials (summarized in Table 2), the FDA cleared a liquid-based EPEF in September of 2021 to support catch-up growth in term infants with growth failure or those who may be at risk of growth failure, as well as infants who need more energy or are experiencing fluid limitations.[26]

Medscape: What remaining issues and challenges need to be addressed in this medical space?

Dr Goday: As discussed, while some randomized controlled clinical trials have reported EPEF as a viable option that can be tolerated just as well as energy-supplemented formulae, and which may help infants reach target energy demands faster, future trials should aim to compare EPEF to a standard control arm, namely current approaches used for increasing energy intake of term infants.[1]However, this is complicated since concentrated formula recommendations can vary in terms of energy level and the composition of fortifiers, so developing a uniformly adhered to control protocol will be instrumental for new studies to implement going forward.[1]

Lastly, as discussed earlier, it is important for providers and specialists to be aware of and treat any preexisting disorders or comorbidities an infant may have in order to optimally address the malnutrition. Therefore, it is important for clinicians to continue moving towards a multidisciplinary care model in which physicians and other specialists collaborate with one another to identify and treat underlying causes of elevated metabolic demand and/or problems with feeding in infants cases of growth failure.[16,19,20]

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