Working group reports: evaluation of the evidence to support practice guidelines for nutritional care of preterm infants—the Pre-B Project–4

Daniel J Raiten; Alison L Steiber; Susan E Carlson; Ian Griffin; Diane Anderson; William W Hay, Jr; Sandra Robins; Josef Neu; Michael K Georgieff; Sharon Groh-Wargo; Tanis R Fenton; the Pre-B Consultative Working Groups

doi:10.3945/ajcn.115.117309

. 2016 Jan 20;103(2):648S–678S. doi: 10.3945/ajcn.115.117309

Working group reports: evaluation of the evidence to support practice guidelines for nutritional care of preterm infants—the Pre-B Project^¹^–^⁴

Daniel J Raiten ^5,^*, Alison L Steiber ⁶, Susan E Carlson ⁷, Ian Griffin ⁸, Diane Anderson ⁹, William W Hay Jr ¹⁰, Sandra Robins ¹¹, Josef Neu ¹², Michael K Georgieff ¹³, Sharon Groh-Wargo ¹⁴, Tanis R Fenton ¹⁵; the Pre-B Consultative Working Groups

PMCID: PMC6459074 PMID: 26791182

ABSTRACT

The “Evaluation of the Evidence to Support Practice Guidelines for the Nutritional Care of Preterm Infants: The Pre-B Project” is the first phase in a process to present the current state of knowledge and to support the development of evidence-informed guidance for the nutritional care of preterm and high-risk newborn infants. The future systematic reviews that will ultimately provide the underpinning for guideline development will be conducted by the Academy of Nutrition and Dietetics’ Evidence Analysis Library (EAL). To accomplish the objectives of this first phase, the Pre-B Project organizers established 4 working groups (WGs) to address the following themes: 1) nutrient specifications for preterm infants, 2) clinical and practical issues in enteral feeding of preterm infants, 3) gastrointestinal and surgical issues, and 4) current standards of infant feeding. Each WG was asked to 1) develop a series of topics relevant to their respective themes, 2) identify questions for which there is sufficient evidence to support a systematic review process conducted by the EAL, and 3) develop a research agenda to address priority gaps in our understanding of the role of nutrition in health and development of preterm/neonatal intensive care unit infants. This article is a summary of the reports from the 4 Pre-B WGs.

Keywords: enteral nutrition, growth, nutrient requirements, parenteral nutrition, preterm birth

INTRODUCTION

As highlighted in the Pre-B Executive Summary (1), the meeting was designed to provide the 4 Pre-B working groups (WGs)¹⁶ ample opportunity for within- and between-group conversations in support of their deliberations. After the meeting each WG was provided with additional opportunities to interact via teleconference and e-mail. The following reports represent the summaries of the WG deliberations.

After consultation with the scientific steering committee, 4 broad themes and potential workgroup co-chairs were identified. Once recruited, the co-chairs then worked with the Pre-B Secretariat (NIH staff) to identify and recruit WG members with requisite expertise in the respective WG thematic areas. The WG members are listed as part of the Pre-B Consultative Group [Supplemental Material (WG and meeting participant list)]. The 4 thematic areas and co-chairs are listed in Text Box 1.

Text Box 1 . Pre-B thematic WGs.

WG 1: Nutrient Specifications for Preterm Infants

Chairs: Steven Abrams, University of Texas–Austin

Tay Kennedy, Oklahoma State University

Ian Griffin, University of California–Davis

Susan E Carlson, University of Kansas Medical Center

WG 2: Clinical/Practical Issues in Enteral Feeding of Preterm Infants

Chairs: Diane Anderson, Baylor College of Medicine

William Hay, University of Colorado

WG 3: Gastrointestinal and Surgical Issues

Chairs: Sandra Robins, Inova Children's Hospital

Josef Neu, University of Florida

WG 4: Current Standards of Infant Feeding

Chairs: Michael Georgieff, University of Minnesota

Sharon Groh-Wargo, Case Western Reserve University–School of Medicine

Tanis Fenton, University of Calgary

Each WG was asked to develop a summary report organized as follows: a list of priority topics, a review of each topic including a brief rationale for the need to address this topic, followed by the associated questions that might be addressed via systematic reviews, and questions to be answered with new research and data. In terms of the presentation of these summaries the following 4 caveats should be noted.

1) Topics within each WG summary are not listed in any particular order of priority.
2) WGs did not always address issues specific to current definitions of preterm infants either by gestational age (GA) or weight. This may be addressed during the systematic review process, as allowed by the existing literature.
3) Postdischarge issues were addressed on a case-by-case basis as each WG deemed necessary.
4) WGs also acknowledged a number of “cross-cutting issues,” including the use of human milk (mother’s and donor), the role of the caregivers, and all aspects of the evolving appreciation of the human gut microbiome. This was particularly relevant for the topics covered by WGs 2 and 3. These issues were addressed where relevant and feasible, but the lack of focus on them should not be inferred to imply that they are not a priority.

WG 1: NUTRIENT SPECIFICATIONS

Chairs: Ian Griffin and Susan E Carlson

Topic 1: What is the appropriate biological frame of reference for establishing the nutrient needs of parenterally or enterally fed preterm infants? (See Text Box 2.)

Text Box 2 . WG 1: nutrient specification topics.

1) What is the appropriate biological frame of reference for establishing the nutrient needs of parenterally or enterally fed preterm infants?
2) What nutrients are conditionally essential in preterm infants?
3) What factors affect nutrient requirements in preterm infants (before hospital discharge)?
4) How do nutrient requirements of otherwise healthy, formerly preterm infants differ from term infants of the same corrected age after hospital discharge?
5) What are the pre- and postnatal modifiers of nutrient requirements of formerly preterm infants, and how do these resulting requirements differ from those of term infants of the same corrected age after hospital discharge?
6) Can we individualize nutrient intakes in preterm infants, and if so, how?

Rationale

Infants born early in the third trimester are nutritionally challenged as a result of the interruption of maternal transfer/fetal accretion of micronutrients (vitamins, trace minerals) (2), macronutrients (e.g., protein, fat) (3), and long-chain PUFAs [LC-PUFAs; arachidonic acid (AA, 20:4n–6) and DHA (22:6n–3)] (4). Infants born prematurely may also be developmentally unable to produce the necessary amount of metabolically essential forms of key nutrients (e.g., DHA and AA). Failure to meet these nutrient needs is not uncommon during hospitalization, even for preterm infants who have an uncomplicated course. Moreover, it may also be the case that by hospital discharge, stores of many nutrients are still low compared with the stores that would be found in term-born infants at the same postconceptional age.

The consequences of these deficits can manifest in many ways. For example, most preterm infants do not achieve a growth trajectory similar to the last intrauterine trimester (5). Mineral deficiencies that influence bone or acid-base balance have also been recognized (6). Because of these problems with growth and bone development much research has been focused on the protein, vitamin, mineral, and energy needs of preterm infants. However, it is less recognized that preterm infants who reach term-corrected age have a lower lean mass and a higher percentage of body fat than term infants before and after hospital discharge (7, 8).

These differences in body composition may be related to stresses on protein metabolism associated with early birth. They may also be associated with alterations in amino acid concentrations due to immature metabolic pathways, delayed amino acid administration, and lower than required enteral protein intake (7). However, it is also conceivable that these differences may reflect the different ways that protein and energy are supplied ex utero compared with in utero.

Although little is known about the potential mechanisms to explain long-term effects of higher body fat early in life, it is hypothesized that these changes have implications for future health (9). The ability to more fully understand the potential mechanisms underlying the developmental origins of health and chronic disease demands a better understanding of what is “normal,” in terms of the maternal/fetal nutritional environment. Moreover, our ability to determine the nutritional needs of preterm infants is contingent on having a frame of reference to determine what is “normal” for an infant at a given point in his or her development.

The ability to clarify these relations will be contingent on a better understanding of the role the placenta in moderating the transfer of nutrients. Logic might dictate that the provision of nutrients to preterm infants based on maternal transfer might lead to more biologically relevant formulations. For example, placental transfer of linoleic acid is limited (10), meaning that exposure to high amounts of linoleic acid does not occur until term birth. In contrast, intravenous lipids and preterm formulas provide very large amounts of linoleic acid to the preterm infant, and there might well be long-term health effects. Elevated cord blood linoleic acid has been observed in infants at risk of atopic eczema (11).

Currently, the approach to determining nutrient needs of preterm infants has been empirical and based on extrapolation from the needs of term infants. Only in cases in which frank nutritional deficiencies are recognized or a clinical problem emerges is attention paid to the role of a particular nutrient for preterm infants. Due to this limited frame of reference underlying the unique needs of preterm infants in the hospital and postdischarge, these infants are at risk of being provided either too much or too little of specific essential nutrients either via parenteral or enteral nutrient sources. Moreover, the forms of the nutrients provided might be problematic in the context of developmental metabolism. Finally, it must be recognized that nutrient requirements may be lower when given parenterally, rather than enterally, because parenteral nutrition (PN) does not allow for the moderating effect of <100% absorption for some nutrients. In summary, the amount, form, and mode of delivery of nutrients to preterm infants must be informed by a better understanding of the baseline with regard to 1) the maternal/fetal in utero interface and placental function, 2) an understanding of developmental metabolism as pertains to nutrient utilization, and 3) unique aspects of different modes of nutrient delivery that might affect form and amount of nutrients delivered.

Data and research priorities

What are the best tools to assess
- ○ optimal short- and/or long-term bone health in preterm infants;
- ○ whether premature infants develop osteopenia during early adulthood;
- ○ normal ranges of protein (total protein, prealbumin), energy biomarkers (serum glucose, proinsulin), lipid biomarkers (triglycerides, cholesterol) that predict better nutrient status and long-term health status in preterm infants; and
- ○ macronutrients that predict long-term morbidities in preterm infants.
What are the best biomarkers and cutoffs for defining the status of micronutrients (vitamins and most trace elements) and LC-PUFAs in preterm infants at birth and at discharge?
Nutrient requirements and outcomes:
- ○ At what corrected age does micronutrient and LC-PUFA status reach that considered sufficient on the basis of biomarkers appropriate for term infants (and are these same biomarkers as used in term infants appropriate for all nutrients)?
- ○ Can long-term outcomes be improved by better control of micronutrient and LC-PUFA status?
- ○ Can long-term outcomes be improved by accelerating recovery from previous insufficiency of micronutrients and LC-PUFA status?
Implications of timing and formulation of nutrient delivery for nutrient requirements:
- ○ Do the nutrient compositions of PN and preterm formulas need to be improved?
- ○ What is the relative impact postdischarge on nutrient status between preterm formula compared with postdischarge formulas?
- ○ Should breastfed infants continue to receive nutrient fortifier for some period of time after hospital discharge? For how long? What clinical evidence do we need to decide?
- ○ Is there an optimal macronutrient intake (quantity or quality) to achieve a body composition closer to that of term infants of the same postconceptional age?

Topic 2: What nutrients are conditionally essential in preterm infants?

Rationale

Current nutrient recommendations for preterm infants are based on guidelines that are >30 y old and centered around either term infant needs or data from a preterm population who were considerably older than what is currently seen in today’s neonatal intensive care unit (NICU) (12–14). In addition, parenteral nutrients are designed to mimic profiles of term breastfed infants. These recommendations therefore do not adequately account for developmental metabolic differences that can affect nutrient requirements, either in terms of form or amount.

Conditionally essential nutrients are physiologically important compounds that are normally not essential because they can be synthesized from available precursors. They become essential nutrients, and must be provided directly, under specific circumstances, such as physiologic immaturity, higher developmental need, or certain medical conditions. Examples of some potential conditionally essential nutrients for preterm infants are listed in Text Box 3.

Text Box 3 . Developmentally sensitive, potentially conditionally essential nutrients.

Amino acids: in preterm infants, specific amino acids cannot be synthesized adequately from their precursors due to hepatic immaturity (15).
- ○ l-Cysteine: in human adults l-cysteine can be synthesized de novo from methionine and serine and is therefore a nonessential amino acid.
- ○ It has been suggested that cysteine might be a conditionally essential in all preterm infants because of biochemical immaturity (16, 17), although more recent studies (18, 19) suggest that this may be true only in preterm infants at <32 wk of gestation.
Choline and carnitine:
- ○ Choline and carnitine are historically not included in the earlier recommendations for preterm infants.
- ○ More recent recommendations suggest that these may also be conditionally essential in the preterm infant (14, 20).
Vitamin B-6 is provided in the form of pyridoxine added to PN solutions and infant formulas.
- ○ Pyridoxine must be converted to pyridoxal phosphate requiring an enzyme (pyridoxine phosphate oxidase) that does not reach normal adults concentrations until 1–2 wk postpartum (21).
- ○ Conversion of pyridoxine to pyridoxal phosphate also requires the enzyme pyridoxal kinase. Pyridoxal kinase is inhibited by theophylline, a drug commonly provided to preterm infants (22).
LC-PUFAs: synthesis of AA and DHA from their respective precursors, linoleic acid and α-linolenic acid, is inadequate to meet the high needs of preterm infants (23), and the need for AA and DHA is already increased because of early birth (4).

On the other end of the spectrum, the metabolic immaturity of preterm infants may place them at risk of overexposure to certain nutrients. For example, higher protein supplementation may increase the concentrations of branched-chain amino acids in preterm infants, with potential long-term adverse neurodevelopment (24, 25).

Data and research priorities

What are the optimal dose and form of each amino acid in PN solutions?
What is the optimal composition of parenteral multivitamins and trace element combinations for preterm infants and should composition vary across the different stages of development [i.e., extremely low birth weight (ELBW), very low birth weight (VLBW), near term]?
Is it important to provide DHA from birth or can supplementation be postponed until infants are receiving full enteral feedings?
Is it better to provide AA to parenterally fed preterm infants or is the conversion of linoleic acid to AA adequate?
Is it better to provide preterm infants the active form of vitamin B-6 (pyridoxal 5′ phosphate) rather than pyridoxine?
Is choline conditionally essential in parenterally fed preterm infants?

Topic 3: What factors affect nutrient requirements in preterm infants (before hospital discharge)?

Rationale

Preterm birth, especially when it occurs before 34 wk of gestation, is an abnormal pregnancy outcome. Causes of preterm birth include maternal malnutrition (over- or undernutrition), stress, and smoking. These and other environmental factors also influence placental development [e.g., smoking reduces iron transfer to the fetus (26), stress is associated with reduced birth weight (27)] and therefore maternal to fetal transfer of nutrients. Problems with nutrient transfer are manifested as undergrown [intrauterine growth restriction (IUGR) or small-for-gestational-age (SGA)] infants. Fetal access to selected nutrients may also be limited due to low maternal nutrient intake or poor maternal nutrient status. In the absence of deliberate efforts to assess mothers for these nutrient deficiencies, it is unlikely that nutrient deficiencies would be detected.

It is reasonable to consider that preterm infants exposed to such environments are nutritionally compromised compared with infants of the same GA from a more optimal pregnancy. The following briefly summarizes the critical pre- and postnatal factors that may influence nutrient requirements of preterm infants.

GA

As highlighted in topic 1, fetal nutrient requirements vary widely during gestation (28). Most nutritional guidelines for preterm infants were developed for infants >1000 g birth weight and at >28 wk GA (29). However, because of the earlier interruption of nutrient accretion and development immaturity, smaller infants (<1000 g; <28 wk GA) may be at even greater risk of nutritional deficits at birth. Thus, nutritional guidelines based on the needs of preterm infants born at >28 wk of gestation are unlikely to be the same as those of smaller, more premature infants.

SGA and IUGR status

Many preterm infants (up to 50% at the same GAs) may have IUGR (30). IUGR is a heterogeneous syndrome with a common end result, poor fetal growth. In many cases, IUGR may lead to, or necessitate, early delivery of the fetus. Some, but not all, of these etiologies are related to reduced placental function and reduced transfer of nutrients (including oxygen) across the placenta (31). However, it is unclear if all causes lead to similar nutritional consequences or whether the nutritional status (both macronutrient and micronutrient) is similar in all infants of similar degrees of growth retardation.

It is not certain that the optimal nutrition/growth trajectory of IUGR infants is the same among infants whose causes of IUGR differ. Moreover, it is not clear whether nutrient requirements for IUGR infants are best expressed in terms of kg/d (which implies some commonality in growth rate) or in terms of kcal/d (which implies some commonality in terms of compositional nature of growth) (32).

Route and type of nutrient administration

As referred to above and discussed in greater detail by WG 2 below, the provision of nutrients intravenously (parenterally) compared with orally (enterally) influences requirements, as does the type of enteral feeding provided [e.g., mother’s own milk (MOM), banked human milk, formula, etc.]. Issues pertaining to the transition from parenteral to enteral feeding modalities will be addressed by WG 2.

With regard to nutrient specifications, it is important to note that the variety of options for feeding preterm infants (e.g., MOM, with or without a variety of different fortifiers, preterm formula, postdischarge formula, and term formula) leaves many questions in and of themselves about the relative ability to adequately meet the infant’s actual requirement. A further layer of complexity is added when factors that influence the choice of any of these options (e.g., developmental stage, metabolic/clinical condition, etc.) is considered.

Growth rate

Human growth is a dynamic process that varies in quantity and quality throughout gestation and in the first year of life (27, 33). Furthermore, many populations are exposed to adverse environmental conditions and inadequate nutritional intakes that affect fetal growth. Maternal diet may be inadequate for fetal transfer. Recent evidence suggests that infant and child growth are more affected by health, social determinants of health, and environmental conditions than by ethnic differences (33). When mothers’ nutritional health needs are met and other environmental considerations are minimized, both fetal growth and newborn length are similar across diverse geographical settings (27).

Maternal nutritional status and comorbidities

Maternal comorbidities [e.g., pregnancy-induced hypertension, obesity, diabetes mellitus (type 1, type 2, or gestational)] may reduce nutrient transfer and lead to fetal growth restriction (34) or may lead to increased nutrient transfer and fetal overgrowth. It is reasonable to consider that some nutrient deficiency/excess may influence the physiologic capacity of infants to adapt to extrauterine life, including their response to intensive care or ability to resist infection. Specific examples include the following:

Vitamin D: maternal vitamin D deficiency in pregnancy is common (35) and leads to infants with poor vitamin D status, which is related to infectious illness (36–38).
Vitamin A: important for lung function; vitamin A deficiency during mechanical ventilation may be relatively more damaging to the preterm infant’s lungs, although results appear to be mixed (39).
Glucose: excess glucose during the first trimester has been shown to be teratogenic, and hyperglycemia in utero leads to alterations in metabolic and endocrine phenotypes of the offspring (40).

The ability to define nutrient specification across the continuum of preterm births requires a fuller appreciation and more comprehensive clinical assessment of a number of in utero, maternal, and ex utero conditions that can potentially affect nutrient needs of these vulnerable infants.

Data and research priorities

What are the implications of GA at birth, size at birth (<1500, <1000, or <500 g; SGA, IUGR), obesity/excessive weight gain (overnutrition) during pregnancy, pregnancy-induced hypertension, diabetes mellitus (type 1, type 2, gestational), chronic stress (elevated cortisol), maternal undernutrition, and preeclampsia?
What are the implications of route and type of nutrient administration for nutrient needs of preterm infants?

Topic 4: How do nutrient requirements of otherwise healthy, formerly preterm infants differ from those of term infants of the same corrected age after hospital discharge?

Rationale

The preterm infant at hospital discharge, or at term corrected age, differs greatly from the newborn term infant. The preterm infant typically weighs substantially less, and has a different body composition, than the term infant of the same corrected age. Evidence suggests that more rapid growth—before hospital discharge, between hospital discharge and term corrected age, and between term corrected age and 4–12 mo corrected age—is beneficial to long-term neurodevelopment, with little evidence of metabolic risk (41). To achieve this catch-up growth, the nutritional needs of preterm infants will be in excess of those of slower growing term infants.

In addition to differences in weight between newborn term infants and preterm infants at the same corrected age, marked differences in body composition have been observed. The weight deficit seen in preterm infants mostly consists of a deficit in lean rather than fat mass (42) as well as deficits in bone mineral content (43). Body composition at term corrected age is significantly affected by prematurity and nutritional and nonnutritional factors.

Less is known about the changes in micronutrient status, but these may also be different between term and preterm infants. An example of one such difference is iron. It has been known for many decades that the iron status of preterm infants is suboptimal at hospital discharge. Iron deficiency is very likely to occur unless supplementary iron is supplied as medicinal iron or as iron-fortified formula (44).

The nutritional requirements of “healthy” preterm infants after hospital discharge are likely to be increased relative to term infants to allow the reversal of these presumed nutrient deficits. In this regard, iron may be considered a “proof of concept,” because iron accretion by the preterm infant is far below the in utero rate and significant deficits in total body iron accrue by the time of term corrected age. This does not appear to lead to clinical problems before hospital discharge or before term, but the reduced iron stores of the preterm infant at term corrected age means that the subsequent need for iron is much greater than in the term infant. It can be surmised that additional iron (either as supplements or as fortificants) is required to prevent significant nutritional effects (iron deficiency anemia) later in infancy.

The increased nutritional needs of preterm infants relative to term infants may be partly met by the increased volume of intake that is seen in formula-fed infants after hospital discharge (7). However, changes in the content of some nutrients within the diet may also be necessary. Because preterm infants are able to adjust their volume of intake in response to changes in the caloric density of formula, increasing the caloric density of a term formula is likely to affect nutrient intake. However, such changes in intake would not affect the nutrient:energy ratio of the diet, which can be altered only through fortification/supplementation.

Trials of postdischarge formulas provide the most evidence on which to base the nutritional management of preterm infants during this time period. These formulas are typically intermediate between the composition of term and preterm formulas, although preterm formulas have also been used during this period. Although interpretations of these data differ (45), postdischarge formulas appear to improve bone mineral content, and probably somatic growth in some populations (46). However, these studies compared different diets (typically different formulas) and provide limited data on the requirements for specific nutrients. Furthermore, the applicability of this information to the human-milk–fed infant is limited. Significant disruption to the mother-infant dyad is required to increase the intake of macronutrients in the human-milk–fed infant, either by replacing some feedings with a concentrated fortified formula or adding a human-milk fortifier to some, or all, of the infant’s human-milk feedings. Such an approach has been successfully carried out in research settings, but the effect on growth is inconsistent (47, 48).

Data and research priorities

What is the body composition (lean mass, fat mass) of preterm infants at term corrected age?
What is the body composition of preterm infants during infancy? Does birth weight correlate with alterations in body composition?
Does increased fat mass in the neonatal period translate into metabolic syndrome, obesity, and diabetes later in life?
What is the micronutrient status of preterm infants at term corrected age and what micronutrient intakes are required, after hospital discharge, to prevent the overt signs of deficiency and to lead to optimum long-term outcomes?
What biomarkers are available to estimate the macro-/micronutrient status of preterm infants at, and beyond, term corrected age?

Topic 5: What are the pre- and postnatal modifiers of nutrient requirements of formerly preterm infants and how do these resulting requirements differ from those of term infants of the same corrected age after hospital discharge?

Rationale

As outlined in topic 3, a number of factors inherent to medically compromised preterm infants can influence their nutritional care in the hospital. Those factors may also have implications for the long-term nutritional care of these infants after leaving the NICU. Similarly, those maternal factors that might affect the infants’ course may also have longer term implications postdischarge. Moreover, the issues raised in topic 4 may also need to be considered in the care of the medically compromised preterm infant postdischarge. Thus, all of the uncertainties outlined above are also true for preterm infants with more complex medical histories. In addition, the effects on medically complex preterm infants of maternal health, common neonatal morbidities, feeding and nutritional practices, and growth rates on body composition, growth, and macronutrient and micronutrient deficits are unclear. The range of previous exposures that may affect the nutritional needs after hospital discharge (or after term corrected age) in these infants is extremely wide and included in Text Box 4.

Text Box 4 . Previous exposures that might affect postdischarge nutritional needs.

Prenatal conditions, such as
- ○ maternal diabetes (type 1, type 2, gestational),
- ○ placental insufficiency, and
- ○ in utero (fetal) growth restriction
Postnatal exposures, such as
- ○ necrotizing enterocolitis,
- ○ chronic lung disease,
- ○ SGA birth, and
- ○ exposure to medications (steroids, diuretics, methylxanthines, etc.)
Previous nutritional management, such as
- ○ duration and composition of PN (e.g., high-glucose infusion with permissive hyperglycemia, higher protein supplementation),
- ○ amount and type of enteral nutrition (human milk, preterm formula, term formula), and
- ○ nature and timing of nutritional supplements [e.g., iron (49), vitamin D]
Ongoing medical conditions (short bowel syndrome and resulting surgeries, the presence of ostomies, previous gut resections, chronic lung disease)
Medications (steroids, diuretics, etc.)
Nature of feedings (human milk, preterm formula, postdischarge formula, term formula etc.)
Timing of weaning and type of weaning food used (rice cereal, meat-based weaning foods, etc.)

In general, limited data exist with regard to the long-term effects of these exposures and conditions on nutritional requirements either during hospitalization or after discharge or term corrected age. One exception is the effect of jejunostomies or ileostomies on zinc absorption and excretion. In a small group of such infants, zinc absorption was low and endogenous fecal zinc excretion was high. This resulted in negative zinc balance in the infants, at a time when the zinc requirement for tissue growth would be expected to be high. Even after gut re-anastomosis (at a mean corrected GA of 4 wk after term), zinc absorption remained low and was not different from the study before the anastomosis (50). Whether these observations exemplify similar outcomes for other nutrients remains to be determined.

Data and research priorities

What are the effects of SBS, PN-associated cholestasis/liver disease, and NEC on micronutrient status at term adjusted age?
What are the effects on micronutrient absorption before and after term corrected age, and how is this affected by the type of enteral feeding (human milk, formula, elemental formula) in infants who had experienced SBS, PN-associated cholestasis/liver disease, or NEC?
What are the effects of modifications in macronutrients (e.g., higher glucose infusion to compensate for lower lipid intake) in infants with SBS, PN-associated cholestasis/liver disease, and NEC on body composition and long-term associated metabolic disease, obesity, and diabetes?
What are the effects of maternal diabetes, prediabetes, and obesity on iron absorption and iron status at, and beyond, term corrected age?
What are the effects of maternal diabetes, prediabetes, and obesity on preterm and term infant body composition and metabolic status?
What are the long-term effects of crossing weight percentiles in preterm infants? Are there differences if born too small or too large?

Topic 6: Can we individualize nutrient intakes in preterm infants, and if so, how?

Rationale

Preterm infants are an extremely heterogeneous population. Even among VLBW infants (birth weight <1500 g) the range of GAs at birth is wide. Given the differences in body composition, surface area to volume ratio, physiologic maturity, etiologies, etc., it is improbable that the nutritional requirements of infants born at different GAs would be the same. As discussed above, these differences are partly due to differences in growth rate, because weight gain steadily decreases (in terms of g · kg⁻¹ · d⁻¹) during the last trimester of pregnancy.

When these differences are estimated with the use of a factorial method, the nutritional needs of infants vary widely depending on the weight of the fetus. For example, between weights of 500 and 700 g the fetus gains 21 g · kg⁻¹ · d⁻¹; to match that rate of weight gain, the preterm infant will likely need enteral intakes of ∼105 kcal · kg⁻¹ · d⁻¹ and 4.0 g protein · kg⁻¹ · d⁻¹ (equivalent to a protein:energy ratio in the enteral diet of 3.8 g protein/100 kcal of energy) (51, 52). In comparison, to match the in utero growth of the fetus between 1500 and 1800 g, the preterm infant will require somewhat less protein (3.6 g · kg⁻¹ · d⁻¹), more energy (128 kcal · kg⁻¹ · d⁻¹), and a lower protein to energy ratio (2.8 g protein/100 kcal of energy) (51, 52). In contrast, mineral requirements change little (Table 1), depending on body size.

TABLE 1.

Mineral requirements of preterm infants with different weights¹

	Weight
Requirements	500 to <1000 g	1000 to <1500 g	1500 to <2000 g
Calcium, mg · kg⁻¹ · d⁻¹	184	178	173
Phosphate, mg · kg⁻¹ · d⁻¹	126	124	120
Magnesium, mg · kg⁻¹ · d⁻¹	6.9	6.7	6.4
Sodium, mg · kg⁻¹ · d⁻¹	3.3	3.0	2.6

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Modified from reference 53 with permission from Karger.

In Europe, some manufacturers produce different formulas for infants of different weights to mirror these estimated nutrient requirements. For example, a formula intended for use in infants weighing <1500 g may contain 3.7 g protein/100 kcal, one for infants weighing 1500–2500 g may contain 2.7 g protein/100 kcal, and a formula for infants weighing 2500–3500 g may contain 2.4 g protein/100 kcal. These formulas also differ in their mineral and vitamin contents as well. Although these formulations are logical, it is not clear that they improve outcomes. Such formulas are unavailable in North America.

The major limitation of these factorial calculations (Table 1) is the lack of good information on nutrient absorption and balance in preterm infants. Of the studies that exist, many are old, focus on preterm infants of relatively higher GA, and are carried out at older postnatal ages. When studies have been carried out in smaller preterm infants, it appears that nutrient intakes may be considerably lower than is appropriate (54). The absence of recent well-conducted nutrient-balance studies in preterm infants has led to profound uncertainty over the nutrient requirements of these infants and is a critical research need.

The use of different nutritional targets for preterm infants of different GA or different weight might be considered stratified nutrition rather than individualized nutrition, because targeted intakes are still based at the group level. True individualization requires individual-level information to guide intakes, and the most likely source of such information is from the use of nutritional biomarkers. True individualization of nutrient intake in preterm infants has been studied by using blood urea nitrogen to adjust the amount of protein fortification to human-milk–fed preterm infants (55). This approach was shown to lead to both increased protein intakes and to improved growth (55). However, a critical unanswered question is whether the benefits were due to the higher protein intake in the “adjustable” group (the rising tide lifts all ships) or due to the ability to adjust protein intake to the amount required by each individual. Anecdotally, this approach may be far less successful in units in which higher protein intakes are the standard.

Many other factors may modify the nutritional needs of individual preterm infants, including the previous duration of PN and the type of enteral nutrition (EN). Some nutrients may not be added to PN in the expectation that they will soon be supplied by enteral feedings. Conversely, some nutrients (e.g., vitamins) may be added to PN in amounts that meet 100% of the presumed nutrient requirements of preterm infants, even though much (maybe a majority) of nutrition is being provided enterally. For some nutrients, the nature of the enteral supply (e.g., human milk compared with formula) may be just as important as the amount of enteral supply (56).

Some previous disease exposures—for example, gut resection—may alter the nutrient needs of preterm infants; this may be especially true for nutrients whose absorption occurs at limited sites in the gastrointestinal tract. Ongoing diseases, such as chronic lung disease and congenital or acquired heart disease, may increase the nutritional needs of preterm infants (e.g., energy), and the use of diuretics and steroids could increase mineral requirements.

Data and research priorities

What are the effects of GA at birth, postnatal age, and corrected GA on nutrient absorption and balance? How do these differences alter body composition?
What effect does the form of enteral nutrient delivery (MOM compared with donor milk compared with formula, fortified compared with unfortified human milk) have on nutrient absorption in preterm infants? And how is this affected by differences in GA at birth, postnatal age, and corrected GA?
How is nutrient absorption affected by coexisting morbidities of prematurity?
What is the relation between biomarkers of iron status and iron absorption, iron utilization, and iron balance in preterm infants?
Does the use of a wider range of human milk fortifiers or formulas designed for infants of different weights or GAs improve growth and other clinically relevant outcomes in preterm infants?

WG 2: CLINICAL/PRACTICAL ISSUES IN ENTERAL FEEDING

Chairs: Diane Anderson and William Hay

Topic 1: Impact and importance of trophic feedings for VLBW infants (see Text Box 5)

Text Box 5 . WG 2: clinical/practice issues in enteral feeding topics.

1) What is the impact and importance of trophic feedings for VLBW infants?
2) What, when, and how to feed?
3) How should feeding intolerance be treated?
4) What is the importance of developmental, behavioral, and environmental factors in oral feeding of preterm infants?
5) Should enteral feedings be fortified, and how?
6) What is the impact of support and education of care providers with regard to enteral feeding?
7) What are the goals of enteral feeding and how should progress be assessed?
8) What, when, and how to conduct transitional feeding?
9) What are the special challenges in enteral feeding?

Rationale

As an alternative to enteral fasting in developmentally immature preterm infants who might not be able to tolerate full enteral feedings, trophic feedings are commonly initiated ostensibly to help foster development of the gastrointestinal tract (57). Trophic feedings are defined as enteral feedings with a milk volume up to 24 mg · kg⁻¹ · d⁻¹ (1 mL · kg⁻¹ · h⁻¹), beginning within 96 h of birth and continued for at least 5 d or until at least 1 wk after birth (58). Trophic feedings are frequently introduced as the first feedings for premature infants who are considered at risk of NEC and are generally initiated with infants weighing <1500 g at birth. Many NICUs use a longer “trophic feed period” for infants with a birth weight <1250 g or <1000 g. Although most NICUs do not treat SGA infants differently from those who might be “appropriate for gestational age” (AGA) of the same birth weight, many show more concern about starting or advancing enteral feedings when IUGR/SGA infants had abnormal aortic/umbilical artery velocimetry (from absent to reversed end-diastolic flow). Birth weight is more important than GA in initiating trophic feedings, because SGA/IUGR infants are notoriously difficult to feed and are at increased risk of NEC. The efficacy and safety of trophic feeding compared with enteral fasting were recently systematically reviewed (58), with no reported differences in either benefit or harm in VLBW infants. However, investigations and clinical practices vary and thus present ongoing questions about timing, duration, volume provided, type of milk used, and which infants by birth weight should be provided with trophic feedings. The common use of trophic feeding demands a concerted effort to address these issues.

Data and research priorities

What are the effects of trophic feedings on growth and development of the gastrointestinal tract?
Are there differences between continuous and bolus trophic feedings?
What is the difference in response to trophic feedings in ELBW infants and those with severe IUGR, as documented by abnormal Doppler flow studies of umbilical arteries?
What are the implications of trophic feedings that are started and stopped a number of times?
What are the indications to delay trophic feedings beyond 96 h?
What are the indications to discontinue trophic feedings before a minimum of 5 d?
On what day of life should trophic feedings be started? For example, before 24 h compared with after 24–96 h?
Are there differences in the effects of trophic feedings on the basis of type of nutritional source?
What are the benefits of human milk compared with formula for trophic feedings?
Are there differences between donor milk and MOM for trophic feedings?

Topic 2: Feeding—what, when, and how?

Rationale

This is one of the most common subjects covered in the newborn/preterm infant populations in the Cochrane Review database (45, 58–66). Thus, the available literature is extensive and has been subjected to many systematic reviews. It is generally recognized that MOM is the preferred source of nutrition for all preterm infants. The need to fortify MOM is a subject of continued research interest and is covered under the WG 2 section entitled “Topic 5” below.

Issues associated with the use of donor milk are less clear. For example, if donor milk is initiated, how long should it be continued if MOM is not available? The implications of using donor milk even if fortified on outcomes such as growth or neurodevelopment remain unclear. Research is needed to determine how long donor milk should be used to achieve decreased morbidity, yet allow for adequate and acceptable growth. The superior growth with special formulas for preterm infants compared with even fortified human milk must be balanced with the increased morbidity and mortality in the absence of human-milk use. Despite the slower growth of infants fed either MOM or banked/donor milk, they have better neurologic outcomes than do infants fed formula, which is referred to as the “breastfeeding paradox” (67).

Data and research priorities

What is the rate of advancement of feeding volumes for best feeding outcomes with the lowest morbidities after an uncertain period of trophic feedings (birth weight <2000 g)?
What is the ideal timing for the use of milk fortification:
- ○ during the advancement of feedings or
- ○ when the full volume of feedings is achieved for VLBW infants?
What are the benefits of bolus compared with continuous gastric drip feedings via a feeding pump?
What are the advantages of transpyloric drip feedings with a feeding pump?
What are the benefits of standardized feeding protocols on growth and morbidities?

Topic 3: Feeding intolerance

Rationale

Feeding intolerance occurs in ∼75% of VLBW infants (68, 69). The nonspecific nature of the signs of feeding intolerance have not been 1) clearly prioritized or 2) validated to assist in determining who is at greatest risk of developing bowel complications. The clinical signs of feeding intolerance include both gastrointestinal and other system findings. Although no standard ways exist to define abnormal gastric residuals, approximately half of feeding intolerance is associated with the presence of gastric residuals. Factors contributing to feeding intolerance are outlined in Text Box 6.

Text Box 6 . Factors contributing to feeding intolerance.

Lower GA and birth weight
Presence of asphyxia, respiratory distress, and delayed feeding
The developing gut microbiota:
- ○ The developing gut microbiome has emerged as a major factor in the overall health of preterm infants (69, 70).
- ○ Medications such as antibiotics and type of feeding in preterm infants can affect the state of the gut microbiome (71, 72).
Hemodynamic changes in preterm infants strongly affect feeding tolerance, but it remains unclear what the optimal feeding strategies are for such common cardiovascular problems as PDA (73).
Gastroesophogeal reflux disease: although gastroesophageal reflux is a normal and common occurrence in preterm infants, gastroesophogeal reflux disease is less common, difficult to diagnose, and difficult to treat effectively (74).

Data and research priorities

What are the effects of altered gut microbiota with use of antibiotics and duration of antibiotic use?
Does checking and responding to gastric residuals affect clinical outcomes?
What are defined contraindications to enteral feeding (presence of PDA, hypotension, lines, etc.)?
What is the effect of a blood transfusion on feeding and gut outcomes?
When is the optimal time to refeed damaged bowel (gastroschisis, postsepsis, post-NEC)?
What is the impact of human milk compared with formula on feeding tolerance and long-term health outcomes for late-preterm infants?
What is the impact of maternal magnesium exposure on feeding tolerance?

Topic 4: Importance of developmental, behavioral, and environmental factors in oral feeding of preterm infants

Rationale

Oral feeding ability is affected both by underlying disease states and by neurodevelopmental readiness (75). Preterm infants develop the ability to feed orally between 32 and 44 wk GA. Studies of predictors for oral feeding success and interventions to optimize preterm infant oral feeding are limited in number. Some of the more common interventions are listed in Text Box 7.

Text Box 7 . Oral feeding interventions studied to date.

Nonnutritive suckling with a pacifier during gavage feeding (76). It has been reported that this intervention was associated with
- ○ a significant decrease in length of hospital stay and
- ○ a reduction in feeding transition time, defined as the number of days from first introduction of bottle feeding to the time when all milk volume is taken from bottles.
Oral motor stimulation before the initiation of oral feedings and often directed by occupational therapy or speech therapy services (77).
Other techniques include
- ○ body positioning (supine, prone, and side-lying),
- ○ oral support (chin and cheek support during feeding),
- ○ body sensorimotor intervention, and
- ○ specific bottle systems.

Although limited, these studies are laying the foundation for the development of best practices for a problem that is surprisingly complicated. Preterm infant feeding is complicated by infant respiratory health and respiratory support needs, individual infant differences in maturity, the balance of bottle compared with breastfeeding, design of the multidisciplinary team (neonatology, lactation, occupational therapy, speech therapy, parents), and the pressure for hospital discharge when adequate oral feeding is the only remaining obstacle.

Data and research priorities

What are the benefits of oral care with colostrum before enteral and particularly nipple feeding is begun?

Topic 5: Fortification of enteral feedings

Rationale

Numerous studies have shown that preterm infants require nutrient fortification of MOM, banked human milk, or standard (nonexempt) term formula to optimize growth and neurodevelopmental outcome (78, 79). Several different fortifiers are available to support growth and sustain enteral feeding tolerance (human-milk fortifiers, formula fortifiers, human-milk–based fortifiers, donor human-milk cream, and high-protein supplements), with minimal data available to show whether any of these products are more or less efficacious. In addition, current consensus guidelines recommend providing a transitional formula or fortified human milk for 6–9 mo after hospital discharge. However, studies that compared nutritionally dense postdischarge formula with term formula provided inconsistent results with regard to improvement in long-term growth and showed no differences in neurodevelopment (65). Multinutrient fortification of human milk after hospital discharge did not affect growth or neurodevelopmental outcomes (80). There are no guidelines on whether or not to fortify milk for the late-preterm infant, even though a substantial amount of brain development occurs during the final month of gestation. The relative impact of type, dose, duration, and timing of enteral feeding fortification on growth and neurodevelopmental outcome requires further investigation.

Data and research priorities

What is the impact of using exclusively human milk–based fortifiers for preterm infants on risk of NEC and long-term growth?
What is the impact of using centralized milk preparation facilities in the NICU on milk composition, including reproducibility/consistency of composition?
What is the impact of using centralized milk preparation facilities in the NICU on the attitudes and prevalence of use among the multidisciplinary team?
What is the impact of manipulating fortification products for the individual patient with growth failure, feeding intolerance, or risk factors for poor absorption (SBS or cholestasis) or allergic colitis?
What is the relative impact of specific types of formula fortifiers, including partially hydrolyzed whey protein fortifiers, on growth and development?
What is the relative value of existing and new methods to transition the preterm infant to breastfeeding?
What are the best methods to maintain the mother’s milk supply during the first year of life while continuing human-milk fortification?
What is the ideal timing of initiation and advancement of fortification?

Topic 6: Impact of support and education of care providers with regard to enteral feeding

Rationale

Approaches to oral feeding of preterm infants at the time of hospital discharge are complicated. Potential problems include limitations in oral feeding ability due to immaturity (discharge before term age) and/or lung disease [bronchopulmonary dysplasia (BPD)], extrauterine growth restriction (EUGR) requiring increased nutritional density for catch-up growth, and restrictions to maternal/infant interactions and therefore limitations in breastfeeding experience.

At hospital discharge, feeding plans may be complex and include feedings with increased nutritional density and/or combinations of breast- and bottle-feeding. These feeding plans are confounded by the use of products in ways other than how they are labeled for preparation (e.g., postdischarge formula mixed to 24 kcal/ounce or postdischarge formula added to MOM), leading to potential misadministration by caregivers. Additional risks are limited oral feeding (breast or bottle) experience by caregivers at hospital discharge and lack of direction to the postdischarge pediatric care team on growth expectations and instructions to decrease nutritional density as intake and growth improve. Therefore, both under- and overfeeding are potential consequences for the preterm infant post–hospital discharge. In addition, preterm infants have significant obstacles to reaching the goal of sustaining breastfeeding through the first postnatal year, including inadequate outpatient education and support of the lactating mother.

Evidence is limited with regard to methods to optimize preterm infant breastfeeding at home. Despite improvements in in-hospital preterm infant/mother lactation support, only 50% of mothers who initiate breast pumping continue to produce milk at their infant’s hospital discharge and ≤25% are providing milk at 3–6 mo postdischarge. Research must identify methods for preterm infant–mother dyads to overcome the barriers to successful breastfeeding. The barriers are multidimensional and include maintaining the mother’s milk supply, measurement of infant nutritional intake adequacy, and the development of infant oral ability at the breast (81–84).

Data and research priorities

Identification of methods for preterm infant–mother dyads to overcome the barriers to successful breastfeeding

Topic 7: Goals and assessment of enteral feeding success

Rationale

One of the primary goals for the preterm infant is the successful establishment of full enteral feedings, preferably with human milk. The early initiation of enteral feedings shortens the time to establishment of full enteral feedings and has not been associated with an increase in NEC (58). Enteral feeding adequacy is most commonly assessed anthropometrically (trajectories of weight, length, and head circumference), which have been shown to be reasonable predictors of neurodevelopmental outcome (85). However, there is still a considerable need for more sophisticated methods of measuring enteral feeding adequacy, such as biomarkers, nutrient panels, and more precise measurements of organ growth and body composition. Some of these issues are addressed by WG 4, but WG 2 added the following suggested questions from their specific perspective.

Data and research priorities

What is the relative value of available methods for evaluating enteral feeding adequacy during NICU hospitalization, including the identification of important early-growth milestones, time to regain birth weight, maintenance of growth variables along birth percentile, lack of postnatal growth restriction, or body composition?
What are new enteral feeding strategies that decrease the time to regain birth weight, maintain consistent growth along birth percentiles, and decrease length of hospital stay?
What is the effect of routine use of individual plasma amino acid concentrations to assess the adequacy of enteral protein delivery?
What is the effect of routine use of plasma medium- and long-chain fatty acid concentrations to assess the adequacy of enteral lipid delivery?

Topic 8: Transitional (from parenteral to enteral) feeding

Rationale

There is a paucity of data that describe the optimal method to make the transition from full PN to full EN feedings while maintaining optimal nutrient intakes and growth. A retrospective review of 156 infants born at <32 wk of gestation compared the 3 phases of feeding (full PN, transitional PN + EN, and full EN) and found the highest incidence of poor growth (weight gain <10 g · kg⁻¹ · d⁻¹) during the transitional phase of feeding. Between the full PN and transitional phases, energy intakes were stable but protein intake and protein to energy ratio declined as EN volume advanced. Poor growth during the transitional phase was significantly associated with growth failure (weight <10th percentile) at discharge when adjusted for birth weight, GA, and severity of illness (86). Protein intake may be increased during the transitional feeding phase by adjusting the protein content of PN and/or by the use of increased protein-content enteral feedings (fortified breast milk or preterm formula). The impact of individualizing feeding practice to optimize protein intake and protein:energy ratio requires further investigation.

Data and research priorities

What is the impact of fortification of human milk before the infant reaches 100 mL · kg⁻¹ · d⁻¹ of enteral feedings on growth and nutrient intake (energy, protein, and minerals) during the transitional phase of feeding?
What is the optimal composition of human-milk fortifiers during the transition period? Is it constant for vitamins and minerals?
What is the ideal method for fortification of banked milk, which is already variable in nutrient content?

Topic 9: Challenges in enteral feeding—special considerations

Rationale

As highlighted in previous sections, enteral feedings are often either limited to trophic volumes or withheld completely in the critically ill preterm infant, especially when there are concerns for intestinal hypoperfusion. The main concern for feeding under these conditions is risk of developing NEC or spontaneous intestinal perforation, which both are associated with an increased mortality risk or neurodevelopmental impairment (87). Moreover, several conditions result in the interruption of enteral feedings, including hemodynamic instability, symptomatic PDA, administration of a blood transfusion, or prenatal exposures such as IUGR.

Given these myriad contingencies, a need exists to address how best to alter enteral feeding protocols for preterm infants. This also leads to the larger question of whether critically ill preterm infants have different enteral nutrient requirements than do comparable healthy preterm infants, which is an issue that is covered in greater detail by WG 3.

Data and research priorities

What is the impact of administering EN on anabolic growth in preterm infants who are within the acute phase of illness?
What are the best methods for determining “enteral feeding readiness” in preterm infants?
What is the need for the development of radiographic or functional assessments to predict enteral feeding readiness in preterm infants (e.g., superior mesenteric artery blood flow)?
Should a preterm infant receiving medication to treat a symptomatic PDA be fed?
Is it necessary to interrupt enteral feedings when a preterm infant is receiving a blood transfusion, given concerns for transfusion-related acute intestinal injury?
When should enteral feedings be restarted and/or advanced after medical and surgical treatment of NEC?

WG 3: GASTROINTESTINAL AND SURGICAL ISSUES

Chairs: Sandra Robins and Josef Neu

Topic 1: Congenital surgical diseases (see Text Box 8)

Text Box 8 . WG 3: gastrointestinal and surgical issues topics.

1) Congenital surgical diseases
2) Gastroschisis
3) NEC
4) Cholestasis/PN-associated liver disease/intestinal failure–associated liver disease
5) SBS
6) Cardiac surgical issues
7) BPD
8) Retinopathy of prematurity

Rationale

Congenital surgical diseases are associated with major neonatal nutritional morbidity because of both the underlying disease processes and the metabolic issues incurred by treatment. Neonatal gastrointestinal malformations that manifest with almost immediate nutritional problems include the following: esophageal atresia, duodenal atresia, and jejunoileal atresia. Survival for each of these disorders now exceeds 90%. Some of the key features of these conditions are highlighted in Text Box 9.

Text Box 9 . Key features of congenital surgical diseases in preterm/term infants.

Esophageal atresias
- ○ Those with a “long gap” often experience the most pronounced feeding problems, including oral aversion.
- ○ This subset of patients often has significant lifelong gastrointestinal morbidity (88). The best possible surgical solution to long-gap esophageal atresia remains to be defined.
Intestinal atresia
- ○ The surgical techniques to repair intestinal atresias are well established; however, protracted PN is still required.
- ○ Median (IQR) times for attaining full EN in jejunoileal and duodenal atresia are 17 (9–40) d and 10 (7–20) d, respectively (89).
- ○ Cisapride appears to be of some benefit in children with secondary intestinal motility problems, but its side effects are potentially fatal and hence its use is highly restricted (90).
- ○ Safer and more effective prokinetic agents are required, as well as basic studies to characterize why dysmotility is present in neonates with congenital as well as acquired intestinal disorders.
Thoracic diseases
- ○ Congenital diaphragmatic hernia and congenital heart disease are also associated with neonatal nutritional difficulties.
- ○ In congenital diaphragmatic hernia, both elevated caloric demands due to increased work of breathing and reduced intake from gastroesophageal reflux may impede growth.
Congenital heart disease
- ○ Fluid restriction is often required and the delivery of adequate quantities of macronutrients is problematic.
- ○ Not only is protein intake decreased but neonates with cardiorespiratory failure who require heart-lung bypass manifest high rates of net protein catabolism.
- ○ The provision of adequate protein appears to be central to optimizing anabolism in neonates with both congenital diaphragmatic hernia and congenital heart disease (91, 92).

Intestinal atresias are a major cause of SBS, which will be covered in greater detail in WG 3 “Topic 5” below. The advent of multidisciplinary pediatric intestinal failure programs has been associated with both improved mortality and an increase in research activity (93). Despite expanded investigation, many questions remain. Retrospective data suggest that breast milk or elemental formulas enhance the transition to full EN in neonates with SBS (94); however, prospective studies are lacking. In selected neonates, bowel-lengthening operations have been thought to improve enteral tolerance, but evaluation has been restricted to case series and a voluntary registry (95). In addition, hormonal manipulation to promote bowel adaptation, particularly in the form of teduglutide [glucagon-like peptide 2 (GLP-2) analog], has shown show promise for the treatment of SBS (96). The results of a recently completed pediatric trial are pending. Animal research is ongoing with the evolution of novel techniques such as tension-induced bowel lengthening and tissue-engineered small intestine (97, 98). A further interesting observation is that as survival in SBS improves, significant chronic nutritional problems, including metabolic bone disease, are becoming evident (99).

Although advances in surgery, anesthesia, and critical care have resulted in marked improvements in survival for neonates with congenital anomalies, an area of nutritional research that has been incompletely pursued is the characterization and modulation of the metabolic stress response. It is important to underscore that surgery, anesthesia, and analgesia all interact to affect the perioperative catabolic response in neonates (100). Interesting quantitative studies, some that incorporate the use of stable isotopic techniques, are available, but the best nutritional and metabolic management of both premature and full-term perioperative neonates remains to be defined.

Research questions

What interventions will minimize oral aversion in patients with congenital gastrointestinal diseases?
Can we characterize and treat the intestinal motility disorders attendant to neonatal surgical diseases?
How can we best organize trials to define the many unknown aspects of the optimal nutritional, medical, and surgical management of SBS neonates?
What are the long-term nutritional consequences of neonatal gastrointestinal and thoracic disease?
How can we quantify the metabolic response in surgical neonates and ameliorate its deleterious consequences, including net protein catabolism?

Topic 2: Gastroschisis

Rationale

Gastroschisis is a congenital abdominal wall defect. Infants are born with their intestines, and occasionally other abdominal organs, herniating through a small defect in the abdominal wall. Key features of gastroschisis are outlined in Text Box 10.

Text Box 10 . Key features of gastroschisis.

Gastroschisis is a congenital abdominal wall defect. Infants are born with their intestines, and occasionally other abdominal organs, herniating through a small defect in the abdominal wall.
Intestinal atresias have been reported in 10–20% of infants with gastroschisis (101), and infants with gastroschisis are at risk of developing NEC. These infants are generally classified as complex gastroschisis.
Birth prevalence of gastroschisis is increasing with near doubling between 1995 and 2005 in the United States (101, 102).
Although most patients with gastroschisis do relatively well, gastroschisis is listed as one of the most common diagnoses in intestinal transplant registries.
Risk factors for gastroschisis include prematurity and SGA status, which puts infants at risk of growth problems and neurodevelopmental delay (103, 104).
Gastroschisis is associated with significant morbidities, including gastroesophageal reflux disease, sepsis, cholestasis, motility disorders, and short gut syndrome (103).
Growth
- ○ Growth restriction is common in infants with gastroschisis, with ∼ 20% noted as SGA at birth (103).
- ○ Infants with gastroschisis are noted to have continued poor growth throughout the first year, with approximately one-third of infants below the 10th percentile at 16–24 mo (104).

Little information exists to guide our nutritional management of these infants. After the closure of the hernia, whether staged in a silo or a primary repair, there is often a delay in the return of gut function. Some centers studied having a set time to start enteral feeding postclosure and reported decreasing their length of stay (105). A descriptive study linked earlier enteral feedings to fewer days of PN, fewer infections, and a shorter length of stay (106). Those infants who could be fed early will do well, and those who have a prolonged ileus are more likely to have difficulties with enteral feedings.

Maternal human milk confers many immunologic and neurodevelopmental benefits, and it appears that it is very well tolerated in these infants (107). Another study showed decreased time to full feedings and discharge with the use of human milk but compared human milk with a cow-milk–based formula (108). A recent retrospective cohort study described non–IgE-mediated cow-milk protein allergy (100). The mode of enteral feeding to be used is unknown, with variations from by-mouth ad libitum to nasogastric bolus or to nasogastric continuous feedings, sometimes interspersed with by-mouth feedings in 1-h windows off of the continuous infusion. Continuous feedings have been shown to enhance absorption in patients with damaged gut (109, 110).

Feeding problems are common in infants with gastroschisis, with a delay in achievement of full by-mouth feedings noted. The neuromarkers of esophageal motility in infants with gastroschisis were not normal (103). Some infants therefore may have a physiologic basis to their difficulty with oral feedings. How this information can be integrated into a feeding algorithm is not known.

Neither energy nor protein needs of these infants have been well described, either early in the course with PN or later with enteral feedings. When enteral feeding is delayed or not tolerated, cholestasis and its associated nutritional problems are common.

Research and data priorities

For surgical neonates such as those with gastroschisis:

Is there benefit to the use of donor human milk as the initial source of nutrition in the absence of MOM?
For what length of time should donor milk be used?
Should infants be started with continuous or bolus feedings or a combination?
Should MOM and/or donor human milk be fortified and with what?
If an infant is not growing what should be the best approach, increased volume or density?
If a more elemental formula is used, how long until switching to a less elemental product and what would be the path?

Topic 3: NEC

Rationale

Progress in the eradication of NEC in the past 50 y has been nearly nil and the disease appears to be increasing in some countries that previously were thought to have an admirably low incidence of this disease (111). There are several reasons for the lack of progress, but one of the factors is the broad terminology of what is included under the term “NEC,” a condition that encompasses different diseases on the basis of major differences in pathophysiology. For example, a staging system developed in the 1970s that includes stage I “NEC” (112). This term is misleading because it actually represents a very broad set of conditions and usually is not associated with necrosis as implied.

The terminology with regard to NEC needs to more accurately reflect the clinical continuum. Because the pathophysiology, treatment, and prevention may be very different at different points in the etiology and care of NEC, it will be critical to find ways to differentiate key stages. The diagnosis of NEC is problematic, necessitating better diagnostic and predictive biomarkers. Although several diagnostic biomarkers have been investigated (e.g., intestinal fatty acid binding protein), none are currently used. Predictive biomarkers are needed to determine those infants at highest risk of NEC and to help target preventative therapies.

How to nourish infants without disposing them to NEC is critical. Enteral feeding is clearly a major conundrum with NEC. The lack of enteral feeding may actually have major adverse consequences and may predispose to the disease, whereas overaggressive feeding may exacerbate the development of NEC. The composition of both EN and PN may play a role in NEC.

Although MOM appears to be very helpful, questions remain about the value of donor milk for the prevention of NEC. With the increasing availability of donor milk in pediatric center milk banks, controlled studies are warranted to test whether banked donor milk is as effective as MOM in the prevention of NEC. In addition, other alternatives to human milk need to be considered. Whether the addition of supplements such as arginine or omega-3 fatty acids to human milk may prevent NEC is also not clear (see the WG 1 section for some relevant questions). Finally, as new knowledge emerges with regard to the development and role of the gut microbiome, and its relevance to the prevention, care, and treatment of NEC needs to be considered.

Research and data priorities

What is the best approach to defining and diagnosing NEC? Is there a categorical approach to delineating the different entities that have been termed “NEC” in common databases?
What is the best approach to delineate the pathophysiology of the most common form of NEC?
Is the concentration (osmolality) of the feedings an important factor for the prevention of NEC?
Can bovine colostrum be safely substituted for human milk to provide immune protection and trophic stimulus for the human infant intestine?
How long should feedings be withheld for an episode of medical NEC (NEC not requiring surgery)?
What constitutes the most appropriate PN for an episode of medical NEC? How long should it be provided? How can PN for infants who require surgery for NEC be optimized?
When refeeding is initiated, should human milk (MOM or donor) be used or should a partially hydrolyzed or elemental formula be used?
How quickly should infants with NEC be allowed to return to full enteral feedings?

Topic 4: Cholestasis/PN-associated liver disease/intestinal failure–associated liver disease

Rationale

PN is an essential component of the care and treatment of premature, low-birth-weight, and other hospitalized infants with SBS and intestinal failure (113). PN-associated liver disease (PNALD) is a common metabolic complication, which presents clinically as increased serum biochemical markers, such as direct bilirubin, bile acids, and liver transaminases. Also at risk are infants who have SBS, especially those who require prolonged (>60 d) PN because of intestinal failure after intestinal resection. In these cases, intestinal failure–associated liver disease (IFALD) occurs, which is a multifactorial disease that often occurs in neonates.

A key element of PN that has been implicated in the pathogenesis of PNALD is the lipid component (114–116). The persistence of PNALD in pediatric clinical care has prompted recent investigations into nutritionally optimal lipid intake and fatty acid composition as well as the safety and health benefits of currently approved and newer-generation lipid emulsions. Some of the key issues associated with lipids in PN are highlighted in Text Box 11.

Text Box 11 . Key features of the role of lipids in PNALD (114–116).

Lipids are an essential dietary group of nutrients that must be included in PN.
In the United States, the only Food and Drug Administration–approved lipid emulsions are enriched with the fatty acids linoleic acid (n–6) and oleic acid (n–9), but are devoid of DHA and EPA, n–3 LC-PUFAs, and medium-chain fatty acids.
The US-approved emulsions are plant-based seed oils that contain phytosterols, which are cholesterol-like molecules that have been linked as a cause of liver injury in PNALD (114).
Current attempts at decreasing or eliminating phytosterols include the following:
- ○ reduced doses of soy-based fat emulsions to ≤1 g · kg⁻¹ · d⁻¹,
- ○ the use of a fish-oil emulsion (which has no phytosterols), or
- ○ the use of a mixture of soy oil, medium-chain triglycerides, olive oil, and fish oil (117, 118).

In terms of potential mechanisms that can explain PNALD, research in the past decade has uncovered an important enterohepatic endocrine hormone signaling pathway that is relevant to bile acid homeostasis, which is a critical factor in lipid metabolism. Studies show that lipid emulsions can affect bile acid stimulation of intestinal farsenoid X receptor (FXR)–induced expression of fibroblast growth factor 19 (FGF19).

The significance of FGF19 in human bile acid metabolism is that enteral bile acid activation of intestinal FXR is a key mechanism in the feedback suppression of bile acid synthesis. Thus, during PN, there is diminished bile secretion and reduced activation of intestinal FXR. The loss of gut FXR activation results in a cascade leading to persistent activation of bile acid synthesis and accumulation of bile acids in hepatocytes, a process that contributes to cholestasis. The concept that enteral bile acid can be used therapeutically to reduce PNALD has been tested with promising results (119, 120).

The only Food and Drug Administration–approved bile acids that are available to test this approach are chenodeoxycholic acid (Chenodal; Manchester Pharmaceuticals) and ursodeoxycholic acid (Actigall; Watson Pharmaceuticals), which is a secondary bile acid produced by intestinal bacteria. Neither of these bile acids is Food and Drug Administration–approved for pediatric use, yet ursodeoxycholic acid is often used in pediatric cholestatic conditions. An emerging bile acid designed with maximal FXR agonist activity is obeticholic acid (6α-ethyl-chenodeoxycholic acid). The therapeutic use of obeticholic acid is currently being tested in clinical trials for adult liver diseases.

Research and data priorities

Can bile acid therapeutic approaches improve the treatment of PNALD/IFALD in preterm infants with intestinal failure? How does bile acid affinity for FXR and FGF19 secretion effect PNALD/IFALD?
Can ethanol lock prophylactic therapy decrease the risk of central line–associated bloodstream infections in preterm infants at risk of PNALD?

Topic 5: SBS

Rationale

Survival rates for preterm infants, including those with various pathological conditions in the gastrointestinal tract, have increased dramatically (121). Recent refinements in the provision of PN have further improved these outcomes. However, many of these neonates suffer a major loss of intestinal length due to surgical resection, congenital defect, or disease-associated loss of absorption. SBS leads to an inability to maintain nutrient balance when fed a normal diet (122).

In cases of SBS-associated intestinal failure in which defined enteral diets are not sufficient to meet nutrient needs, prolonged PN is necessary (123). Intestinal failure is defined as the requirement of PN for >60 d. Intestinal adaptation is a complex series of coordinated mucosal, endocrine, and secretory events that ultimately allow for an increase in nutrient absorption, so that the patient can reach nutritional sufficiency without the need for PN.

The major challenges of existing therapy are that 1) the only method to stimulate intestinal adaptation is enteral feeding and 2) the use of PN may be detrimental to the adaptive process. There is universal agreement that enteral feeding is preferred to PN to meet the high energy and nutrient requirements of preterm infants. Key features of enteral feeding in the context of SBS are listed in Text Box 12.

Text Box 12 . Enteral feeding and SBS.

Enteral nutrients are the primary stimulus for intestinal adaptation by acting
- ○ directly to provide energy and protein for the intestinal enterocytes or
- ○ indirectly to trigger the release of intestinal hormones, increase pancreatic-biliary secretions, neural factors, and intestinal blood flow.
In patients with SBS, the transition from PN to EN should be made as soon as possible; yet, beyond this broad recommendation, there are many areas of controversy in the use of EN in premature infants and infants after surgical resection (124).
This includes the rate of increase in feedings, the type of EN used, the pattern of feeding (bolus or continuous), and the use of specific types of nutrients and pharmacologic therapies. Human milk is the recommended form of EN in infants with SBS; yet, when human milk is not available, the specific types of formula that provide for optimal intestinal adaptation remain to be established.
EN triggers the release of multiple trophic gut hormones, but the only ones that have approval for human use are glucagon-like peptide 2 analog and growth hormone.

As a result of an evolving understanding of the physiology of gut development potential, alternative interventions for SBS have emerged, most prominently GLP-2, which has been characterized as follows:

GLP-2 appears to be a key factor in signaling adaptation because it exerts a variety of functions that are especially beneficial for SBS conditions ranging from
- ○ suppressing gastric emptying and secretion and
- ○ improving intestinal barrier function to
- ○ stimulating bowel growth and nutrient absorption.
The ability to stimulate endogenous GLP-2 secretion in patients with SBS by therapeutic use of parenteral short-chain fatty acids or enteral bile acids has shown promising potential in neonatal animal models (125).
In adult human SBS studies, parenteral treatment with GLP-2 or its analogs has been shown to improve nutrient and fluid absorption.
Given the high amounts of endogenous production during the neonatal period, it is likely that GLP-2 treatment of preterm infants with SBS may facilitate the robust intestinal growth during this critical development period.

The recent approval of a commercial GLP-2 analog (Gattex; NPS Pharmaceuticals Inc.) for the treatment of adult SBS in the United States and Europe is promising and may pave the way for the pediatric indication (126). This paucity of translation into clinical practice is related to a number of scientific unknowns about short- and long-term physiologic effects of hormonal therapies, regulatory issues, and safety concerns. Thus, there continues to be a need to establish the mechanisms, efficacy, and safety of various therapies for infants with SBS.

Research and data priorities

Are there microbial therapeutic measures or “prebiotic” approaches that could improve the adaptation of the bowel?

Topic 6: Cardiac surgical issues

Rationale

Optimizing nutrition delivery and postnatal growth are relevant issues for the preterm infant cardiac population, because most surgical interventions are not technically feasible until size and weight requirements of a near-term infant have been achieved. However, nutrition delivery in the preterm infant cardiac population is challenging given their multimorbidities of immature intestinal function and cardiac-related intestinal ischemia risk factors. Postnatal growth failure is a widespread health problem among infants with congenital heart disease, specifically infants with single-ventricle lesions including hypoplastic left heart syndrome (127–129).

The morbidities of early postnatal growth failure include poor wound healing, increased infection risk, prolonged hospitalizations, and long-term neurodevelopmental disability, including worse school performance (130, 131). Despite the sobering short- and long-term sequelae of early postnatal growth failure, there is a paucity of knowledge with regard to optimal perioperative nutrition practices for infants with cardiac conditions. The current perioperative nutrition paradigm emphasizes aggressive caloric delivery and enteral feeding algorithms for the term infant (132–135).

For the preterm cardiac population, best-practice guidelines remain elusive, resulting in clinical decisions largely driven by anecdotal and personal experiences, extrapolation from the term cardiac infant literature, and extrapolation from the preterm noncardiac infant literature. This clinical conundrum highlights the importance of a systematic review to identify best nutrition practices and gaps in research.

Research and data priorities

How does early preoperative enteral feeding affect postnatal intestinal mucosal development and do those effects sustain through the postoperative period?
What is the characterization of the gut microbiome before and after an infant has undergone cardiac surgery with cardiopulmonary bypass and perioperative antibiotics? How does early enteral feeding affect the microbiome in preterm infants who require neonatal cardiac surgery? Is the gut microbiome a potential target for therapeutic intervention in neonates who experience feeding intolerance after cardiac surgery?
What are the mechanisms of intestinal injury after exposure to cardiopulmonary bypass?
What is the best method for defining and confirming milk protein “allergy” or food protein–induced enterocolitis? What is the incidence of food protein–induced enterocolitis in infants with congenital heart disease? Are there associations between preoperative enteral feeding and postoperative food protein–induced enterocolitis?
What are the indications to transition from human milk to formula?

Topic 7: BPD

Rationale

BPD, also called chronic lung disease, is common in infants born prematurely. It is associated with oxidative injury to developing lungs. For the purposes of this project, the definition of BPD is oxygen supplementation being required at 36 wk corrected GA. With the increasing survival of ELBW infants, a “new BPD” with physiology and outcomes that are different from those of VLBW and larger infants has been described (136, 137). Fluid management, ventilation strategies, inflammation, infection, and conditionally unique nutrient requirements have been studied in the effort to optimize outcomes of infants with BPD (138, 139). Lung development and recovery from injury continues for years; nutrition strategies that support optimal recovery need to be addressed well after the infant leaves the NICU (136).

There is significant interplay between nutrition and risk or prevention of BPD. Early fluid management has been found to play a role in the complex physiologic processes that contribute to lung development and recovery from oxidative stress; once BPD develops, fluid restriction may affect the ability to deliver adequate nutrients for growth (140). Antioxidant and pro-oxidant nutrients have been evaluated in the development of BPD. One antioxidant example is vitamin A, which has been the focus of several studies in relation to lung development (39, 141–144). Inositol’s effect on pulmonary surfactant development and the incidence of BPD has been reviewed (145). The work of breathing for infants with BPD may increase energy needs (146), but the method of feeding may affect oxygen consumption (147, 148). Nutrition strategies that result in normal growth may limit the development of BPD (149). The ability to coordinate suck, swallowing, and breathing may be delayed in infants with chronic lung disease, potentially delaying the development of feeding skills, which in turn may affect growth.

Research and data priorities

Are there conditionally essential nutrient requirements for infants at risk of BPD: for example, inositol, DHA, calcium, phosphorus, or N-acetylcysteine?
Do the most immature ELBW infants have a different kind of lung disease, resulting in a different kind of BPD compared with infants born at a higher GA? If so, is there a need for different nutritional support and follow-up?
Are late-preterm infants (those born at 34–36 wk GA) at risk of BPD that can be affected by supplementation of antioxidants or other specialized nutrition support?
What is the maximum safe feeding concentration (calories/ounce) for premature infants with BPD?
What feeding strategies best promote the development of gastrointestinal motility and discourage gastroesophageal reflux with aspiration?
What is the optimal nutritional support for ex-preterm infants with BPD between term age and 2 y of age?
Does MOM need supplementation beyond the standard recommendations for term infants of the same corrected GA?

Topic 8: Retinopathy of prematurity

Rationale

Retinopathy of prematurity (ROP) is a disorder of the developing retina of preterm infants. In the most severe form, it can lead to blindness. Guidelines for screening and treatment of ROP have been published (150). Although prematurity and the use of oxygen are risk factors for ROP, nutrition/feeding strategies may play a protective role. Efforts to improve early energy intake along with the use of human milk, vitamin A supplementation, vitamin E supplementation, and intravenous fish oil have been shown to affect the rate of ROP (151–155).

Research and data priorities

Is DHA the effective component of intravenous fish-oil emulsions that reduces ROP?
Do antioxidants such as vitamins A and E protect infants from the development of ROP? If so, how much is needed for how long and at what age?

WG 4: CURRENT STANDARDS OF INFANT FEEDING

Chairs: Sharon Groh-Wargo, Michael Georgieff, and Tanis Fenton

Topic 1: For preterm AGA, large-for-gestational-age, or SGA infants, how is growth failure defined (weight, length, and occipitofrontal circumference in hospital, at discharge, and after discharge)? (See Text Box 13.)

Text Box 13 . WG 4: current standards of infant feeding topics.

1) For preterm AGA, LGA, or SGA infants, how is growth failure defined (weight, length, and occipitofrontal circumference in hospital, at discharge, and after discharge)?
2) Are AGA, LGA, or SGA preterm infants at equal or greater risk than similar term infants for the following after discharges or later in life: chronic noncommunicable diseases (e.g., obesity, diabetes, cardiovascular disease, metabolic syndrome) or poorer neurodevelopment?
3) In AGA, LGA, or SGA preterm infants, is growth pattern (i.e., weight, length, occipitofrontal circumference, weight gain velocity, linear growth velocity, body proportionality, and body composition) in the hospital, at discharge, and after discharge specifically associated with noncommunicable diseases, poorer neurodevelopment, or self-reported quality of life after discharge or later in life?
4) Among preterm infants, is feeding type (e.g., MOM, donor milk, formula, mixed, solids) and duration/time of introduction associated with risk of poor neurodevelopmental outcomes, noncommunicable diseases or atopic disease, impaired immune competency, or an altered microbiome after discharge or later in life?
5) Among preterm infants, is the amount of protein intake in the hospital and after discharge associated with noncommunicable diseases, differences in body stature and composition, or different neurodevelopmental outcomes?
6) Among preterm infants, which assessments of neurodevelopment in childhood (e.g., Bayley scales, Wechsler Preschool and Primary Scale of Intelligence) are valid (or sensitive and specific) measurements (i.e., predictive of long-term function)?
7) Is there evidence that levels/cutoffs of essential nutrient biomarkers (e.g., ferritin, prealbumin, phosphate, vitamin B-6) either are the same in preterm infants as those for term infants or change with GA, and is that change driven by postconceptional age or postnatal age?
8) Among preterm infants, are commonly used, clinically available measures (e.g., anthropometric measurements and serum biochemistry values) sensitive or specific “biomarkers” to assess nutritional status (i.e., sufficient, marginal, or deficient) during hospitalization and after discharge?
9) Among preterm infants, which nutritional biomarkers during hospitalization and after discharge are associated with neurodevelopment, bone health, and metabolic health?
10) Among preterm infants, is a specific microbiome, as may be influenced by type of feeding (e.g., MOM or banked human milk) or specific nutrients (e.g., LC-PUFAs, iron), associated with gut health and related functions in childhood or adulthood?
11) Does bone mineral content in hospital, at discharge, and at follow-up predict later body stature and bone mineralization as well as risks of osteoporosis in adulthood?

Rationale

The American Academy of Pediatrics recommends growth of preterm infants to “approximate the growth and composition of weight gain for a normal fetus” (44). The terms “growth failure” and EUGR in neonatology generally refer to weight-for-age <10th percentile at discharge from the NICU, at ∼36 wk. However, this categorization may not be appropriate after the usual extracellular fluid loss in the first days of life, which results in decreases in percentile/z score losses. This extracellular fluid loss puts many AGA infants in the <10th-percentile category. For infants to gain percentiles/z scores to re-cross to above the 10th percentile, many infants would need to gain weight faster than the fetal rate. In addition, EUGR is usually defined by weight-for-age status alone, which is not a recommended practice for any other age group (156, 157); weight-for-length status is recommended for infants older than term age. It has been suggested that length, head circumference, and parental stature (158) should also be considered for the assessment of weight status.

Whether it is more appropriate to reassign a new z score trajectory target once preterm infants decrease their extracellular volume in the postnatal environment, or whether they should return to their birth z score trajectory, remains a theoretical question. Therefore, the use of a weight-gain trajectory beginning after extracellular volume loss, with guidance provided by the size distribution of the fetus, is the most appropriate goal for preterm infants to follow until a more representative and validated growth pattern can supersede this.

The cutoffs for SGA and large-for-gestational-age (LGA) are usually defined as less than the 10th percentile and greater than the 90th percentile compared with the size of infants of the same GA at the time of birth, because being SGA has been associated with adverse outcomes (159). However, these cutoffs may be physiologically arbitrary, based on statistics (186) rather than health status, and do not assess whether the infants are small, appropriate, or large relative to their individual genetic potential. Studies have found that these designations are arbitrarily based on statistical cutoffs (160), and arbitrary designations are not sensitive or specific to actual growth variables, such as body fat content (161).

Data and research priorities

Is weight less than the 10th or 3rd percentiles at the time of hospital discharge associated with adverse health or neurodevelopmental outcomes once neurologic insults (including cerebral palsy, intraventricular hemorrhage, and periventricular leukomalacia) are controlled for?
Is infant weight recovery to their birth percentile or z score superior to maintaining at their post–initial-weight-loss percentile or z score, in terms of adverse health or neurodevelopmental outcomes, once neurologic insults (including cerebral palsy, intraventricular hemorrhage, and periventricular leukomalacia) are controlled for?
Should the definition of growth failure take into account the weight loss in the first few days of life and the resulting percentile/z score?
Should the definition of growth failure consider anthropometric measurements other than weight?

Topic 2: Are AGA, LGA, and SGA preterm infants at equal or greater risk than similar term infants for the following after discharges or later in life: chronic noncommunicable diseases (e.g., obesity, diabetes, cardiovascular disease, metabolic syndrome) or poorer neurodevelopment?

Rationale

Evidence from epidemiologic research exists to suggest that being born “too small or large” or “too early” is associated with greater risk of noncommunicable chronic diseases (NCDs) in later life (162), sometimes appearing as early as childhood. Such events are attributed to exposures to adverse factors or events in the fetal or early neonatal environment that may “program” the metabolic processes of the body to produce different phenotypes.

Whether a causal pathway exists between low birth weight, obesity, and NCDs later in life was recently questioned (163). The hypothesis may be militated by factors such as social determinants of health (163). Recent studies showed an inverse relation between social determinants of health and the prevalence of obesity in children (164). A recent systematic review that examined the relations between growth and neurodevelopment and metabolic outcomes found a lack of congruence between intervention and observational studies, which raises the possibility of confounding by other factors. (165).

With respect to preterm birth as a risk factor for NCDs, a measurable association between preterm birth and insulin sensitivity has been noted among infants and young children; however, in later years, the strength of this association weakens, and current body composition becomes the variable most strongly associated with insulin sensitivity (166).

Severe undergrowth or overgrowth in the early postnatal period in term IUGR infants was related to poorer neurodevelopment in childhood in a J-shaped relation by Pylipow et al. (167), whereas BMI was linearly related. This study supported the idea of developmental origins and critical periods in the neonatal period, and begs the question whether the same principles apply to preterm infants. Were there other factors, such as socioeconomic ones (163), that led to different feeding practices that could have accounted for these findings?

Data and research priorities

Longitudinal, prospective data on birth size and adverse health outcomes in different geographical regions followed to varying ages are needed.
Data that control for postnatal factors may influence the health outcomes of interest, such as quality of early diet (e.g., MOM, banked human milk, formula, and days with PN), social determinants of health, childhood diet, lifestyle, gender, etc., may be important.
Does control of current body size create a spurious relation between early factors (infant size and/or early growth) and NCD risk in later life?
Assessment of the role of confounding and effect modification of the associations between either size at birth or growth with NCDs by extraneous factors such as social determinants of health and neonatal morbidities, including neurologic insults, is needed.
Improved data on quality of dietary components as a potential modifier of selected outcomes, throughout the clinical care period beginning with PN and including exclusive use of MOM, combined MOM and fortifier, or banked human milk are needed.

Topic 3: In AGA, LGA, or SGA preterm infants, is growth pattern (i.e., weight, length, occipitofrontal circumference, weight gain velocity, linear growth velocity, body proportionality, and body composition) in the hospital, at discharge, or after discharge specifically associated with NCDs, poorer neurodevelopment, or self-reported quality of life after discharge or later in life?

Rationale

An association has been noted between early rapid growth of preterm infants and surrogate markers of later risk of cardiovascular disease or metabolic syndrome (168); however, several studies also controlled for current weight, which may have inadvertently created an association (165). In addition, one of the studies (168) failed to control for size for GA, which was strongly associated with the rapid weight gain in the first 2 wk of life. An association between small size for GA and social determinants of health has been well established (169, 170). Thus, it is entirely possible that adult-onset diseases are due to the many social determinants of health in addition to or rather than small gestational size. The ability to address the association between growth and later outcomes has a number of methodologic challenges, as outlined in Text Box 14.

Text Box 14 . Challenges in interpretation of data linking body composition to long-term outcomes.

Several different methods have been used to calculate growth velocity in preterm infants, and the method used influences the magnitude of the result (171).
Concern has been expressed with regard to the body composition of former preterm infants, upon reaching term-equivalent age. When compared with term infants, former preterm infants are distinguished by their
- ○ low quantity of lean body mass (42),
- ○ percentage of body fat (42), and
- ○ quantity of intra-abdominal fat
The percentage of body fat has been suggested as an indicator of poor outcomes and risk of adult-onset diseases. However, some studies show that
- ○ fat deposition may be an extrauterine effect and
- ○ the higher body fat of preterm infants relative to term infants is not maintained beyond early infancy because of the following:
  - ▪ preterm infants do not continue to increase their body fat (172) beyond discharge from the hospital, whereas term infants proceed to their increase body fat percentage through the first months after birth (8, 173) and
  - ▪ the difference in intra-abdominal fat between preterm and term infants is not maintained at 5–7 y of age (172).
Neonatal morbidity: higher intra-abdominal fat in preterm infants, compared with term infants at term age, has been associated with their degree of neonatal morbidity (172) and diminishes with age (172). Therefore, this intra-abdominal fat may be a transient effect, without lasting effects.

With specific regard to neurodevelopment, growth failure in the hospital and postdischarge has been associated with poorer subsequent neurodevelopment in preterm infants. However, more data are needed to determine the following: 1) which aspect of growth failure (stunting, wasting, etc.) is associated with which aspects of neurodevelopment [intelligence quotient (IQ), motor outcomes, processing] and 2) whether this differs if the growth failure includes an intrauterine component or is strictly postnatal. Moreover, little is known about when catch-up growth is too late to spare neurodevelopment, or whether overgrowth after undergrowth is a risk factor for preterm infants.

Data and research priorities

Define the most appropriate anthropometric measurement or measurements and methods to assess risk to neurodevelopment.
Define if there is a growth critical period (e.g., a period analogous to what is established for term infants relative to linear growth at birth and up to 1 y, but not afterward).
Longitudinal data are needed that link growth and body composition observed in the hospital, at discharge from the hospital, and in the first year of life to later health outcomes, with control for neurologic insults (cerebral palsy, intraventricular hemorrhage, and periventricular leukomalacia), size at birth (SGA, AGA, or LGA), and social determinants of health.
Randomized trials on nutrition interventions in the hospital and/or the first year of life that provide observations of disease risk later in life are needed.
Assess the role of confounding and effect modification of the associations between either size at birth or growth with adult-onset diseases by extraneous factors such as social determinants of health and neonatal morbidities, including neurologic insults.
Adapt current assessment tools and discover new assessment tools (e.g., , mid- arm circumference, arm muscle area, abdominal circumference, and ponderal index) to measure body composition, develop normative data sets, and relate measurements to relevant health outcomes.

Topic 4: Among preterm infants, is feeding type (e.g., MOM, donor milk, formula, mixed, solids) and duration/time of introduction associated with risk of poor neurodevelopmental outcomes, NCDs, or atopic disease, impaired immune competency, or an altered microbiome after discharge or later in life?

Rationale

Aside from its nutrient content, MOM is beneficial due to the presence of diverse bioactive components that confer enhanced digestive capability, immune protection, and immune competency. However, MOM is not always available, sufficiently available, or capable of meeting desirable somatic growth goals. As a result, other diets must be available as an alternative or supplement for preterm infants. In the preterm or critically ill newborn population, insufficient evidence exists as to the optimal delivery (timing, dose) of MOM to achieve its biological protections and enhanced health in these infants. In addition, the evidence is insufficient with regard to the risks:benefits of either the dietary alternatives to MOM (donor milk, formula, cow-milk–derived human-milk fortifiers, human-milk–derived human-milk fortifiers) or delivery strategies (timing, dose) with particular regard to achieving optimal short- and long-term health outcomes.

Health outcomes along the continuum of life and development that are potentially influenced by dietary type and delivery include neurodevelopment, metabolic health, immune competency, and atopic disease and establishment of the mucosal microbiome, which are reviewed in more detail in Text Box 15. The following highlights some of the challenges in making these connections.

Text Box 15 . Salient points about key factors affecting functional outcomes of interest.

Neurodevelopment

Begins at conception and is dependent on a web of factors that result in adequate cognitive functioning and emotion regulation (174).
Major changes occur during the fetal period, a time when neurodevelopment is at its most vulnerable (175).
Maternal dietary imbalances, nutrient deficiencies, physical inactivity, obesity, and excess weight gain during pregnancy are linked to problems with cognition and emotion regulation in offspring.
In the early postnatal period, exposure to MOM has associated benefits with such outcomes as cognitive functioning on the Bayley scales in both term and preterm infants.

Body composition and metabolic health

Multiple studies have shown a protective association between breastfeeding and
- ○ lower rates of childhood obesity [breastfeeding compared with no breastfeeding was associated with a 15% decrease (95% CI: 1%, 26%) in the odds of childhood overweight (176)] and
- ○ with reduced blood pressure (177).
Conversely, early introduction of solids has been associated with adiposity in toddlers in a birth cohort study in the United Kingdom (178) and the United States (179).
Another study found no association between breastfeeding and adiposity after controlling for family-based sociodemographic, maternal lifestyle, and childhood factors (180).

Immune competency and atopic disease

Exclusivity and duration of breastfeeding in infancy have been investigated in relation to outcomes of allergic disorders (181) and asthma (182).
Formula feeding and early introduction of solids have been associated with increased allergic disorders, although inconsistencies remain (183).
Recent studies and meta-analyses suggest that breastfeeding may protect against recurrent wheeze and asthma in later childhood (184–187).
Recent birth cohort analyses have not uniformly supported the late introduction of solids as protective against allergy, and there has been a signal for harm in some cohorts.
Delayed introduction of solids to 6 mo is associated with a greater risk of allergy, although reverse causality bias may account for this (188).

Microbiome

The infant gut microflora composition may play an important role in the development of immunity and responses to food intake.
The gut microbiota during infancy is influenced by mode of nutrient delivery, type of infant feeding, hospitalization, antibiotic use, type of delivery (vaginal or cesarean delivery), and prematurity (189).
Evidence exists that the microbiome of the pregnant mother is associated with metabolic changes in pregnancy, and its transfer to the newborn may influence the metabolic response of the developing infant. Thus, the distinct microbiome signature of the meconium of newborn infants can be altered by maternal metabolic and health status (190).
The presence of specific strains of maternal enteric bacteria in the meconium implies that the fetus may be exposed to microbes from the maternal gut in utero (191) and points to the maternal gut as a key player in the development of fetal gut microbiome.
Human milk
- ○ is a source of macro- and micronutrients (192); differences in human-milk composition have been reported due to maternal nutritional and metabolic status (193);
- ○ contains bacteria essential for infant gut colonization;
- ○ is a rich source of carbohydrates that act as prebiotics and promote a healthy neonatal gut microbiota; and
- ○ contains a number of nonnutritive factors that influence the ontogeny and health of the infant microbiome, most prominently human milk oligosaccharides.
- ○ Human milk oligosaccharides are of no nutritional value because they are indigestible by the infant; however, they play an essential role in driving microbial diversity and promoting the maturation of the microbiota (194, 195).

Although often compelling, the evidence with regard to the impact of nutrition and feeding practice and neurologic development is not consistent (196), perhaps due to confounding. Such studies are longitudinal, retrospective, or prospective cohort designs that have inherent limitations in factors such as recall bias (for retrospective studies), lack of adjustment for maternal diet in pregnancy, and detailed or frequent dietary assessment of infants/children or other potential confounding variables such as maternal IQ, social determinants of health, and quality of the home environment.

Similarly, studies that relate individual determinants to the development of abnormal metabolic factors, which later can become cardiovascular risk factors, have suggested that after birth, infant nutrition exposure (breastfeeding, formula-feeding, and the energy density of the feedings) is likely to have an impact and may influence the development of abnormal lipid and glucose concentrations and high blood pressure. However, limitations of all of the studies cited are that they were not conducted in only preterm infants and had limited control for potentially confounding variables.

With specific regard to nutrition and immune competence, few, if any, studies were conducted in preterm infants. Nutritive and nonnutritive components of human milk, formula, and solid foods and feeding practices may also shape the infant microbiome, programming growth rates and body composition, promoting differential microfloral colonization, promoting atopic disorders in children, and shaping behavioral responses to foods and eating (197).

Maternal gut dysbiosis may be a result of obesity, poor nutrition, or even stress; and this could ultimately affect the microbes the fetus is exposed to in utero, thus serving to alter fetal gut development. Such variation in fetal gut microbiome composition (and ultimately gut development) may lead to changes in long-term gut function and influence metabolic compromise. Moreover, the rapid colonization initiated by bacteria and substances such as human milk oligosaccharides activates the immune system and initiates host protection against pathogens. Breastfed infants experience fewer infections, perhaps due to increased production of antimicrobial compounds, and decreased intestinal permeability as a result of increased mucin production (198).

Because the nutrients in human milk are used as substrates by the gut microbiota, they may also play a critical role in the ontogeny of the gut microbiome, perhaps by providing selective pressure on the gut microbes. Therefore, changes in maternal nutrition could change the nutritional content of MOM, as well as possibly the milk microbiota, which would directly affect neonatal gut colonization.

Probiotics of various sources have been added to infant formulas fed to preterm infants. The effectiveness of such sources of prebiotics in the prevention of NEC has been evaluated in several studies, with mixed results. The systematic reviews on this topic are not conclusive, which is likely due to the considerable variation in the type and amounts of probiotics tested and heterogeneity among the studies (199). The long-term impact of microbiome diversity in early life to health at older ages has not, to our knowledge, been studied nor have studies of the microbiome focused on preterm infants.

Data and research priorities

Assess the role of confounding and effect modification of the associations between breastfeeding with neurodevelopment (with maternal IQ and sociodemographic and lifestyle factors); metabolic health risks of obesity, diabetes, cardiovascular disease, and metabolic syndrome; risk of atopic disease; immune competency; and the microbiome (with extraneous factors such as social determinants of health and lifestyle-related factors).
Establish evidence-based dietary practices in the initiation and delivery of MOM in preterm or critically ill newborn infants.
Establish evidence-based dietary practices in the absence of sufficient MOM.
Establish evidence-based practices on nutrient fortification of MOM and donor milk.
Longitudinal cohort studies or randomized clinical trials of EN practices to determine the relative risk in short- and long-term health outcomes as a function of dietary exposures are needed.
Identify early biomarkers of nutritional exposures linked to health outcomes. These markers will inform nutritional efficacy in a timely manner and with fewer subjects, thus minimizing the costs and intensiveness of large clinical trials of nutritional intervention.

Topic 5: Among preterm infants, is the amount of protein intake in the hospital and after discharge associated with NCDs, differences in body stature and composition, or different neurodevelopmental outcomes?

Rationale

On the basis of estimates of in utero protein accretion and losses and correction for the inefficiency in conversion of dietary protein to body protein, Ziegler (51) estimated that an enteral protein intake of 4.0 and 3.9 g · kg⁻¹ · d⁻¹ will meet the average requirement of preterm infants weighing ≤1200 and 1200–1500 g, respectively. Although there are few empirically derived data for infants weighing <1200 g on which to confirm these estimates, protein intakes of 3.0–3.4 g · kg⁻¹ · d⁻¹ for infants who weigh >1200 g were shown to produce daily weight gains similar to fetal accretion rates, with higher intakes of 3.7–4.2 g · kg⁻¹ · d⁻¹ needed to support catch-up growth. Some examples of studies that attempted to address the possibility for deviation from this recommendation are highlighted in Text Box 16.

Text Box 16 . Studies evaluating the impact of protein intake in preterm infants.

Two recent studies of very preterm infants fed human milk showed improved growth when fortified to provide 4.2 and 3.5 g · kg⁻¹ · d⁻¹ at full enteral feedings (200, 201).
Kuschel and Harding (79), in a Cochrane review of 4 earlier trials in infants fed human milk, reported that the addition of a protein supplement at ∼1.5 g · kg⁻¹ · d⁻¹ to human milk resulted in small but significant increases in weight gain and linear and head growth.
Biasini et al. (202) reported improved growth and early neurodevelopment in human-milk–fed infants weighing <1250 g who were fed 4.8 g protein · kg⁻¹ · d⁻¹ compared with 3.5 g protein · kg⁻¹ · d⁻¹.
Fenton et al. (203), in a recent Cochrane review of randomized controlled trials, concluded that protein intakes in the range of 3.0 to <4.0 g · kg⁻¹ · d⁻¹ from formula accelerated weight gain compared with intakes <3.0 g · kg⁻¹ · d⁻¹. However, there was insufficient evidence to make specific recommendations with regard to protein intakes >4.0 g · kg⁻¹ · d⁻¹ and limited information on long-term outcomes such as neurodevelopment.
An older published study (204) is often cited as reason for concern over “high” protein intake in VLBW infants. In this study,
- ○ preterm infants were fed bovine-based formula (casein dominant) to provide 3.0–3.6 or 6.0–7.2 g protein · kg⁻¹ · d⁻¹ during initial hospitalization;
- ○ at 3 y, infants born weighing <1300 g and fed the higher protein–containing formula had lower IQ scores; and
- ○ experts in the field have postulated that it was the mix of amino acids supplied and not the absolute amount of protein fed that was explanatory; however, this emphasizes the need for caution (205).

There is an absence of data on the most appropriate protein intake for preterm infants after discharge. Young et al. (65) in their Cochrane Review concluded that there is an inconsistent effect on growth to 12–18 mo from feeding an energy (72–74 kcal/100 mL) and multinutrient postdischarge formula containing 1.8–1.9 g/100 protein compared with a standard term formula (66–68 kcal and 1.4–1.7 g/100 mL) to preterm infants. However, there was some evidence of an advantage of feeding preterm formula containing 2.0–2.4 g protein/100 mL and 80 kcal/100 mL after discharge. It is important to note that many trials in this review excluded infants with significant morbidities or who were not growing well at discharge. Clinicians report that they are most concerned with the growth of predominantly human-milk–fed infants early after discharge. However, few have systematically examined whether a proactive approach to nutrient fortification of human milk might be appropriate. Of the 2 randomized controlled trials available, it appears that nutrient fortification of infants after discharge can be done without significantly influencing breastfeeding, at least in the short term (47). Future studies should focus on predominantly human-milk–fed infants instead of those in whom only a minor proportion of total enteral feedings are from human milk. O’Connor and colleagues showed in a small sample of infants that fortification of half of the human milk fed to predominantly human-milk–fed infants to ∼80 kcal and 2.2 protein/100 mL for 12 wk after discharge resulted in better growth, supported bone mineralization, and improved visual development compared with infants discharged to home on human milk alone (47, 206, 207).

Data and research priorities

Do protein intakes in preterm infants (>4.2 g · kg⁻¹ · d⁻¹) during initial hospitalization result in improved growth, neurodevelopment and in the absence of adverse outcomes?
Establish the ideal amount of protein (and energy, calcium, phosphorus, and zinc) that should be added to human milk after discharge to support growth, bone mineralization, and neurodevelopment of preterm infants after discharge.
Determine which specific subgroups of infants should be targeted for nutrient intervention after discharge on the basis of tools (biomarkers) that assess short- and long-term health outcomes.
Develop tools that assess the longer term impact of higher amounts of protein on obesity and metabolic and cardiovascular outcomes.

Topic 6: Among preterm infants, which assessments of neurodevelopment in childhood are valid (or sensitive and specific) measurements and predictive of long-term function (e.g., Bayley scales, Wechsler Preschool and Primary Scale of Intelligence)?

Rationale

Most studies of preterm infant neurodevelopmental outcomes end at 18–22 mo. The endpoint often coincides with the conclusion of routine clinical follow-up for most VLBW infants and potential attrition of study samples. The assessments are typically general tests of infant performance, because that is what can most easily be performed across multiple sites. This approach is likely misguided for 2 reasons: 1) the predictive value of general tests of infant performance (e.g., the Bayley scales) conducted at <2 y for IQ at 8 y is poor (208) and 2) nutrient effects on brain development are relatively subtle (compared with intracranial hemorrhage or birth asphyxia) and may not be demonstrable on generalized testing (209). Conversely, some previous studies have ascribed larger-than-likely effects of growth failure or nutrient deficits (on the basis of the known biology of the nutrients) on general tests of function (suggesting confounding variables such as degree of illness) (210). “Signature” outcomes based on the biology of the nutrient effect on the brain are highly desirable (e.g., if a nutrient affects myelination, the speed of electrical processing, such as evoked responses, should be assessed).

Data and research priorities

Define the predictability relation between neurodevelopmental assessments used in early childhood (e.g., Bayley-III at 24 mo corrected age) and those assessments used at school age and in adolescence.
Develop and test the sensitivity and specificity of new tests of brain performance that can be applied early in life and that index nutrient-sensitive brain domains. Define their relation to later school-age performance.

Topic 7: Is there evidence that levels/cutoffs of essential nutrient biomarkers (e.g., ferritin, prealbumin, phosphate, vitamin B-6) either are the same in preterm infants as those for term infants or change with GA, and is that change driven by postconceptional age or postnatal age?

Rationale

The American Academy of Pediatrics (44) recommends that preterm infants grow similarly to the fetus and maintain fetal concentrations in blood and tissues. Cord blood sampling provides an accessible method to assess preterm fetal cord blood. Phosphate, magnesium, and alkaline phosphatase in cord blood serum decrease with GA; calcium increases with GA (211).

Phosphate offers an example of the potential effects of GA and clinical course/care on biomarker concentrations and interpretation. Although most of the literature on phosphate for preterm infants emphasizes phosphate’s role in bone mineralization, phosphate also has roles in glucose metabolism. Serum phosphate decreases in response to infused glucose in adults (212). Furthermore, low serum phosphate may limit clinical stability, because it is required for tissue sensitivity to insulin in adults (213), as well as glucose-induced insulin secretion in rats (214).

Appropriate standards for concentrations of clinical nutritional biomarkers are necessary to provide useful information about nutrient status in preterm infants. Many nutrients have different reference values during the neonatal period compared with adulthood. Nutrient concentrations in preterm neonates differ from those in term infants because of reduced stores (e.g., incomplete iron or calcium loading during the missed third trimester), immature enzymatic pathways of either synthesis or breakdown (e.g., vitamin B-6, DHA), or reduced protein (e.g., prealbumin, retinol-binding protein) synthesis. Standard curves for some (e.g., ferritin, prealbumin, transferrin), but not all, biomarkers have been generated in preterm infants from cross-sectional cord blood data gathered at various GAs. It is unclear whether biomarker concentrations are driven by postconceptional age, postnatal age, or both.

Data and research priorities

Establish GA curves for all biomarkers of all nutrients provided to preterm infants.
Prioritize by starting with nutrients that have biggest impact on long-term health (including neurodevelopment) and with nutrients that are at greatest risk for deficit or overload in preterm infants.
Link biomarker values to physiologically relevant outcomes, both acutely (status) and long term.

Topic 8: Among preterm infants, are commonly used clinically available measures (e.g., anthropometric measurements and serum biochemistry values) sensitive or specific to assess nutritional status (i.e., sufficient, marginal, or deficient) during hospitalization and after discharge?

Rationale

The validity of whether a biomarker indexes the nutrient of interest may be affected by other nutrient status or nonnutritional factors—for example, energy (calorie) adequacy, maturity, inflammation, or renal status. For example, alkaline phosphatase and serum phosphorus have been used as markers for inadequate intakes of calcium and phosphorus as well as osteopenia in preterm infants, although not all studies agree on their importance (166, 215, 216). Similarly, blood urea nitrogen has been used as an indicator of protein excess in preterm infants; however, a cutoff to indicate protein excess has not been identified. Blood urea nitrogen is also associated with postnatal age and renal function (217).

The adequacy of nutrient status is generally assessed by comparing a patient’s value with reference or standard curves. Abnormal nutrient status is determined by values that lie outside of population statistical cutoffs (e.g., 5th and 95th percentiles). Although these cutoffs may index either exposure or abnormalities in the physiology of the given nutrient, they do not necessarily relate to functionally relevant health endpoints (e.g., neurodevelopment, obesity, metabolic health). The fact that a measure may indicate a given status does not in and of itself reflect the cause of that status (i.e., due to exposure or a physiologic response to any of a myriad of possible factors). Nor does it necessarily reflect the functional significance. Thus, for preterm infants, it will be necessary to develop data to support the interpretation of a given value as reflecting either exposure or status (adequate, marginal, deficient) compared with a functionally relevant physiologic response.

Data and research priorities

Link biomarker concentrations to physiologically relevant outcomes, both acutely and long term.
Define the relation between clinically available chemistries (blood, urine) or biomarkers and appropriate growth (e.g., between the 10th and 90th percentiles), growth failure (e.g., <10th percentile), and excessive growth (e.g., > 90th percentile) during the NICU hospitalization and after discharge for AGA, LGA, and SGA infants or weight-for-height and length-for-age and the 2nd or 98th percentiles as per the CDC 2013 guidelines (156)
Define the “value” (e.g., positive predictive value, negative predictive value) of clinically available chemistries (blood, urine) or biomarkers during hospitalization and such measures of health status as hematocrit or bone mineral status or of long-term morbidities such as BPD, neurodevelopment, and metabolic and bone health.

Topic 9: Among preterm infants, which nutritional biomarkers during hospitalization and after discharge are associated with neurodevelopment, bone health, and metabolic health?

Rationale

Surrogate intermediary measures of risk of adverse outcomes of neurodevelopment and bone and metabolic health are required to identify infants at risk of adverse health outcomes and to assess the effects of nutritional interventions.

Data and research priorities

Any biomarker whose relation to long-term outcomes has not been identified by the above systematic review questions should be investigated. Priority should be given to nutrients that, in preclinical models or from data from term infants, are postulated to affect a clinically relevant outcome, including chronic lung disease, neurodevelopment, metabolic health, risk of cancer, and bone health.
Identify critical periods for these nutrients (i.e., when is normalizing a previously abnormal nutritional state too late to rescue the desired phenotype to be like the child born at term)

Topic 10: Among preterm infants, is a specific microbiome, as may be influenced by either type of feeding (e.g., MOM or banked human milk) or specific nutrients (e.g., LC-PUFAs, iron), associated with gut health and related functions in childhood or adulthood?

Rationale

The development of the intestinal tract is vital for infant health because it is the largest defense barrier and contributes significantly to the immune system. An understanding of the role of nutrition in these processes will define efficacy of nutritional interventions and provide early markers of nutritional outcomes.

Altered intestinal development (including the microbiome) and barrier function have been linked to NEC (see WG 3 section) and in immune-mediated diseases in later childhood and adulthood, including atopic disease (asthma), autism, celiac disease, inflammatory bowel disease, and obesity. Aspects of intestinal development that may reflect infant and later adult outcomes include the microbiome, intestinal barrier function, Paneth cells and defensin production/function, and goblet cells and mucin production/function.

As highlighted in WG 4 “Topic 4,” early delivery results in the cessation of maternally derived and amniotic nutrients that facilitate intestinal development. Postnatally, breastfed infants experience fewer infections, due at least in part to increased production of antimicrobial compounds, and decreased intestinal permeability as a result of increased mucin production. The impact of varying infant gut microbiota on gut health in infancy, childhood, or adulthood has not been well studied in preterm infants. Although WG 4 topic 4 highlighted the implications of feeding regimen on the development and function of the gut microbiome, this topic focuses on the need to further understand the function and short-/long-term health implications of the gut microbiome.

Data and research priorities

Little, if any, data exist on the relation of maternal factors, maternal microbiota, and infant microbiota and whether such associations convey any health benefits to preterm infants in early life or later childhood.
Establish a set of intestinal development markers that are critical for infant health and, when aberrant, predict disease. These markers will serve as outcomes of nutritional efficacy.
Establish evidence-based nutritional practices that are linked to the enhancement of specific markers of intestinal development.
Animal to infant (translational) studies are needed to define mechanistic pathways of intestinal development that are modulated by diet/specific nutrients and ultimately guide future trials and clinical practice.

Topic 11: Does bone mineral content in the hospital, at discharge, and at follow-up predict later body stature and bone mineralization as well as risks of osteoporosis in adulthood?

Rationale

Preterm infants are known to have lower nutrient reserves and increased nutritional requirements for all nutrients including minerals and vitamins important to bone health. PN, human milk, and standard infant formulas do not meet nutritional needs, so fortified human milk and preterm formulas with higher nutrient density are routinely fed. There is some evidence that improved early nutrition improves bone mineral content in early infancy, although the evidence is conflicting (218–222). Bone mineral content can be measured by dual-energy X-ray absorptiometry but requires careful attention to detail (219, 223, 224).

Data and research priorities

Prospective data are needed on the relation of nutritional intake from various intravenous and enteral sources and bone mineral content followed longitudinally to various ages.
Randomized trials on nutrition interventions in the hospital and/or the first year of life that provide observations of risk of osteoporosis later in life are needed.

The members of the Pre-B Consultative Working Groups and their affiliations are listed in Supplemental Material.

Supplementary Material

ajcn117309SupplementaryData1

Click here for additional data file.^{(30.8KB, docx)}

Acknowledgments

We acknowledge the contributions of the following Academy of Nutrition and Dietetics’ staff members who assisted throughout the process and in particular supported the WGs in their report-development process and/or in the revision of this manuscript: Deepa Handu, Taylor Wolfram, Lisa Moloney, and Mujahed Kahn. Special acknowledgment goes to Rosa Hand for her exemplary service and support in all aspects of manuscript development, submission, and revision. We thank Kripa Raghavan and Alexandra Porter for their role in support of the Pre-B process and meeting. We also thank Dennis Bier, Director of USDA/Agricultural Research Service Children’s Nutrition Center and his staff for hosting and support of the All-hands Meeting at Baylor University.

The authors’ responsibilities were as follows—DJR and ALS: conceived of the project and the project plan and provided oversight; and SEC, IG, DA, WWH, SR, JN, MKG, SG-W, and TRF: participated in the WG discussions, coordinated the drafting of their respective WG reports, and participated in all aspects of manuscript review and revision. None of the authors had any conflicts of interest to declare.

ABBREVIATIONS

AA: arachidonic acid
AGA: appropriate for gestational age
BPD: bronchopulmonary dysplasia
ELBW: extremely low birth weight
EN: enteral nutrition
EUGR: extrauterine growth restriction
FGF19: fibroblast growth factor 19
FXR: farsenoid X receptor
GA: gestational age
GLP-2: glucagon-like peptide 2
IFALD: intestinal failure–associated liver disease
IQ: intelligence quotient
IUGR: intrauterine growth restriction
LC: long-chain
LGA: large for gestational age
MOM: mother’s own milk
NCD: noncommunicable disease
NEC: necrotizing enterocolitis
NICU: neonatal intensive care unit
PDA: patent ductus arteriosus
PN: parenteral nutrition
PNALD: parenteral nutrition–associated liver disease
ROP: retinopathy of prematurity
SBS: short bowel syndrome
SGA: small for gestational age
VLBW: very low birth weight
WG: working group

FOOTNOTES

Presented at the meeting “Evaluating the Evidence to Support Guidelines for the Nutritional Care of Preterm Infants: The Pre-B Project” held at the USDA/Agricultural Research Service Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, 31 July–1 August 2014.

Travel support for the Baylor meeting was provided by the Academy of Nutrition and Dietetics, the American Society for Parenteral and Enteral Nutrition, the American Academy of Pediatrics, ASN, the International Formula Council, and the National Institute of Child Development and Health and Division of Nutrition Research Coordination at the NIH.

The views presented here are those of the authors and not necessarily the NIH.

¹⁶

Abbreviations used: AA, arachidonic acid; AGA, appropriate for gestational age; BPD, bronchopulmonary dysplasia; ELBW, extremely low birth weight; EN, enteral nutrition; EUGR, extrauterine growth restriction; FGF19, fibroblast growth factor 19; FXR, farsenoid X receptor; GA, gestational age; GLP-2, glucagon-like peptide 2; IFALD, intestinal failure–associated liver disease; IQ, intelligence quotient; IUGR, intrauterine growth restriction; LC, long-chain; LGA, large for gestational age; MOM, mother’s own milk; NCD, noncommunicable disease; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; PN, parenteral nutrition; PNALD, parenteral nutrition–associated liver disease; ROP, retinopathy of prematurity; SBS, short bowel syndrome; SGA, small for gestational age; VLBW, very low birth weight; WG, working group.

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PERMALINK

Working group reports: evaluation of the evidence to support practice guidelines for nutritional care of preterm infants—the Pre-B Project1–4

Daniel J Raiten

Alison L Steiber

Susan E Carlson

Ian Griffin

Diane Anderson

William W Hay Jr

Sandra Robins

Josef Neu

Michael K Georgieff

Sharon Groh-Wargo

Tanis R Fenton

ABSTRACT

INTRODUCTION

Text Box 1 . Pre-B thematic WGs.

WG 1: Nutrient Specifications for Preterm Infants

WG 2: Clinical/Practical Issues in Enteral Feeding of Preterm Infants

WG 3: Gastrointestinal and Surgical Issues

WG 4: Current Standards of Infant Feeding

WG 1: NUTRIENT SPECIFICATIONS

Topic 1: What is the appropriate biological frame of reference for establishing the nutrient needs of parenterally or enterally fed preterm infants? (See Text Box 2.)

Text Box 2 . WG 1: nutrient specification topics.

Rationale

Suggested systematic review questions

Data and research priorities

Topic 2: What nutrients are conditionally essential in preterm infants?

Rationale

Text Box 3 . Developmentally sensitive, potentially conditionally essential nutrients.

Suggested systematic review questions

Data and research priorities

Topic 3: What factors affect nutrient requirements in preterm infants (before hospital discharge)?

Rationale

GA

SGA and IUGR status

Route and type of nutrient administration

Growth rate

Maternal nutritional status and comorbidities

Suggested systematic review questions

Data and research priorities

Topic 4: How do nutrient requirements of otherwise healthy, formerly preterm infants differ from those of term infants of the same corrected age after hospital discharge?

Rationale

Suggested systematic review questions

Data and research priorities

Topic 5: What are the pre- and postnatal modifiers of nutrient requirements of formerly preterm infants and how do these resulting requirements differ from those of term infants of the same corrected age after hospital discharge?

Rationale

Text Box 4 . Previous exposures that might affect postdischarge nutritional needs.

Suggested systematic review questions

Data and research priorities

Topic 6: Can we individualize nutrient intakes in preterm infants, and if so, how?

Rationale

TABLE 1.

Suggested systematic review questions

Data and research priorities

WG 2: CLINICAL/PRACTICAL ISSUES IN ENTERAL FEEDING

Topic 1: Impact and importance of trophic feedings for VLBW infants (see Text Box 5)

Text Box 5 . WG 2: clinical/practice issues in enteral feeding topics.

Rationale

Suggested systematic review questions

Data and research priorities

Topic 2: Feeding—what, when, and how?

Rationale

Suggested systematic review questions

Data and research priorities

Topic 3: Feeding intolerance

Rationale

Text Box 6 . Factors contributing to feeding intolerance.

Suggested systematic review questions

Data and research priorities

Topic 4: Importance of developmental, behavioral, and environmental factors in oral feeding of preterm infants

Rationale

Text Box 7 . Oral feeding interventions studied to date.

Suggested systematic review questions

Data and research priorities

Topic 5: Fortification of enteral feedings

Rationale

Suggested systematic review questions

Data and research priorities

Topic 6: Impact of support and education of care providers with regard to enteral feeding

Rationale

Working group reports: evaluation of the evidence to support practice guidelines for nutritional care of preterm infants—the Pre-B Project^¹^–^⁴