Approach to enteral nutrition in the premature infant

INTRODUCTION — Premature infants have greater nutritional needs in the neonatal period than at any other time of their lives. The nutrient needs are inherently high at this stage of development to match the high rates of nutrient deposition achieved by infants in utero [1]. In addition, they often have medical conditions that increase their metabolic energy requirements, including hypotension, hypoxia, acidosis, infection, and surgery. Additional impediments to growth are physiologic immaturity of the gastrointestinal tract, including decreased gastrointestinal motility and reduced intestinal enzyme activity, and therapies such as corticosteroids.

Early and adequate nutritional support is needed to achieve appropriate rates of weight gain, which are almost twice that of a term infant, and to avoid postnatal growth failure [2,3]. Despite intensive nutritional strategies for premature infants, growth failure remains a major problem [4]. However, intensive feeding strategies must be balanced with potential risks. As an example, while early initiation of enteral feedings has been shown to benefit premature infants, very rapid advancements of enteral feedings may result in feeding intolerance or necrotizing enterocolitis (NEC). In addition, it is important to choose feeding practices associated with improved outcomes for premature infants, such as the use of human milk rather than formula [5,6]. In some cases, when it is not possible to provide full enteral feedings due to an infant's medical condition, it may be necessary to provide partial or total parenteral nutrition. (See "Parenteral nutrition in premature infants".)

Issues related to enteral nutrition in the premature infant are reviewed here. The composition of the feeding, including human milk, formula, and human milk fortifiers (HMFs), is discussed elsewhere. (See "Nutritional composition of human milk and preterm formula for the premature infant" and "Human milk feeding and fortification of human milk for premature infants".)

NUTRITIONAL GOALS — The nutritional goal for premature infants is to achieve rates of growth and nutrient accretion that match those achieved by infants of similar gestational age in utero, while avoiding complications that can be caused by nutritional therapies.

Intrauterine growth and nutrient accretion — Several different growth standards are available for tracking growth of premature infants. These standards are designed to reflect intrauterine growth rates, which are generally not attained during extrauterine growth of premature infants. The relative merits of these growth charts for monitoring growth in premature infants are discussed separately. (See "Growth management in preterm infants", section on 'Normative growth data'.)

Rates of intrauterine nutrient accretion during the third trimester have been estimated from chemical analysis of fetal cadavers [7,8]. Data for several minerals have been corroborated by contemporary noninvasive neutron activation techniques [9].

Energy requirements — The energy (caloric) requirements to achieve optimal growth are calculated from the estimated resting energy expenditure (REE) plus the energy requirements for activity (including feeding), thermoregulation, fecal loss, growth, and chronic medical conditions (table 1). In term infants between 8 to 63 days of postnatal age, REE varies from 49 to 60 kcal/kg/day [10].

For premature infants, the clinical condition and activities dictate the daily energy requirements, as follows:

●For enterally fed premature infants, the average daily energy requirements are 110 to 130 kcal/kg/day [11,12]

●For parenterally fed premature infants, the energy requirements are lower (90 to 100 kcal/kg/day for infants <1500 g) because of less fecal energy loss, fewer episodes of cold stress, and somewhat less activity [12]

●For infants with chronic illness, such as bronchopulmonary dysplasia, energy requirements may be higher due to increased REE, activity, and, possibly, fecal losses [13,14]

Nutrient requirements — Suggested enteral intakes for other nutrients are listed in the table (table 2); the requirements for parenterally given nutrients may differ. The appropriate enteral intake for a particular nutrient can be estimated from established rates of intrauterine accretion, plus estimation of daily losses, divided by the bioavailability (net absorption) of the nutrient [15].

As an example, this approach can be used to estimate calcium (Ca) requirements as follows:

●Intrauterine accretion rate (bone deposition) – 105 mg/kg/day

●Urinary losses – 5 mg/kg/day

●Cutaneous losses – 2 mg/kg/day

●Subtotal net Ca requirement – 112 mg/kg/day

●Net absorption of dietary Ca – 50 percent

●Total Ca intake to meet requirement – 224 mg/kg/day

Clinical conditions will affect absorption of nutrients. For example, absorption of Ca and phosphorus is affected by postnatal age and intake of lactose, fat, and vitamin D. (See "Management of bone health in preterm infants", section on 'Enteral nutrition'.)

NUTRITIONAL ASSESSMENT AND MONITORING — Nutritional assessment of the premature infant requires determination of the daily energy and nutrient requirements for optimal growth. This assessment requires a knowledge of nutritional biochemistry and neonatal medical conditions.

The infant's progress is then monitored by the rate of growth and daily assessments of fluid, energy, and nutrient intake. The nutrient targets are then readjusted if the target growth rate is not met. The dietitian is a key resource to ensure an intake that meets nutrition goals and is compatible with the infant's medical condition.

Rate of growth — Growth is monitored by serial measurements of weight, length, and head circumference and compared with growth standards [16-19]:

●Weight is assessed daily, targeting a minimum increment of 15 to 20 g/kg/day from 23 to 36 weeks gestation [16,20]. Traditionally, once the infant reaches 2 kg body weight, the goal can be a weight gain of 20 to 30 g/day.

●Length is assessed weekly, preferably using a length board, targeting an average increment of 1 cm per week.

●Head circumference is assessed weekly, targeting an average increment of 1 cm per week.

Growth parameters are charted on sex-specific growth curves for premature infants. We attempt to keep infants growing at rates above the 10^th percentile on these charts whenever possible, but steady growth along lower percentiles is also acceptable. The charts are helpful for monitoring growth, and computation of the weekly rate of growth is also important. Available growth standards for premature infants are discussed separately. (See "Growth management in preterm infants", section on 'Normative growth data'.)

Laboratory monitoring — The nutritional status of the very low birth weight (VLBW) infant (birth weight ≤1500 g) is monitored by serial evaluations of biochemical indices.

At our institution, we perform these measurements, as indicated in the table (table 3), until the values are in the target range and stable. Other neonatal intensive care units (NICUs) may monitor more (or less) frequently. These assessments include the following:

●Hemoglobin is monitored to assess for anemia, which may affect rate of growth. However, in the NICU, anemia generally is not caused by nutritional deficiencies. (See "Anemia of prematurity (AOP)".)

●Bone mineral status is assessed by routine laboratory monitoring of serum phosphorus and alkaline phosphatase activity; a protocol for monitoring is summarized in the algorithm (algorithm 1) and discussed in more detail separately. (See "Management of bone health in preterm infants", section on 'Laboratory monitoring'.)

●Protein status is assessed by monitoring levels of blood urea nitrogen (BUN). BUN >10 mg/dL suggests protein sufficiency [21]. It remains uncertain whether high BUN values (eg, BUN >50 mg/dL, with normal renal function) are a clinically useful marker for excessive protein intake. Serum albumin reflects long-term protein intake (half-life of 21 days), so it is usually not helpful as a marker of protein status in the NICU.

●Electrolytes (serum sodium, chloride, and bicarbonate) are typically measured at least once after the transition from parenteral nutrition to full fortified feeds and more often in infants who receive diuretics, who are fed unfortified human milk, whose intakes are limited, or who have slow growth. Infants with abnormal results may require more frequent monitoring and potentially supplementation.

●Zinc and copper may be measured in infants with unusual intestinal losses, such as those with enterostomies or short bowel syndrome. These measurements are not needed in premature infants without these conditions. (See "Chronic complications of short bowel syndrome in children", section on 'Nutritional complications'.)

The trend in biochemical indices may be more reflective of nutritional status than isolated values. Infants who are receiving parenteral nutrition require more frequent monitoring, especially of electrolytes and glucose. (See "Parenteral nutrition in premature infants", section on 'Monitoring'.)

INFANTS REQUIRING TUBE FEEDING — Infants weighing ≤1800 g birth weight (usually ≤32 weeks gestation) typically require tube feeding until they are sufficiently mature to feed directly from the breast or artificial nipple. The approach depends upon the infant's maturity and clinical condition. Our general approach is outlined below, followed by sections providing the rationale.

Oral feeding should be initiated when the infant demonstrates signs of readiness, which typically occurs when the tube-fed infant is between 32 and 34 weeks gestational age. (See 'Infants who can feed orally' below.)

Overview of initiation and advancement of feeds — All neonatal intensive care units (NICUs) should adopt a protocol to ensure prompt initiation and advancement of feeds; the details of timing, composition, and rate of advancement vary. Our NICU's protocol for stable infants requiring tube feedings (typically ≤1800 g birth weight) is outlined below (table 4). Infants with significant feeding intolerance or other medical problems may progress more slowly.

●Colostrum – We give colostrum to infants within the first six hours of life, once a mother is able to express colostrum. We provide 0.2 mL of expressed colostrum every three hours to the buccal mucosa using a small syringe (0.1 mL to each side of buccal mucosa). We use a syringe for milk delivery, based on a study that showed that this dose and delivery method are associated with increased absorption of selective immunoglobulin A (sIgA) and lactoferrin [22]. Other NICUs use a swab to the oropharyngeal mucosa with expressed colostrum every three hours. We continue to administer mother's milk via syringe to the buccal mucosa until the infant is taking full oral feeds. Oropharyngeal colostrum provides immune benefits to the infant as well as an early initiation of maternal milk expression, which favors overall milk production [23-25].

●Parenteral nutrition – For infants ≤1500 g birth weight, "starter" parenteral nutrition (glucose, amino acids, calcium [Ca], and lipids) is given when feasible to supply part of the energy and nutrient needs. Other high-risk infants such as those with congenital bowel anomalies, congenital heart disease, or congenital diaphragmatic hernia may also require early parenteral nutrition. (See "Parenteral nutrition in premature infants", section on 'Parenteral nutritional requirements'.)

●Trophic feeds – For all infants, small-volume ("trophic") feeds are started within the first day of life and ideally within six hours of life if medically stable.

•For most infants, the feeds are given via oropharyngeal or nasogastric tube at 20 mL/kg/day, divided into boluses given every three hours. For very immature infants (22 to 24 weeks gestational age), most NICUs use a more cautious approach. (See 'Trophic feeds' below and 'Intermittent versus continuous' below.)

•Feeding is begun with unfortified mother's own milk. If mother's own milk is not available, pasteurized donor human milk is recommended for infants ≤1500 g birth weight [5]. For infants >1500 g birth weight, formula designed for a premature infant may be used if mother's own milk is unavailable [12,26]. (See 'Milk strength and content' below.)

•Trophic feeds may be given to infants who have an umbilical artery catheter (UAC) and an umbilical venous catheter in place or are undergoing medical treatment for patent ductus arteriosus (PDA). (See 'Adjustment for concurrent medical conditions' below.)

●Advancement of feeds – Feeding volume is advanced gradually. As feeds are advanced, a human milk fortifier (HMF) is added to boost the nutrient intake. In our NICU, the timing of advancement and fortification depends upon the infant's birth weight; our protocol is outlined in the tables (table 5A-B). The rate of advancement also depends on feeding tolerance, which is assessed by serial monitoring of clinical signs and symptoms. (See 'Rate of volume increase' below and 'Fortification of feeds' below and 'Feeding intolerance' below.)

As enteral feeds are advanced, the parenteral nutrition solution is gradually decreased. The parenteral nutrition is discontinued when the enteral feeds reach 100 mL/kg/day.

●Target volume – The target volume for feeds is 160 mL/kg/day of fortified human milk. (See 'Target volume' below.)

Milk strength and content — Whenever possible, human milk should be used rather than formula [5,6]. Full-strength (undiluted) milk should be used throughout the feeding protocol.

When mother's milk is not available, pasteurized human donor milk should be used for very low birth weight (VLBW) infants (≤1500 g) [5,6,27,28]. In this case, common practice is to continue donor human milk feeds until the infant reaches approximately 34 weeks postmenstrual age, weighs 2000 g, and/or is ready for hospital discharge [29]. A preponderance of evidence suggests that human milk is associated with lower rates of necrotizing enterocolitis (NEC) and feeding intolerance in VLBW infants compared with preterm formula [26,30]. Some Muslim families may be reluctant to use pooled human donor milk due to Islamic belief about milk kinship, although the interpretation varies among different Muslim communities. This issue calls for culturally sensitive conversations to help the family make a fully informed decision and explore alternatives to pooled donor milk, if needed [31]. (See 'Fortification of feeds' below and "Human milk feeding and fortification of human milk for premature infants", section on 'Use of donor milk'.)

A diet of human milk achieves full enteral feeds more rapidly than a diet of formula. In a study of 127 premature infants (birth weight ≤1250 g), infants fed at least 50 percent human milk achieved full enteral feeds more rapidly than those fed formula alone [32]. In addition, feeding full-strength formula triggers earlier and more consistent intestinal motility responses to feeding compared with diluted formula [33] or water [34].

Trophic feeds — We suggest early initiation of low-volume enteral feeds, known as "trophic" feeds or "gastrointestinal priming." For infants who are very premature or ill, the low-volume feeds usually are continued for several days before advancing the milk volume [35]. Some clinicians may be comfortable with a more rapid advancement of feeds, such as giving trophic feeds for only one to three days, and adding HMF to human milk feeds early in the course of feeding advancement (see 'Fortification of feeds' below). Limited evidence supports this approach [36].

The safety of early trophic feeds was supported by a meta-analysis, which concluded that early initiation of trophic feeds was not associated with an increased risk of NEC or all-cause mortality in VLBW infants and may reduce the risk of invasive infection [37]. A separate meta-analysis found that early initiation of feeds (<72 hours of life) was associated with reduced mortality (relative risk 0.69, 95% CI 0.48-0.99) and shorter hospital stay (mean difference -3.2 days, 95% CI -5.74 to -0.66) [38]. Other benefits suggested by earlier trials include better feeding tolerance, more rapid maturation of intestinal motility patterns, and improved markers of bone health [35,39-44].

The rationale for early introduction of feeds is that lack of enteral nutrients impairs intestinal development, manifested by diminished intestinal size and weight, atrophy of mucosa, and delayed maturation of intestinal enzymes and motility; some of these effects may be mediated by diminished production of gastrin, which is a trophic hormone for intestinal growth. In addition, lack of enteral nutrients increases intestinal permeability and bacterial translocation, suggesting that it might predispose to sepsis or other infectious complications [39,45-47].

Rate of volume increase — Feeding protocols are important tools to support progressive advancement of feeds, combined with close monitoring of an infant's feeding tolerance, which in turn varies with the infant's age and state of health. The details of such protocols vary among centers. Accumulating evidence suggests that feeds can be advanced more rapidly than previously thought for infants who are healthy and show no signs of feeding intolerance, when used in the context of a carefully managed protocol.

We suggest the following approach (table 4):

●For healthy infants weighing <1000 g, advance feeds by 20 to 30 mL/kg/day (table 5A). Some institutions may choose to advance feeds on the lower end of this range in infants receiving formula or early fortification (eg, fortifier added when feeding volume reaches 60 mL/kg/day). Other institutions may choose to advance at the higher end of this range (ie, advancing by 30 mL/kg/day) in order to reach full feeds more quickly and reduce the risks associated with an intravenous catheter and parenteral nutrition.

●For healthy infants weighing 1000 to 1500 g, and especially those fed exclusively or partially with breast milk, advance feeds by increments of 30 mL/kg/day (table 5B).

Substantial clinical evidence supports this approach of early initiation and relatively rapid advancement of feeds in the context of a carefully managed protocol [48-55]. As an example, one meta-analysis concluded that, for VLBW infants, more rapid advancement of feeds (30 to 40 mL/kg/day compared with 15 to 24 mL/kg/day) does not increase the risk for NEC [54] and another found benefits on time to regain birth weight and shorter hospital stay [55]. A separate randomized trial in 2793 preterm infants (48 percent birth weight 1000 to 1500 g and 37 percent birth weight <1000 g) found that advancing feeds in increments of 30 mL/kg/day compared with 18 mL/kg/day did not affect risks of NEC, late-onset sepsis, or survival without moderate to severe neurodevelopmental disability [53]. Most of the infants in this trial were fed exclusively or partially with breast milk, and fortifier was added after full feeds were reached. These findings support more rapid advancement of feeds than has been traditionally been used, especially for infants <1000 g. Past practices of slower feeding advancement were based on limited data and studies in which infants received more formula feeds compared with the more modern practice of the use of breast milk [56].

The timing for advancing from trophic to progressive feeds was evaluated in a meta-analysis, which concluded that earlier advancement of enteral feedings (before the fourth day of life) compared with later advancement of feedings (after four to seven days of life) leads to earlier achievement of full feeds without increasing the risk of NEC [37]. A subsequent randomized trial that focused on infants ≤28 weeks gestation evaluated outcomes of even earlier advancement of feeds, in which all infants began trophic feeds on the first day of life and feedings were advanced by 20 to 24 mL/kg/day starting on the second (early feeding) or fifth (later feeding) day of life [52]. Safety outcomes were similar among those managed with early versus later progressive feeding. (See "Neonatal necrotizing enterocolitis: Prevention", section on 'Standardized feeding protocol'.)

Feeding schedule — Most protocols provide enteral feeds every three hours. Feedings for infants <1500 g are typically given as a gradual bolus on a pump over 30 to 60 minutes. However, one study suggests that a more frequent feeding schedule improves feeding tolerance and reduces the time to attain full feedings. This was illustrated in a study of VLBW infants that compared every-two-hour with three-hour feedings [57]. Infants receiving feedings every two hours had a shorter time to reach full enteral feedings, greater weight gain, fewer days when feedings were held, and fewer days of receiving total parenteral nutrition. The magnitude of the effect was greater in infants who were less than 28 weeks gestation.

Fortification of feeds — Initial feeds are with unfortified human milk (mother's own milk or pasteurized donor milk). As feeds are advanced, an HMF is added to boost the nutrient intake:

●In many NICUs, a bovine-derived HMF is used. In this case, we suggest using unfortified breast milk until feeding volume reaches approximately 100 mL/kg/day, then begin fortifying feeds with the HMF, providing 24 kcal/oz. However, this reflects a traditional approach and there are no data to suggest that it is safer than earlier introduction of bovine-derived HMF. As an example, some NICUs may choose to introduce bovine HMF when feeding volume reaches 60 mL/kg/day or even earlier as a method to increase nutrient intake while weaning total parenteral nutrition. Limited evidence suggests that this is safe [36].

●In other NICUs, an HMF derived from donor human milk may be available (eg, Prolact+6). In our NICU, we use this type of HMF for infants ≤1250 g birth weight because of evidence that it leads to fewer complications and improved growth compared with a diet of bovine-derived HMF [58-60]. When using this type of HMF, we start fortification when enteral feeds reach 60 mL/kg/day because early introduction of this type of HMF was found to be safe in controlled trials. Some NICUs may choose to introduce human milk-derived HMF even earlier (eg, when feeding volume reaches 20 to 40 mL/kg/day). This approach was supported by a randomized trial in 150 extremely preterm infants (median birth weight 795 g) that compared early fortification with a human milk-based HMF (added to human milk starting on the second day of feeding) to a diet using standard fortification (fortification with a bovine HMF added to human milk after full enteral nutrition is established, approximately postnatal day 14) [61]. At 36 weeks postmenstrual age, the group treated with early fortification had greater length gain velocity and lesser decline in head circumference for age, with nonsignificant differences in other anthropometric outcomes. The trial did not detect differences in safety outcomes including necrotizing enterocolitis but was underpowered for these outcomes. These results extend previous unmasked studies that suggested that early introduction of fortified feeds is well tolerated when using an all-human milk diet [36,62-64].

The thresholds for fortification and advancement of feeds vary among NICUs. The protocol that we use in our NICU is shown in the tables (table 5A-B). Studies of different types of fortifiers are summarized in a separate topic review. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Indications and fortifier types'.)

Target volume — The target volume for feeds is approximately 160 mL/kg/day of fortified human milk. Commercially available HMFs add approximately 4 to 6 kcal/oz to provide approximately 130 to 150 kcal/kg/day (table 6). This target volume generally supports a weight gain of 15 to 20 g/kg/day. In some NICUs, feeding volumes are advanced up to 180 to 200 mL/kg/day. There is some evidence that target volumes of 180 to 200 mL/kg/day in healthy preterm infants >1000 g birth weight yielded greater increases in weight, length, and head circumference without adverse effects, although this is based primarily on one single-center trial with a wide range of birth weights (1001 to 2500 g) [65,66]. If volumes of enteral feedings are increased to 180 to 200 mL/kg/day, review the total intake of vitamins and minerals from the fortified milk or formula. HMFs and preterm formulas are generally designed to provide an appropriate dose of nutrients at a target volume of 160 mL/kg/day (table 6).

Feeding intolerance — Difficulty tolerating enteral feedings is a major problem for premature infants, especially in those with gestational age below 28 weeks, those who require positive pressure support, or those who have positive blood cultures [67]. Factors that affect feeding tolerance include intestinal motility, gastric emptying, stool output, digestive enzymes, type of feeds (formula or human milk), rapidity of feeding, volume of feeding, concentration of milk, concomitant medications, and medical conditions. An infant's intolerance of enteral feeding is a primary factor for clinical decision-making to initiate, advance, and discontinue feedings. Thus, feeding intolerance may be a major determinant of the duration of hospitalization.

Clinical assessment — Serial assessment of feeding tolerance is important to the management of enteral feeding protocols, but there are no universally agreed upon criteria on which to base this judgment.

●Symptoms and signs suggesting feeding intolerance – Symptoms of feeding intolerance are nonspecific and vary between patients. Most clinicians use a composite of the following clinical symptoms to determine feeding intolerance [68]:

•Emesis

•Abdominal examination – Distention or tenderness, bowel sounds increased or absent

•Gastric residual fluid – Change in quantity of fluid (usually increased volume) or change in color to green (bilious) or red (blood)

•Stool output – Any change in the frequency of stool output and presence of blood in stools

•Other – Increased episodes of apnea and bradycardia, diminished oxygen saturation (desaturation events), and lethargy

Any of these symptoms should prompt the clinician to reassess the infant and evaluate the possibility of feeding intolerance and/or underlying pathology.

●Gastric residual fluid – The gastric residual volume (GRV) is the amount of milk left in the stomach several hours after a feeding and is typically measured just prior to a scheduled feeding [69]. It is an indirect measure of gastric emptying and intestinal function and/or pathology but is nonspecific because it may be affected by the position of the infant or the position of the feeding tube. Although some NICUs routinely measure GRVs in asymptomatic infants, there is no evidence that this practice is a useful guide for feeding advancement or that it helps to avoid or detect the onset of NEC [70-74]. Indeed, in a randomized trial in 143 infants <1250 g birth weight who were fed human milk, omission of GRV measurements increased delivery of enteral nutrition, improved weight gain, and led to earlier hospital discharge without significant effects on risk for NEC or other complications [73]. As a result, many NICUs have abandoned the routine measurement of GRV entirely. However, measurement of GRV may still be useful as part of the assessment of an individual infant with symptoms of feeding intolerance, especially abdominal distension or vomiting.

●Bloody or bilious gastric fluid – The appearance of the gastric residual fluid sometimes provides information about feeding tolerance. Gastric fluid that is green (bilious) usually indicates overdistention of the stomach and retrograde reflux of bile into the stomach but occasionally indicates intestinal obstruction [69]. Blood-tinged gastric fluid is uncommon; when present, it is usually due to a slight mucosal irritation from the indwelling gastric tube but also might indicate an inflammatory process.

●Stool output – Stool output provides an index of intestinal motility. Some clinicians use a small glycerin suppository to stimulate stool output. More rapid evacuation of meconium during the first week of life is associated with improved feeding tolerance in extremely low birth weight infants [75]. Most clinicians perform imaging before considering giving a suppository to rule out intestinal obstruction.

●Blood in stools – The presence of gross blood in stools is usually interpreted as a sign of feeding intolerance and should also raise concern for NEC, especially if combined with other symptoms such as abdominal distension, temperature instability, or increased apneas (see "Neonatal necrotizing enterocolitis: Clinical features and diagnosis"). Measurement of occult blood is not supported by the data and is not recommended. Occult blood in the stool is common in infants in an NICU, and its clinical implications are unclear. As an example, in a study of 95 infants with birth weights ≤1800 g, 58 percent had at least one occult blood-positive stool during the first six weeks of life [76]. Six of the infants developed NEC, two of whom had occult blood in their stool and four of whom had no blood in their stool.

Several conditions other than NEC also may cause gross blood in stool and should be considered when evaluating an infant with this finding:

•Swallowed blood from delivery, suctioning, intubation, gastric tubes, and breast milk from mothers with nipple trauma.

•Anal excoriation or fissures.

•Colitis due to infection (such as cytomegalovirus) or milk protein sensitivity. (See "Food protein-induced allergic proctocolitis of infancy".)

•Coagulopathy or thrombocytopenia.

•Abnormality of the gastrointestinal tract. These are rare and include Meckel's diverticulum, duplication of the small intestine, hemangiomas, lymphangiomas, gastric and duodenal ulcers, intestinal stricture, volvulus, and intussusception. (See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach", section on 'Neonatal period'.)

Management

●Adjustment of feedings – When one or more of the above signs raise significant concerns for feeding intolerance, the clinician may choose to withhold feedings. In this case, the infant should be carefully reassessed and examined prior to the next feeding to aid the decision of whether to resume feedings and/or to make changes in the regimen. Minor or isolated symptoms of feeding intolerance often can be corrected by reducing the volume of feeds or postponing advances in feeding volume. Diluting feeds is not a useful strategy. Multiple or severe symptoms usually require a full evaluation for an underlying problem such as NEC and stopping feeds temporarily. It is important to avoid withholding feeds for prolonged periods of time because lack of enteral feeding hastens the complications of parenteral nutrition and intestinal atrophy.

●Pharmacotherapy – Pharmacotherapy is not recommended as a strategy to manage feeding intolerance in premature infants, because there is little evidence that any agent is effective for this purpose and each is associated with risks.

•Acid suppressants – Acid-suppressing medications such as histamine type 2 receptor antagonists should not be used to treat feeding intolerance. Although these agents were historically used to treat preterm infants with feeding intolerance, they appear to be associated with higher rates of NEC [77]. Similar considerations may apply to acid suppression with proton pump inhibitors [78]. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Agents that reduce gastric acidity'.)

•Erythromycin – Evidence does not support the use of erythromycin for the treatment of feeding intolerance in preterm infants. Although erythromycin has prokinetic properties, the results of clinical trials in this population are inconsistent and it is unclear if it is effective [79,80]. As an example, two meta-analyses of randomized studies found only low-quality evidence for efficacy, except perhaps for higher treatment doses [81,82]. Moreover, there are reports of an association between early use of this drug (in the first month) and the development of infantile hypertrophic pyloric stenosis [83]. (See "Infantile hypertrophic pyloric stenosis", section on 'Macrolide antibiotics'.)

Techniques for tube feeding — Tube feeding is an essential tool in enteral nutrition because premature infants less than 32 weeks gestation at birth typically are unable to suck and/or coordinate sucking and swallowing with breathing. Tube feeding varies by method (intermittent bolus versus continuous feeds) and by route (orogastric, nasogastric, transpyloric, or gastrostomy).

The device used for tube feeding also depends on the duration of the proposed therapy. For infants who are tube-fed only because of their prematurity, a temporary orogastric or nasogastric tube is used because they will eventually be able to orally feed. Infants with major congenital anomalies may require a semi-permanent gastrostomy.

Intermittent versus continuous — Most premature infants can and should be fed with intermittent ("bolus") feeds. For infants <1500 g, intermittent feeds are typically administered using an infusion pump over 30 to 60 minutes; larger infants may tolerate more rapid infusions or gravity feeds. The intermittent feeding method mimics the typical feeding routine of term infants and children and stimulates greater hormonal responses than continuous infusions [84]. Intermittent feeds may also reduce the loss of human milk fat in the feeding tube. In one study, fat loss was greater (up to 40 percent) with continuous feedings [85].

For infants without underlying gastrointestinal disease, there is no clear advantage of either feeding technique on clinical outcomes. In a meta-analysis of nine trials involving more than 900 premature infants with birth weights ≤1500 g, intermittent feeds were possibly associated with a slightly earlier time to reaching full enteral feeds compared with continuous feeds [86]. However, the difference was not statistically significant, the quality of the evidence was low, and there was no detectable effect on growth parameters or risk of NEC. Additionally, most data were based on infants >1000 g birth weight, whereas benefits to continuous feeds may be more likely in infants <1000 g birth weight.

Continuous feeding may be useful for selected infants with underlying gastrointestinal disease because it can improve feeding tolerance and/or enhance nutrient absorption [87]. Continuous feeds are usually used for infants who are fed via the transpyloric route (to avoid "dumping syndrome," which is seen in older individuals when formula enters rapidly into the jejunum) and for those who have had intestinal surgery. An alternative option is to use intermittent feeds but increase the duration of each feed (ie, slow bolus feeds). In a small group of infants who appeared intolerant to intermittent feedings, duodenal motility and gastric emptying appeared to improve following the lengthening of each feed from 30 minutes to up to 2 hours [88].

Gastric versus transpyloric — Most premature infants can and should be given gastric rather than transpyloric feeds. Transpyloric feeding is used in some institutions for selected infants with persistent gastric residuals or emesis in the absence of obvious intestinal pathology, but selection of infants for transpyloric feeds varies among institutions and clinicians.

The potential benefits and risks of transpyloric feeds were evaluated in a systematic review of nine trials [89]. There was no difference in the rate of short-term growth (ie, weight, length, head circumference, and skinfold thickness) between transpyloric versus intragastric feeds. Although there was an increased risk of gastrointestinal disturbance and mortality associated with the transpyloric approach, this may have been due to selection bias, with allocation of the less mature and sicker infants to transpyloric feeds. There was no difference in the incidence of adverse events including NEC, intestinal perforation, and aspiration pneumonia. The authors concluded that there was no benefit to the routine use of transpyloric feeding in preterm infants, while acknowledging methodologic weaknesses in all of the included trials.

Adjustment for concurrent medical conditions — Enteral feeds usually can be implemented and advanced regardless of other medical interventions, as long as the infant is stable. Specific considerations are:

●Infants with a UAC – Enteral feeds can be initiated and advanced in infants who have a UAC in place, as long as the UAC is functioning properly [90]. In the past, concerns were raised about proceeding with enteral feeding in infants who have an indwelling UAC. However, studies of trophic feeds included many infants with a UAC in place and no untoward events were reported [35,41]. Furthermore, a randomized trial found no increased risk of enteral feeding with a UAC in place [91].

●Infants receiving treatment for PDA – In our NICU, we generally provide trophic feeds during medical treatment for PDA if the infant was already receiving feeds prior to starting treatment, although we do not advance feeds until the PDA treatment is completed. This strategy is supported by a study in infants <1250 g birth weight that showed that premature infants who received trophic feedings during ibuprofen or indomethacin treatment for a PDA did not have an increased risk of adverse events, including NEC. Infants who received trophic feeds achieved their target for enteral feedings sooner compared with those who did not [92].

●Infants receiving red blood cell transfusions – In many NICUs, feeds are held for several hours during and after a red blood cell transfusion, although there is no strong evidence to guide this practice. Several studies (primarily retrospective) have suggested an association between red blood cell transfusions and NEC (transfusion-associated NEC) [93,94]. However, it is possible that the risk of NEC might be related to the degree of anemia rather than the red blood cell transfusion [95]. (See "Neonatal necrotizing enterocolitis: Prevention", section on 'Prevent severe anemia/Decrease exposure to RBC transfusion'.)

INFANTS WHO CAN FEED ORALLY

Readiness — Oral feeding should be initiated as soon as the infant demonstrates signs of readiness, which typically occurs when the tube-fed infant is between 32 and 34 weeks gestational age. Initiating oral feeds including breastfeeding is discussed in a separate topic review. (See "Breastfeeding the preterm infant".)

Although there is some variability, many preterm infants born at >34 weeks gestation can be completely fed orally from birth; others require only a brief period of tube feeding.

Diet — Infants with very low birth weights (VLBWs) generally benefit from an enriched diet before and after discharge, especially if there is slow growth or evidence of protein insufficiency or osteopenia on laboratory monitoring [96,97].

Enriched diet

●Indications – Some neonatal intensive care units (NICUs) routinely use an enriched diet for VLBW infants, with careful monitoring to avoid excessive growth. In our institution, we provide this diet to any infant with any of the following characteristics:

•Birth weight ≤2000 g

•Unable to consume at least 180 mL/kg/day due to fluid restriction or poor feeding

•Abnormalities in routine laboratory tests suggesting suboptimal bone health, such as low serum phosphorus or elevated alkaline phosphatase activity with a persistently abnormal trend, or low blood urea nitrogen (BUN) suggesting inadequate protein intake (see "Management of bone health in preterm infants", section on 'Laboratory monitoring')

●Implementation – Several approaches can be used to enrich the diet; the choice depends upon the available products and whether the infant is feeding directly from the breast or from an artificial nipple:

•For infants who are feeding at the breast, provide two or three feedings daily with a transitional "post-discharge" formula (22 kcal/oz) or premature infant formula (30 kcal/oz). These feeds generally substitute for the breast milk feed for a total of at least eight feeds daily (ie, two formula feeds with at least six feeds at the breast or three formula feeds with at least five feeds at the breast).

•For infants who are fed breast milk from an artificial nipple, add bovine milk-based fortifier to breast milk (to provide 22 or 24 kcal/oz) or mix the premature infant formula with breast milk.

•For infants fed only formula, we use a transitional "post-discharge" formula (22 kcal/oz).

For any of above strategies, sterilized liquid (rather than powdered) types of infant formula or human milk fortifier are preferred until the infant is at least 44 weeks postmenstrual age due to the small risk of bacterial contamination of powdered products. The risk is probably minimal when using single-serving packets of powdered human milk fortifier. If formula is only available as a powder in multi-serving cans (eg, in low-resource settings), use with careful attention to clean technique and proper storage. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Indications and fortifier types'.)

A comparison of the nutrients provided by these different discharge feeding strategies is shown in the table (table 7). We change to the discharge diet three to four days prior to the discharge date to ensure tolerance and observe growth. Management of feeds after discharge is discussed in more detail in a separate topic review. (See "Growth management in preterm infants", section on 'Routine nutrient supplementation'.)

Standard diet — For infants who do not meet the above criteria for an enriched diet, we provide feedings of unfortified human milk or term infant formula at 20 kcal/oz, with target volumes of 180 mL/kg/day, and monitor growth closely.

DISCHARGE PLANNING

Discharge criteria — We begin planning for nutrition after discharge when the premature infant has attained approximately 50 percent of the target for full oral enteral feeds. We consider discharge from the neonatal intensive care unit (NICU) when the premature infant is maintaining body temperature in a crib and meets both of the following nutritional milestones:

●Feeding by mouth with good documented intake of one of these diets:

•Standard diet (20 kcal/oz) at >180 mL/kg/day

•Enriched diet (usually 22 kcal/oz, but it is also reasonable to use 30 kcal/oz, to provide maximum nutrition with the smallest amount of non-breast milk diet) at >160 mL/kg/day

•Breastfeeding with complementary formula feeds of 22 to 30 kcal/oz

•Exclusive breastfeeding

●Established growth rate on the above feeds:

•Infants ≤2 kg – Gaining at least 15 to 20 g/kg/day

•Infants >2 kg – Gaining 20 to 30 g/day (not g/kg/day)

Follow up — Ongoing monitoring of growth after discharge is important to verify whether optimal growth will continue on ad libitum breastfeeding or standard term formula. When an enriched diet is used, we suggest continuing it for at least six months post-discharge, as long as the infant does not gain too rapidly and cross growth percentiles upward. It is important to communicate the plan for an enriched diet to the clinician who will manage the infant's care after discharge. (See "Growth management in preterm infants", section on 'After discharge'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nutrition support (parenteral and enteral nutrition) for neonates including preterm infants" and "Society guideline links: Breastfeeding and infant nutrition".)

SUMMARY AND RECOMMENDATIONS

●Goals – The goals of nutritional management for premature infants are to mimic intrauterine rates of growth and nutrient accretion. The initial assessment calculates a target for energy (calories) and other nutrients needed to achieve optimal growth, and targets are then adjusted based on the infant's progress. (See 'Nutritional assessment and monitoring' above.)

●Introducing and advancing feeds – Tube feeding is typically needed for infants weighing ≤1800 g at birth (usually ≤32 weeks gestation). In our neonatal intensive care unit (NICU), we use the following protocol for introducing and advancing feeds, which varies depending on the size and maturity of the infant (table 4):

•Colostrum – Expressed colostrum or breast milk is applied to the oropharyngeal mucosa using a syringe or swab, starting after birth and continuing until the infant is taking some feeds orally.

•Parenteral nutrition – Parenteral nutrition solutions (glucose, amino acids, calcium [Ca], vitamins, and lipids) are started as early as feasible and gradually decreased as enteral feeds increase. (See "Parenteral nutrition in premature infants".)

•Initiate trophic feeds – Trophic feeds are given at 20 mL/kg/day, ideally starting within six hours after birth (when medically feasible), using mother's own milk or pasteurized donor human milk. Trophic feeds are generally continued for one to three days before advancing feed volume. (See 'Milk strength and content' above and 'Trophic feeds' above.)

•Feeding advancement – For healthy infants, the volume of feedings is commonly advanced by 20 to 30 mL/kg/day in infants <1000 g birth weight, 30 mL/kg/day in those 1000 to 1500 g, and 30 to 40 mL/kg/day in infants >1500 g. The feeding volumes and rate of advancement depend upon the size, maturity, and feeding tolerance of the infant; our protocol is outlined in the tables (table 5A-B). (See 'Rate of volume increase' above.)

In general, for infants ≤1500 g birth weight, mother's own milk or pasteurized donor milk is fortified with a human milk fortifier (HMF) partway through the course of feeding advancement. (See 'Fortification of feeds' above.)

•Target volume – Target volume for feeds is 160 mL/kg/day of fortified human milk, which provides between 24 and 28 kcal/oz, depending on the HMF that is used (table 6). The target volume generally is one that supports a weight gain of more than 15 to 20 g/kg/day. When donor human milk is used, we generally switch to premature formula around 34 weeks postmenstrual age. (See 'Target volume' above.)

(See 'Overview of initiation and advancement of feeds' above.)

●Assessment of feeding tolerance – Although there are no universally agreed upon criteria to judge feeding intolerance in premature infants, we use the following clinical criteria (see 'Feeding intolerance' above):

•Emesis

•Presence of bile or blood

•Changes in stool output and presence of blood

•Abdominal distention, tenderness, and bowel sounds

•Increased episodes of apnea and bradycardia, diminished oxygen saturation, or lethargy

Most clinicians use a composite of the above criteria as opposed to a single factor. When present, these parameters should prompt the clinician to evaluate the infant for causes of feeding intolerance and to decide whether to hold feeds temporarily. (See 'Feeding intolerance' above.)

●Initiating oral feeds – Oral feeding should be initiated as soon as the infant demonstrates signs of readiness, which typically occurs when the tube-fed infant is between 32 and 34 weeks gestational age. Most preterm infants born at >34 weeks gestation do not require a prolonged period of tube feeding and many can be completely fed orally from birth. Discharge feeding strategies depend on birth weight, infant growth, and whether the infant is breastfeeding or solely formula-fed (table 7). (See 'Infants who can feed orally' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard J Schanler, MD, who contributed to earlier versions of this topic review.