Premature Infants and Breastfeeding

Benefits of Human Milk for the Preterm

The data are overwhelming. Even the most reluctant of neonatologists have accepted the tremendous importance of human milk to all infants from the most immature to term. The American Academy of Pediatrics (AAP) recommends that mother’s own milk, fresh or frozen, should be the primary diet for premature infants. ¹

As we shall discuss in this chapter, human milk provides developmental benefits for preterm infants that extend into adolescence. The use of exclusive human milk when paired with standardized feeding guidelines can improve tolerance of feedings and decrease the incidence of necrotizing enterocolitis (NEC). Human milk–fed infants have decreased rates of late-onset sepsis, urinary tract infection, diarrhea, and upper respiratory tract infection. Human milk is also associated with decreases in the incidence and severity of retinopathy of prematurity (ROP), improved neurodevelopmental and visual outcomes, and improved feeding tolerance compared with formula. Improved tolerance allows infants to receive fewer days of parenteral nutrition, significantly decreases morbidity, and decreases length of stay.

Maturation of the gastrointestinal tract is supported by components in human milk resulting in improved motility, smaller gastric residuals, and decreased intestinal permeability. Preterm infants have decreased ability to absorb fats. Enzymes in human milk allow for improved fat absorption and intestinal lipolysis.

Research in the science of nutrition for low-birth-weight (LBW) infants and extremely premature infants has advanced tremendously as the technology to study the important questions has improved. Advances in the field of neonatology have contributed to the survival of increasingly more immature infants. The edge of viability is currently about 22 weeks, and these infants will need to be fed to survive.

One of the key points learned retrospectively about survival, generation after generation, has been the critical impact of fluid and nutrition. For the preterm infant, adequate nutrition and growth are the primary goals during their neonatal intensive care unit (NICU) stay. In the past, the early use of unsupplemented drip milk and some donor milks produced poor growth patterns in preterm infants. Drip milk is low in fat and, therefore, low in calories. The protein levels in donor milk from women late in lactation (i.e., beyond 6 to 8 months, when the protein levels have dropped) parallel a child’s decreased biologic needs with the addition of solid foods. These factors contributed to the abandonment of human milk until supplements and fortifiers were developed and studies of the milk of women who had delivered prematurely sparked new investigations.

Policy statements from World Health Organization (WHO), United Nations International Children’s Education Fund (UNICEF), AAP, and other international and national organizations confirm the importance of providing a mother’s own milk to preterm infants and infants who are small-for-gestational-age (SGA). Standard practice in neonatal units is to promote mother’s own milk as the food of choice for all LBW infants. ¹

The absolute standard for evaluating the nutritional outcome of preterm infants remains the intrauterine growth rate. A strategy to minimize mobilization of endogenous nutrient stores is moving from a focus on intrauterine-based, short-term growth and nutrient retention rates to a system that considers long-term growth achievement. ² For the infant with very low-birth-weight (VLBW), nutritional needs are first met primarily by parenteral nutrition with increasing reliance on the advancement of enteral feeds. The enteral feeding of choice is human milk, preferably mother’s own milk or donor human milk if the mother’s own milk is not available. ¹ The optimal time to initiate oral feedings in the smallest and sickest preterm infants is now thought to be as soon as possible after delivery. Prolonged exclusive parenteral nutrition has been replaced with minimal amounts of oral feedings with parenteral nutrition to preserve and maintain intestinal function. These feeds are known as trophic because they are responsible for the growth of the gastrointestinal tract. Feedings should begin soon after birth once physiologic stability is achieved. Usually this involves stable blood pressure and oxygenation, but many units may have their own criteria for when to initiate oral feeds. It is important to have a standardized feeding protocol in the NICU. This has been shown to reduce the incidence of NEC in the preterm neonate. ³ It is interesting that the specific protocol appears to matter less than that each NICU follow their own protocol and minimize variation.

As nutritional markers shift, a preterm infant’s own mother’s milk is now recognized, even by the most skeptical clinicians, as the gold standard to prevent short-term morbidities and enhance long-term outcome. ⁴ With this change comes the recognition that fortified donor milk is clearly superior to artificial feeds.

LBW has been defined by the WHO as a weight at birth of less than 2500 g. ⁵ Overall, it is estimated that 15% to 20% of all births worldwide are LBW, approximating more than 20 million births per year. LBW infants form a heterogeneous group, some born early, some who are born at term but are SGA, and some both early and small. LBW infants account for 60% to 80% of all neonatal deaths and are at high risk for early growth restriction, infectious disease, developmental delay, and death in infancy and childhood.

Gastrointestinal Tract Development

The gastrointestinal tract is one of the first structures defined in the developing embryo. Gut length proceeds rapidly throughout fetal life and for the first years of life. The proton pump is present at 13 weeks’ gestation. Intrinsic factor and pepsin are identifiable a few weeks later ( Fig. 14.1 ). Even in premature infants with extremely low-birth-weight (ELBW), the gastric pH can be lowered to below 4.0. ⁶ Digestive enzymes are capable of intraluminal digestion of fat, protein, and carbohydrates. Although pancreatic lipase and bile salts are minimal in ELBW infants, the introduction of mother’s milk will stimulate maturation and provide lipases and other digestive enzymes.

Bile salt–stimulated lipase is a unique component of fresh, unpasteurized breast milk and promotes triglyceride absorption and digestion. ⁷ The intestinal villi and cellular differentiation occur at about 10 to 12 weeks’ gestation and begin a complex interrelationship with developing epithelium and the mesoderm, according to Newell. ⁸ Lactase and other carbohydrate enzymes begin to appear. Gut motility is thought to appear first as irregular gastrointestinal activity at 23 weeks progressing to organized motility at approximately 28 weeks. Most studies of nutritive sucking and swallowing are done with artificial feeding with a bottle. Suckling at the breast, which begins with peristaltic motion of the tongue and continues down the esophagus, has been initiated by breastfeeding as early as 28 weeks or sooner.

Gastric emptying in premature infants, as measured in most studies, is slow, generating the impression that feedings are not tolerated. However, a recent meta-analysis of 66 publications reported no effect of gestational age on the mean gastric emptying time. ⁹ Gastric emptying is enhanced by human milk and slowed by formula and increased osmolarity ( Box 14.1 ). Half emptying time with human milk is reported to be as rapid as 20 to 40 minutes. ¹⁰ Ultrasound studies have assessed small-volume feeds. Some premature infants show delayed antral distention after a nasogastric feeding with emptying that follows a curvilinear pattern after an initial rapid phase.

Maturation of the small intestinal motility, and hence tolerance of feeds, is enhanced by previous exposure of the gut to nutrition. Early feeding precipitates preferential maturation and thus a more mature response to feeds. Total gut transit time in premature infants varies from 1 to 5 days and is more rapid in those who have received food. ¹¹ In those younger than 28 weeks, it may take as long as 3 days to pass meconium. Breast milk feedings, however, increase motility and stool passage.

When prematurity is complicated by intrauterine growth failure, the resultant cascade of events includes decreased splanchnic circulation and oligohydramnios, poor gut perfusion, decreased growth of the small intestine and pancreas culminating in a fetal echogenic gut, and poor intestinal motility resulting in poor tolerance to milk feeds. It is not uncommon for this to be associated with NEC. These events require careful consideration, including the choice to use mother’s milk, especially beginning with colostrum. In a recent study looking at rates of NEC among infants weighing less than 750 g there was no difference in rates of NEC between infants who are appropriate for gestational age (AGA) and SGA infants. ¹² This group received colostrum from day 1 and donor milk when mother’s own milk was not available, which may have accounted for these results.

Although feeding regimens vary, evidence is strong and consistent that feeding mother’s own milk to preterm infants at any gestation is associated with a lower incidence of infections and NEC and improved neurodevelopmental outcome compared with the use of bovine milk products primarily due to the presence of bioactive agents ( Fig. 14.2 ). ⁴ , ¹³ The challenge is to increase the availability of mother’s milk and to understand the interactions of bioactive factors to produce these and other clinical benefits (see Fig. 14.2 ).

Gastrointestinal Priming

When feedings are delayed in any newborn, luminal starvation results in epithelial cell atrophy. Lung injury may aggravate this because of multiorgan system dysfunction, increasing the risk for intestinal mucosal injury and associated barrier dysfunction. The ultimate injury would be the invasion of bacteria from the gut lumen. ¹⁴ Initiating feeds is a delicate balance between insufficient feeds that fail to trigger gut maturation and excessive feeds that overwhelm the digestive capacity. Also, excessive feeds can result in bacterial overgrowth and injury to the brush border. ¹⁴ When internal nutrients are absent, the intestinal size and weight are diminished; atrophy of the mucosa, delayed maturation of intestinal enzymes, and increased permeability and bacterial translocation may occur. Intestinal motilities, perfusion, and reactions to the usual gastrointestinal tropic hormones are also affected by lack of nutrients. Trophic hormone levels in the plasma are significantly altered by starvation.

In the words of Lucas, ¹⁵ “It is fundamentally unphysiologic to deprive an infant of any gestation of enteral feeding since the deprivation would never normally occur at any stage.” This statement is based on the fact that a fetus normally makes sucking motions and swallows amniotic fluid from early gestation. This may even have a trophic effect on the gut. By the third trimester a fetus is swallowing up to 150 mL/kg per day, which provides as much as 3 g/kg per day of protein. The secretion of gastrointestinal hormones is thought to occur in response to the first postdelivery feedings. ¹⁵ In animals, after only a few days of deprivation of enteral feeds, atrophic changes take place in the gut. ¹⁶ In human infants who have never received enteral feedings, no gut peptide surges occur, not even those of the trophic hormones enteroglucagon, gastrin, and gastric inhibitory polypeptide. These hormones are thought to be key to the activation of the enteroinsular axis ¹⁶ ( Box 14.2 ). Clinical trials of early priming in premature infants showed that infants primed in the first few days or first week had better feeding tolerance to advancing feeds and were weaned from parenteral nutrition promptly. It was also associated with lower serum alkaline phosphatase activity and significant stimulation of gastrointestinal hormones such as gastrin. It also resulted in more mature intestinal motility patterns, greater absorption of calcium and phosphorus, increased lactase activity, increased bone mineral content (BMC), and reduced intestinal permeability. Tyson and Kennedy ¹⁷ reviewed the studies of early priming and found shorter times to full feeding, fewer days when feedings were held, a shorter duration of hospitalization, and no increase in NEC. Many of the involved infants were at high risk for complications by virtue of their own morbidities, including mechanical ventilation, umbilical catheterization, and patent ductus arteriosus. Schanler and Anderson ¹⁸ recommended that ELBW infants who are ill be given small volumes, 10 to 20 mL/kg per day, in the first few days of life to continue for 3 to 7 days before advancing the feeds. ¹⁸ Clinical stability is required before advancing the feeds. These volumes are compatible with the volume of mother’s milk of a mother of a premature infant ( Boxes 14.3 and 14.4 ). In a meta-analysis by Oddie et al., ¹⁹ consisting of 10 randomized controlled trials (RCTs) with over 3700 infants participating, there was no advantage to slow advancement of enteral feeds (daily increments of 15 to 20 mL/kg compared with 30 to 40 mL/kg infant weight). There was no decrease in the risk for NEC or death, but delays (1 to 5 days) in reaching full feeds and higher rates of invasive infections occurred in the slow advancement group. ¹⁹ There have been a number of trials looking at bolus feedings versus continuous feeds. Bolus feeds have been thought to be more physiologic for the infant, resulting in more cyclical hormone surges, and continuous feeds have been described as more appropriate for the extremely preterm infant with better tolerance. All these studies have had issues with blinding and the ideal method of feeding may be infant and unit specific. ²⁰

Berseth ¹¹ reported that the response of the preterm infant’s intestine to entire feedings at different postnatal ages showed significantly more mature motor patterns of the gut and higher plasma concentrations of gastrin and gastric inhibitory peptide. From a management standpoint, early-fed infants were able to tolerate full oral feeds sooner, had fewer days of feeding intolerance, and required shorter hospital stays. Studies varied from infants who were fed at younger than 24 hours of age at 1 mL/h to infants who were fed full feeds starting at days 2 to 7 compared with infants on usual delayed protocols. All showed an advantage to early feeds ¹⁶ ( Table 14.1 and Box 14.5 ). Early enteral feedings are now being embraced thanks to a number of randomized controlled studies supporting the concept.

Requirements of ELBW infants begin with water, the first great need, followed by energy requirements of 120 kcal/kg per day to meet metabolic and growth rates. Protein is key because ELBW infants miss the last trimester when protein and fat are stored. To stop catabolism and promote protein accretion, Brumberg and LaGamma ¹⁴ recommend 3.5 to 4 g/kg per day of protein, presuming a daily loss of 1.1 to 1.5 g/kg of stored protein per day. Protein should start early either orally or by parenteral nutrition.

Human milk is the preferred feeding for all infants, including premature and sick newborns, with rare exception according to the AAP, the WHO, and the National Academy of Medicine (formerly the Institute of Medicine). ¹ , ⁵ , ²¹ For the preterm infant, adequate nutrition and growth are the primary goals during their NICU stay. The goal of postnatal nutrition was proposed to achieve a rate of postnatal growth approximating the intrauterine growth rate of the gestational age–matched fetus. ²² For the VLBW infant, nutritional needs are first met primarily by parenteral nutrition with increasing reliance on the advancement of enteral feeds. The paradigm of extrauterine growth matching intrauterine growth for premature infants based on their gestational age has been called into question. ²³ , ²⁴ The data to support such a paradigm have been called into question based on the measured effects, the period of time postnatally, and potential confounding factors. It has been recommended that new growth standards should be used to assess the postnatal growth of preterm infants based on preterm infants from healthy pregnancies without evidence of intrauterine growth restriction. ²⁵ This standard has been developed and proposed for use by the WHO and the Centers for Disease Control and Prevention (CDC) for use regarding Zika congenital infection and measurement of microcephaly. ²⁴ It is likely that additional data using similar methodology for establishing such a standard will be developed given the primary criticism of such a standard as including too small a cohort of premature infants.

The enteral feeding of choice is human milk, preferably mother’s own milk or donor human milk if the mother’s own milk is not available. ¹ The advantages of human milk feedings include decreased mortality, protection from NEC and sepsis, and improvement in neurodevelopment. Feedings should begin soon after birth, once physiologic stability is achieved. Usually this involves stable blood pressure and oxygenation, but many units may have their own criteria for when to initiate oral feeds. It is important to have a standardized feeding protocol in the NICU. This has been shown to reduce the incidence of NEC in the preterm neonate ³ ( Table 14.2 ). In their review and meta-analysis Patole and de Klerk ³ noted in six studies that the introduction of a standardized feeding regimen (despite it being different from the others) decreased the risk for NEC by 87%. It is interesting that the specific protocol appears to matter less than that each NICU follow its own protocol and minimize variation.

Human milk is better than formula in early feeds in establishing enteral tolerance and discontinuation of parenteral nutrition, in long-term improved neurodevelopmental outcome, and in the psychologic benefit to mothers. Human milk falls short after 4 to 6 weeks in the amount of protein, calcium, and phosphorus, a problem solvable with the use of a human milk fortifier. No substitute has been developed that replaces the many and varied advantages of human milk, however.

Colostrum

The first product produced by the mother is colostrum, which is an important nutrient for the infant and contains many important biofactors. These biofactors are present in the largest amounts in preterm mother’s colostrum. Colostrum has the highest amounts of secretory immunoglobulin A (sIgA), lysozyme, lactoferrin, and cytokines. The high immunoglobulin content of colostrum is mainly IgA, but IgM and IgG are also present in significant amounts. The IgA in colostrum binds to potential infectious pathogens and prevents them from adhering to mucosal epithelium in the neonate. ²⁶ Colostrum also provided T and B lymphocytes, which recognize potential antigens. Oral colostrum has been postulated to be a bridge from the protective biofactors found in amniotic fluid to extrauterine life. For these reasons it is important to administer colostrum once it has been obtained. Colostrum is generally produced in very small amounts, and although it can be given by an orogastric tube, the best option may be direct instillation in the oropharynx. This is due to the presence of a significant amount of lymphoid tissue in the oropharynx, critical in the enteromammary pathway. ²⁷ Colostrum should be the first feeding the infant receives.

Most investigators have concluded that minimal enteral feedings with human milk can optimize growth, development, and progress for small premature infants, even if ventilator dependent. ¹⁶ In most studies, the incidence of NEC has been similar with and without early feeds. ¹⁵ The presence of an umbilical catheter has long been a contraindication to feeding because of the risk for NEC. When Davey et al. ²⁸ investigated this, the incidence of NEC was comparable in infants with and without umbilical catheters.

Other advantages of early feeds include lower serum direct and indirect bilirubin, less apnea and bradycardia, and less need for phototherapy. ²⁹ Benefits from early feeds were measurable with raw maternal milk, pasteurized premature milk, and even to some extent whey-dominant infant formula. Specifically there is evidence of less apnea and bradycardia with early transpyloric tube feedings ( Fig. 14.3 ).

Low-Birth-Weight Infants

VLBW refers to an infant weighing less than 1500 g. The birth of an ELBW premature infant, defined as a weight less than 1000 g, is a nutritional emergency. Even with parenteral nutrition from the first day, weight loss exceeds 10% and it usually takes at least 10 days to regain birth weight. The long-term consequences of early nutrition have a great impact on gut development and neurodevelopment and may well reduce the risk for perinatal brain lesions.

With the availability of surfactant for respiratory distress, infants between 500 and 1000 g are surviving in greater numbers. It is evident that the provision of maternal milk also lowers mortality and morbidity in the preterm infant. This includes overall lower rates of bacterial sepsis, NEC, and death. ³⁰ It has been shown that there appears to be a dose response to maternal milk. Infants appear to require more than 50 mL/kg per day of maternal milk to achieve lower rates of sepsis. A similar dose-response relationship between positive blood cultures and cumulative human milk intake had been shown by Schanler et al. ³¹ This relationship was also seen as a function of human milk intake during the first 2 weeks of life. ³² In this study, there was a 13% decrease in the combined outcome of NEC/death for each 100 mL/kg of ingested human milk. Thus a dose-dependent effect of human milk on mortality was identified. The use of breast milk in the first 10 days of life was shown to decrease combined morbidity and mortality in the first 60 days of life. ³³ In this population, minimal enteral feeds were started on the first day within hours after birth. Infants who received greater than 50% of their total enteral intake from mother’s milk had a significantly lower combined outcome of sepsis, NEC, or mortality. This protection from NEC, sepsis, and mortality may have to do with the active biologic protection derived from immunoglobulins, lactoferrin, and cytokines. The problems of nutrition, however, pose new challenges to the neonatologist. The feedings appropriate for a 2000-g premature infant vary only in volume and frequency from that for full-term infants in most cases. Feedings for VLBW infants must address the advantages and disadvantages of human milk at this point in their growth curve. The composition of mother’s milk varies in some constituents with the degree of prematurity, which is advantageous ( Box 14.6 ).

The advantages of human milk for LBW infants include the physiologic amino acid and fat profile, the digestibility and absorption of these proteins and fats, and the low renal solute load. ³⁴ The presence of active enzymes enhances maturation and supplements the enzyme activity of this underdeveloped gut. The antiinfective properties and living cells protect immature infants from infection and protect against NEC. The psychologic benefit to the mother who can participate in her infant’s care by providing her milk is a less tangible but no less important advantage.

The disadvantages are the possible gaps in certain nutrients that have been estimated to be required for adequate growth, which include the volume of total protein and macrominerals, especially calcium and phosphorus. ³⁵ , ³⁶ , ³⁷ These disadvantages have been overcome with the use of human milk fortifiers in the preterm population.

Optimal Growth for Premature Infants

Optimal growth for infants born prematurely is considered to be the growth curve they would have followed had they remained in utero ( Fig. 14.4 and Tables 14.3 and 14.4 ). ³⁷ Achieving this goal using the immature intestinal tract requires that the nutrients be digestible and absorbable and not impose a significant metabolic stress on the other immature organs, especially the kidneys. Although human milk provides the ideal nutrients, it would require an inordinate nonphysiologic volume to achieve adequate amounts of some nutrients without calculated supplementation. To fill these growth needs, one can use an artificial or chemical formula or use human milk as a base, with all its advantages, and add the deficient nutrients to it.

Special Properties of Preterm Milk

The identification of special quantitative differences in nutrients in the milk of mothers who delivered prematurely created new interest in the use of human milk for premature infants (see Box 14.6 ). Many investigators have contributed to the pool of knowledge after the initial revelations in 1980 by Atkinson et al., ³⁸ , ³⁹ who reported the nitrogen concentration of milk from mothers of premature infants to be greater than that of milk from mothers delivering at term. ⁴⁰

The composition of breast milk is highly variable depending on many factors, including gestational and postnatal age. Mature human milk contains about 87% water, 1% protein, 4% fats, and 7% carbohydrate ( Table 14.5 ). ⁴¹ Breast milk of mothers who deliver prematurely has higher protein content that generally decreases with advancing gestational age. ⁴² These differences were maximal in the first few days of life with differences of approximately 35%. Initial mean protein levels of preterm milk were 2.2 g/dL in a large meta-analysis. Differences were no longer statistically significant by 10 to 12 weeks of life, although in actuality by 5 weeks of age differences in true protein levels were 0.1 to 0.2 g/dL. ⁴¹ Growing preterm infants require between 3.5 and 4.5 g/kg of enteral protein, which breast milk alone cannot provide. ⁴³ Fat content was not statistically different between preterm and term milk, initially at a mean of 2.2 g/dL in the preterm milk, although this was 23% higher than in term milk. Fat and energy content also change with time of day and from start to finish of the feed. Lactose in preterm milk averages 6.2 g/dL and up to 7.05 g/dL at 28 days, peaking at approximately 6 weeks of age ( Fig. 14.5 ). ⁴⁴

The macronutrients calcium and phosphorus are slightly higher in preterm milk than term milk (14 to 16 mEq/L vs. 13 to 16 mEq/L calcium and 4.7 to 5.5 m/L vs. 4.0 to 5.1 m/L phosphorus). Neither term nor preterm milk has adequate calcium and phosphorus for the VLBW infant. ⁴⁵ The preterm infant is missing the third trimester of gestation when accretion rates for calcium and phosphorus are highest and two-thirds of mineral content is acquired. Preterm infants need large amounts of these minerals to achieve adequate extrauterine growth. Magnesium levels in preterm milk are 28 to 31 mg/L, dropping to 25 mg/L at 28 days, and term milk levels are 25 to 29 mg/L. Zinc levels are higher in preterm milk, beginning at 5.3 mg/L and dropping to 3.9 mg/L, whereas term milk begins at 5.4 mg/L and drops to 2.6 mg/L. Sodium levels in preterm milk are higher (26.6 mEq/L, dropping to 12.6 mEq/L), whereas term milk is 22.3 mEq/L, decreasing to 8.5 mEq/L at 28 days. ⁴⁵ Chloride has a similar average (preterm 31.6 mEq/L, decreasing to 16.8 mEq/L, and term 26.9 mEq/L, decreasing to 13.1 mEq/L).

Requirements for Growth in Premature Infants

Protein Requirements in Premature Infants

The whey protein in human milk is an advantage for all infants but especially for premature infants. It includes the nine amino acids known to be essential to humans, as well as taurine, ⁴⁶ glycine, leucine, and cystine, which are considered essential for premature infants. Taurine is not present in cow milk and has to be manufactured and added to formula. ⁴⁷ The premature infant lacks the necessary enzymes for metabolism and has been noted to accumulate nonphysiologic levels of methionine, tyrosine, phenylalanine, blood urea, and ammonia. The placenta provides about 3.5 to 4.0 g/kg per day of amino acids to the fetus. The placenta is able to optimize the amino acids, however, something that cannot be done with enteral feeds. If energy intake is deficient, protein synthesis can be depressed and protein retention reduced. Greater protein intake is risky if energy intake is limited because the amino acids will be oxidized to ammonia and urea. Preterm infants require 30 to 40 kcal/g of protein provided. LBW infants fed mother’s milk exclusively for 2 weeks have been found to have a low protein level. This has led to the need to supplement human milk when the infant tolerates significant amounts of enteral feeds (120 to 150 mL/kg per day). To achieve adequate weight gain, preterm infants require 3.4 g/kg per day of protein. ⁴⁸ In most instances, human milk feeding will progress gradually from small trophic feedings designed to stimulate the newborn gut to full enteral nutrition. Fortifiers are added to human milk when infants are typically tolerating a substantial amount of feeds at about the time when protein levels in their own mother’s milk drops from about 2.5 to 1.5 g/dL. ⁴⁹ Most neonatologists consider fortification at the time when the infants are receiving 80 to 100 mL/kg. Sullivan and Schanler ⁵⁰ and others have shown that introduction of fortifier in human milk does not increase the risk for adverse events, including NEC. In randomized trials there were no adverse effects of introducing fortifier at 40 mL/kg of feeds compared with 100 mL/kg of feeds.

Protein has been shown to be an important component and necessary for adequate growth. ⁴⁸ , ⁴⁹ In a randomized trial by Brumberg et al., ⁵¹ it was demonstrated that infants fed at equivalent energy levels but higher protein contents had significantly improved weight gain, head circumference, and mid-arm circumferences. Assuming a human milk protein level of 1.5 g/dL, most fortifiers add an additional 1.5 to 2.2 g/dL bringing the total enteral protein intake to 3.5 to 4.5 g/dL when fed at 150 mL/kg. These fortifiers derive their protein from either a bovine source or from pooled human milk. Powdered fortifiers are no longer recommended because of the increased risk for bacterial contamination and sepsis. Exclusive human milk diets including human milk–derived fortifier have been associated with a lower rate of NEC than mixed human milk and bovine-based products.

Fat Requirements in Premature Infants

A diurnal variation in the creamatocrits (see Chapter 22 ) of expressed breast milk of mothers delivering prematurely was demonstrated in 39 mothers by Lubetzky et al. ⁵² The creamatocrit was significantly higher in the evening—7.9%±2.9% compared with first morning samples, 6.6%±2.8% ( p < 0.005)—regardless of gestational age or birth weight.

The fat content of mother’s milk is not affected by fetal growth of the infant. Fifty-six lactating mothers of newborns (26 SGA and 30 AGA) had their creamatocrits measured on the third day postpartum and again at 7 and 14 days. ⁵³ Other parameters (maternal age, body mass index, gestational age, weight gain, or parity) were similar except for birth weight for gestational age (SGA or AGA). Fat content of the milk was not affected by fetal growth status.

The requirement for fat for appropriate growth is based on the essential fatty acid proportion as 3% of total caloric intake. Human milk has high levels of linoleic acid (9% of lipids) and adequately meets this requirement. Human milk fat is more readily absorbed in the presence of milk lipase and other enzymes in human milk. It is reported that infants less than 1500 g absorb 90% of human milk fat and 68% of cow milk formula fats. ⁵⁴ This phenomenon is due to the fact that human milk has a very special fat globule containing another protein coat and inner lipid core membrane (milk fat globule membrane [MFGM]) (see Chapter 4 ). The pattern of fatty acids (i.e., high in palmitic 16.0, oleic 18:1, linoleic 18:2 omega-6, and linolenic 18:3 omega-3), their distribution on the triglyceride molecule, and the presence of bile salt–stimulated lipase characterize the lipid system in human milk. ⁵⁵ Digestion of milk triglycerides requires three gastrointestinal lipases: gastric, pancreatic, and bile salt–stimulated lipase (BSSL). Fat globules are broken down into droplets by gastric lipase, further hydrolyzed by pancreatic lipase, and broken down into free fatty acids and free glycerol by the bile salt lipase. ⁷ BSSL activity is high in fresh human milk but nearly completely eliminated after Holder pasteurization. High-pressure processing of donor human milk preserves much of the BSSL activity and may be a promising alternative ⁵⁶ ( Fig. 14.6 ). BSSL is not present in formula, so despite the fact that formula has higher levels of fat, it is not as well absorbed or metabolized.

Fat digestion is efficient in LBW infants who receive their own mother’s milk fresh and untreated. Fat absorption is decreased by calcium supplementation, however, and by sterilizing the milk. If human milk is supplemented with lipids, it will change the ratio of vitamin E to polyunsaturated fatty acid (PUFA). It may be necessary to add vitamin E to keep the ratio of vitamin E to PUFA greater than 0.6 (normally the ratio of human milk vitamin E to PUFA is 0.9). ⁵⁷

Special attributes of human milk for VLBW infants have been confirmed as investigators inspect the value of adding nutrients to formulas specifically for these infants. ⁵⁸ In a study of omega-3 fatty acids on retinal function using electroretinograms, human milk was associated with the best function, followed by formula supplemented with omega-3 fatty acids. This supports the concept that omega-3 fatty acids are essential to retinal development. ⁵⁹

Although human milk contains 250 mg of calcium and 140 mg/L of phosphorus in readily absorbable form, preterm and term milk do not contain sufficient calcium and phosphorus for bone accretion in LBW infants. Rickets has developed in LBW infants who are not supplemented because the requirement for bone growth at this point in the growth curve is high. Calcium and phosphorus fetal accretion increases steadily during the last trimester of pregnancy. Magnesium accretion is unchanged in that period.

Mineral accretion is a complex phenomenon dependent on a number of variables beyond simple levels of calcium, phosphorus, magnesium, and vitamin D. ⁶⁰ Absorption and retention are altered by the quantities of other minerals and other nutrients, including fat, protein, and carbohydrate. Although the calcium-to-phosphorus ratio in human milk is more physiologic than that of cow milk, the low levels of phosphorus may lead to loss of calcium in the urine if not supplemented. ⁶¹

Even with optimal vitamin D and magnesium, the amount of calcium absorbed from preterm milk is not enough to meet intrauterine accretion rates without supplementation. Because human milk phosphorus levels are low, even with high intestinal absorption and high renal tubular reabsorption, compared with the needs of the premature infant, supplementation is necessary to avoid depletion or deficiency. ⁶² Intrauterine accretion rates for calcium and phosphorus were achieved when Schanler and Abrams ⁶³ fed human milk supplemented with calcium gluconate and glycerophosphate to VLBW infants. In their study, supplementation with magnesium was not included. The authors concluded that greater intakes of calcium and phosphorus and not improved bioavailability were responsible for the improved net retention. Premature infants who receive only unfortified human milk never achieve intrauterine retention rates of calcium and phophorus. ⁶³ Therefore it is necessary to fortify human milk for premature infants. Vitamin D requirements in this period of high skeletal development depend on maternal vitamin D status because significant correlation exists between maternal serum and preterm infant cord serum 25-hydroxyvitamin D values. Recommendations for vitamin D have changed dramatically. No longer are maternal stores considered adequate. Work by Wagner et al. ⁶⁴ demonstrated that average women, even with a healthy lifestyle, have low vitamin D levels and thus their infants are relatively deficient at birth, especially infants born prematurely. Mothers of premature infants tend to have lower vitamin D levels than their term counterparts with their preterm newborns showing similar levels of vitamin D insufficiency. The milk was also low in vitamin D. The recommended daily dose of vitamin D for mothers is 1000 units. Obtaining vitamin D blood levels is simple and should be checked early in pregnancy and the dose adjusted. Because infants are no longer exposed to sunlight, dietary sources are crucial. LBW infants quickly become dependent on exogenous vitamin D because fetal storage is minimal. The recommended dietary allowance of 400 units of vitamin D appears to be appropriate for all LBW infants, regardless of feedings, and for term infants. Vitamin D intake of 200 to 400 IU/day for VLBW infants is recommended by the AAP Committee on Nutrition. As the infant grows and weight exceeds 1500 g the dose should be increased to 400 IU/day. ⁶⁵

Other vitamin needs of LBW infants depend on body stores, intestinal absorption, bioavailability of the vitamin, and rates of utilization and excretion. ⁶⁶ Little information suggests that major differences exist in absorption between term and LBW infants, although fat-soluble vitamins depend on bile acids for absorption. (See Chapter 8 for vitamin requirements.) It is recommended that LBW infants receive daily vitamin supplements to address the increased need and borderline levels provided in the volume of human milk they can reasonably consume ( Box 14.7 ).

Box 14.7

Vitamin Supplements for Low-Birth-Weight Infants Fed Human Milk

IU , International units.

• Vitamin B ₁₂ : Only if mother’s diet deficient

• Folic acid: Human milk usually adequate

• Thiamin (B ₁ ): Borderline

• Riboflavin (B ₂ ): Borderline

• Vitamin B ₆ : Human milk usually adequate

• Niacin: Human milk usually adequate

• Vitamin A: 1000 to 1500 IU/day

• Vitamin C: If infant receives supplementary protein up to 60 mg/day

• Vitamin D: 400 IU/day

• Vitamin K: All infants should receive 0.5 to 1 mg at birth; recommended 5 mg/kg per day; human milk borderline

• Vitamin E: 25 IU/day for first month; 5 IU/day after first month; human milk adequate

The mineral supplementation required for LBW infants fed human milk is based on intrauterine accretion rates, which actually may not be achieved ( Table 14.6 ). Not all premature infants fed human milk develop rickets, which occurs infrequently in infants greater than 1500 g. VLBW infants do need supplementation, and cases of rickets are well documented in the literature for this group. ⁶⁷ Supplements are usually not necessary while an infant is receiving fortified human milk or formula and when an infant reaches 40 weeks’ postconceptional age. Hypophosphatemia is a sensitive biochemical indicator of low bone mineralization in VLBW infants fed human milk. Tsang et al. ⁶⁷ recommend weekly measurements of serum phosphorus for the first month and biweekly until 2000 g or 40 weeks’ gestation. A level less than 4 mg/dL phosphorus should be followed by radiographs of the wrists for osteopenia and rickets. Supplementation should be based on an infant’s needs. Calcium levels should also be obtained weekly to evaluate levels greater than 11 mg/dL for too much calcium or too little phosphorus. ⁶³ Supplements of calcium and phosphorus are incorporated in available human milk fortifiers and supplements derived from formula ( Table 14.7 ). Now such supplementation is also available from human milk products: Prolacta CR, product of Prolacta ( Fig. 14.7 , Box 14.8 ; see Table 14.7 ), and Medolac.

Table 14.6

Required Calcium (Ca), Phosphorus (P), and Magnesium (Mg) Intake to Meet Fetal Accretion Rate at 27 and 30 Weeks ^a

From Steichen JJ, Krug-Wispe SK, Tsang RC. Breastfeeding the low birth weight preterm infant. Clin Perinatol . 1987;14:131.

	27 WEEKS			30 WEEKS
	Ca	P	Mg	Ca	P	Mg
Accretion (mg/kg/day)	121	72	3.37	123	72	3.17
Retention (% intake)	50	89	59	50	89	59
Intake (mg/kg/day)	242	81	5.70	246	81	5.37

a Assuming a weight of 1000 g and 1250 g, respectively, in an infant fed human milk.

Table 14.7

Nutrient Composition of Selected Fortifiers and Supplements

From Arslanoglu S, Boquien C-Y, King C, et al. Fortification of human milk for preterm infants: update and recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification. Front Pediatr . 2019;7:76. doi:10.3389/fped.2019.00076 .

		BOVINE-BASED PRODUCTS (PER GRAM OF POWDER)									HUMAN MILK–BASED FORTIFIER (PER VOLUME)
	MULTICOMPONENT FORTIFIERS					PROTEIN SUPPLEMENTS
Fortifier	A	B	C	D	E	F	G	H	I	J	K	L	M	N
Volume (ml)	/	/	/	/	/	/	/	/	/	/	20	30	40	50
Energy (kcal)	4.4 (L)	3.5	3.6	4.9 (L)	3.9 (L)	3.4	3.6	3.6	4	3.7	28	42	56	71
Protein (g)	0.36 PH	0.25 EH	0.2 EH	0.4	0.3	0.82 EH	0.72 EH	0.86 W	0.8 W	0.9 W	1.2	1.8	2.4	3
Na (mg)	9.2	8.0	5.4	5.6	4.2	7.8	8.2	2.1	2	0	20	40	42	45
Ca (mg)	18.9	14.9	10	32	33	5.2	12.8	0	4	0	103	106	108	111
P (mg)	11	8.7	7	18	19	5.2	0.73	0	3	0	53.8	54.9	56	57.5
Iron (mg)	0.5	0	0	0.5	0.1	0	0.007	0	0	0	0.1	0.15	0.2	0.25

EH , Extensively hydrolyzed; HMBF , human milk–based fortifier; L , lipids; PH , partially hydrolyzed; W , whole protein. A , Fortipré, Nestle; B , Fortema, Danone; C , FM85, Nestle; D , Enfamil, Mead Johnson; E , Similac, Ross; F , Aptamil PS, Danone; G , Preemie, Nestle; H , Beneprotein, Nestle; I , Pro-Mix, Corpak; J , Protein instant, Resource; K , HMBF+4, Prolacta; L , HMBF+6, Prolacta; M , HMBF+8, Prolacta; N , HMBF+10, Prolacta.

Box 14.8

Prolact CR 10 mL Human Milk Caloric Fortifier (Human, Pasteurized)

Product Description

• Prolact CR is pasteurized human milk cream derived from human milk. It is composed of 25% fat and provides 2.5 cal/mL. It contains no added minerals.

• Store at –20°C or colder until ready to thaw for preparation and use.

• Available frozen in 30-mL bottles containing 10 mL of product (four bottles per package).

Intended Use

• Prolact CR is intended for use with mom’s own breast milk or donor human milk to achieve a 20 cal/fl oz feeding solution.

Directions for Thawing

Under no circumstances should the product be defrosted or warmed in a microwave .

Remove bottle from the freezer and label with date and time. Thaw product using one of the following methods:

• 1.

  Refrigeration: (2° to 8°C) Place unopened bottle in refrigerator. Once thawed, must be administered within 24 hours. Do not refreeze, keep refrigerated.

• 2.

  Rapid thawing: Place bottle under lukewarm running water, or place in a water bath. Do not submerge top of bottle. Warm only until product is thawed. Continued warming, or exposure to high temperatures, could result in undesirable changes to the product. Wipe outside of bottle with appropriate disinfectant to reduce the risk for contamination. Once thawed, keep refrigerated, do not refreeze. Product must be administered within 24 hours of thawing.

Ingredients

Human milk cream and human milk ultrafiltration permeate.

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