Premature Infants and Breastfeeding

Premature Infants and Breastfeeding

Premature Infants

The data are overwhelming. Even the most reluc- tant of neonatologists have accepted the tremen- dous importance of human milk to all infants large and small.

Research in the science of nutrition for low- birth-weight (LBW) infants and micropremature infants has advanced tremendously as the technol- ogy to study the important questions has improved.

Neonatologists meanwhile have spent the past decades studying the physiology of respiration.

Their advances have contributed to the survival of smaller and smaller infants. The edge of viability is 24 weeks and a weight of 500 g; however, infants have survived under these values. One of the key points learned retrospectively about survival, gen- eration after generation, has been the critical impact of fluid and nutrition. Although human milk has gained prominence in these studies, the early use of unsupplemented drip milk and some donor milks produced poor growth patterns. Drip milk is low in fat and, therefore, low in calories. The pro- tein levels in donor milk from women late in lacta- tion (i.e., beyond 6 to 8 months, when the levels have dropped) parallel a child’s decreased biologic needs with the addition of solid foods. These fac- tors contributed to the abandonment of human milk until supplements were developed and studies of the milk of women who had delivered prema- turely sparked new investigations.

This discussion highlights only the important issues; the reader is referred to reviews such as the exhaustive summary of human milk for the prema- ture infant in the technical review of the optimal

feeding of LBW infants for the World Health Orga- nization (WHO) by Edmond and Bahl36that was released in 2006. Policy statements from WHO, UNICEF, and other international and national organizations confirm the importance of providing a mother’s own milk to preterm and small-for- gestational-age (SGA) infants. Standard practice in neonatal units is to promote mother’s own milk as the food of choice for all LBW infants.130 Edmond and Bahl state that their review confirms this position worldwide.Nutritional Needs of the Preterm Infantby Tsang et al.132is an international collabo- ration that involved many major premature infant centers in discussions to create unity out of a tre- mendous disparity of practice and various recipes for nutritional support in 1993. This collaboration also produced a consensus on individual nutrient requirements for infants of less than 1000-g birth weight, for 1000- to 1750-g infants, and for post- discharge management. In spite of these strong statements, however, neonatologists have not reached a consensus on the feeding of premature infants.69The absolute standard for evaluating the nutritional outcome of preterm infants remains undefined. A strategy to minimize mobilization of endogenous nutrient stores is moving from a focus on intrauterine-based, short-term growth and nutri- ent retention rates to a system that considers long- term growth achievement.102The optimal time to initiate oral feedings in the smallest and sickest pre- term infants is under revision.97Prolonged exclusive parenteral nutrition is being replaced with minimal amounts of oral feedings with parenteral nutrition to preserve and maintain intestinal function. As nutritional markers shift, a preterm infant’s own mother’s milk may well be recognized, even by 524

the most skeptical clinicians, as the “gold standard”

to prevent short-term morbidities and enhance long-term outcome. With this change comes the recognition that even fortified donor milk is supe- rior to artificial feeds.

LBW has been defined by WHO as a weight at birth of less than 2500 g. The global incidence of LBW is 15.5%, which includes 20.6 million infants born each year, only 35% of which occur in devel- oped countries. 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 retarda- tion, infectious disease, developmental delay, and death in infancy and childhood.

A normal full-term infant can usually be breastfed with only minor adjustments, even with- out the support of medical expertise. When an infant cannot nurse directly at the breast, is provid- ing mother’s milk appropriate? What is the overall prognosis for ever feeding at the breast or, perhaps, for survival itself? Parents are so awed by the med- ical staff of special and intensive care nurseries that they are often afraid to bring up the subject of breastfeeding. In addition, the nursery staff may be so busy balancing electrolytes and adjusting ven- tilators and monitors that they have not thought to ask what plans the mother might have had for feed- ing before the infant developed a problem (Table 15-1).

The birth of an extremely LBW (ELBW) prema- ture infant is a nutritional emergency. Even with parenteral nutrition from the first day, weight loss exceeds 10%, and it takes at least 10 days to regain birth weight. The long-term consequences of early

nutrition have a great impact on neurodevelopment and may well reduce the risk for perinatal brain lesions. Fetal and postnatal events affect gut development.

Gastrointestinal Tract Development

The gastrointestinal (GI) 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 of gestation. Intrinsic factor and pepsin are identifiable a few weeks later (Figure 15-1). Even in ELBW premature infants, the gastric pH can be lowered to 4.0. Digestive enzymes are capable of intraluminal digestion of fat, protein, and carbohydrates. Although pancre- atic lipase and bile salts are minimal in ELBW infants, the introduction of mother’s milk will stim- ulate maturation and also provide lipases and other digestive enzymes.

The intestinal villi and cellular differentiation occur at about 10 to 12 weeks’ gestation and begin a complex interrelationship with developing epithe- lium and the mesoderm, according to Newell.111 Lactase and other carbohydrate enzymes begin to appear. Gut motility is believed to appear first as irregular GI activity at 23 weeks progressing to orga- nized 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.

TABLE 15-1 Risks of Neonatal Mortality According to Timing of Initiation of Breastfeeding in Singletons Who Initiated Breastfeeding and Survived to Day 2

Initiation of Breastfeeding No. of Infants (%) No. of Deaths (% risk)∗ aOR 1 (95% CI)† aOR 2 (95% CI){

Within 1 h 4763 (43) 34 (0.7) 1 1

From 1 h to end of day 1 3105 (28) 36 (1.2) 1.45 (0.90-2.35) 1.43 (0.88-2.31)

Day 2 2138 (20) 48 (2.3) 2.70 (1.70-4.30) 2.52 (1.58-4.02)}

Day 3 797 (7.3) 21 (2.6) 3.01 (1.70-5.38) 2.84 (1.59-5.06)}

After day 3 144 (1.3) 6 (4.2) 4.42 (1.76-11.09) 3.64 (1.43-9.30)}

Total 10,947 (100) 145 (1.3)

pLRT<0.0001 pLRTẳ0.0001 ptrend<0.0001 ptrend<0.0001

*% risk, number of deaths/number of infants in exposure category.

†Adjusted for sex, birth size, gestational age, presence of a congenital anomaly, health on the day of birth, health at the time of interview, mother’s health at the time of delivery, age of mother, parity, educational level of mother, mother having cash income, household water supply, place of defecation, number of antenatal visits, place of birth, and birth attendant.

{Adjusted for all factors mentioned previously plus established breastfeeding pattern.

}The combined aOR for initiation of breastfeeding after 1 day was 2.88 (95% CI, 1.87 to 4.42).

aOR,Adjusted odds ratio;CI,confidence interval;LRT,likelihood ratio test.

Edmond KM, Zandoh C, Quigley MA, et al: Delayed breastfeeding initiation increases risk of neonatal mortality,Pediatrics 117:e380, 2006.

Gastric emptying in premature infants is slow, generating the impression that feedings are not tol- erated. Gastric emptying is enhanced by human milk and slowed by formula and increased osmolar- ity (Box 15-1). Half emptying time with human milk is reported to be as rapid as 20 to 40 minutes.70 Ultrasound studies have assessed small volume feeds. Some premature infants show delayed antral distention after a nasogastric feeding with empty- ing 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 pre- cipitates 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.12In those younger than 28 weeks, it takes 3 days to pass meconium. Breast milk feedings, however, increase motility and stool passage.

When prematurity is complicated by intrauter- ine growth failure, the resultant cascade of events includes decreased splanchnic circulation and oligohydramnios, poor gut perfusion, decreased growth of the small intestine and pancreas culmi- nating in a fetal echogenic gut, and poor intestinal motility resulting in poor tolerance to milk feeds. It is not uncommon for this to result in necrotizing enterocolitis (NEC). These events require careful consideration, including the choice to use mother’s milk, especially beginning with colostrum.

Although feeding regimens vary, evidence is strong and consistent that feeding mother’s own milk to preterm infants at any gestation is associ- ated with a lower incidence of infections and NEC and improved neurodevelopmental outcome compared with the use of bovine milk products.36 The challenge is to increase the availability of mother’s milk (Figure 15-2).

GI Priming

When feedings are delayed in any newborn, lumi- nal starvation results in epithelial cell atrophy. Lung injury may aggravate this because of multiorgan system dysfunction, increasing the risk for intesti- nal mucosal injury and associated barrier dysfunc- tion. The ultimate injury would be the invasion of bacteria from the gut lumen.21 Initiating feeds is a delicate balance between insufficient feeds that fail to trigger gut maturation and excessive feeds that overwhelm the digestive capacity. Also, exces- sive feeds can result in bacterial overgrowth and injury to the brush border.21When internal nutri- ents are absent, the intestinal size and weight are Post-menstrual age (wk)

Primitive gut formed Gut rotation

Villi

Digestive enzymes

Small intestine mature

Swallow

Gastrointestinal motor activity

Organized motility Nutritive sucking and swallowing

Structure Function

0 8 16 24 28 32 36 40

Figure 15-1. The ontogenic timetable showing structural and functional gastrointestinal development. (Modified from Newell SJ: Enteral feeding of the micropremie,Clin Perinatol27:221, 2000.)

BOX 15-1. Factors Affecting Gastric Emptying Faster gastric

emptying No effect Slower gastric emptying Breast milk

Glucose polymers Starch Medium-

chain triglycerides Prone position

Phototherapy Feed

temperature Nonnutritive

sucking

Prematurity Formula milk Caloric density Fatty acids Dextrose

concentration Long-chain

triglycerides Osmolality Illness

diminished; atrophy of the mucosa, delayed matu- ration of intestinal enzymes, and increased perme- ability and bacterial translocation may occur.

Intestinal motilities, perfusion, and reactions to the usual GI 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,83 “It is fundamentally unphysiological to deprive an infant of any gesta- tion 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 swallow- ing up to 150 mL/kg/day, which actually provides as much as 3 g/kg of protein per day. The secretion of GI hormones is believed to occur in response to the first postdelivery feedings.132In animals, after only a few days of deprivation of enteral feeds, atro- phic changes take place in the gut.85 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 hor- mones are believed to be key to the activation of the enteroinsular axis85 (Box 15-2). 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 phos- phatase activity and significant stimulation of GI

hormones such as gastrin. It also resulted in more mature intestinal motility patterns, greater absorp- tion of Ca and P, increased lactase activity, increased bone mineral content (BMC), and reduced intestinal permeability. Tyson and Ken- nedy133reviewed 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 actually at high risk for complications by virtue of their own morbidities, including mechanical ventilation, umbilical cathe- terization, and patent ductus arteriosus. Schanler123 recommended that ELBW infants who are ill be Component promotes

intestinal adaptation to extrauterine life slgA, growth factors,

hormones, oligosaccharides

Component initiates or enhances functions that

are poorly expressed in the infant lipids, cytokines,

hormones

Component prevents infection and inflammation

slgA, lactoferrin, lysozyme PAF-AH, cytokines, MFGM

oligosaccharides Component benefits, but does not compensate for,

immaturity of the intestine nucleotides, oligosaccharides,

growth factors Component

compensates for developmental immaturity of the intestine

slgA, lactoferrin, lysozyme PAF-AH, cytokines

enzymes Component is protected

from digestion slgA, lactoferrin, oligosaccharides

Component promotes establishment of beneficial microbiota

slgA, lactoferrin, α-LA oligosaccharides

Figure 15-2. Strategies for beneficial effects of bioactive agents in human milk. Human milk contains bioactive agents with overlapping and synergic effects on intestinal development of neonates. MFGM,Milk fat globule membrane; PAF-AH, platelet-activating factor-acetylhydrolase. (Modified from Goldman AS: Modulation of the gastrointestinal tract of infants by human milk. Interface and interactions. An evolutionary perspective,J Nutr130:426S, 2000.)

BOX 15-2. Biology of the Gut in VLBW Infants

• Swallows amniotic fluid daily, up to 150 mL/kg/day

• Potential for gut atrophy if not fed

• All of gastrointestinal track is immature

• Enzymes and nutrients in human milk enhance maturation

• Higher total body water, muscle mass, growth accretion rates, and oxygen consumption

• Higher evaporative water loss due to greater surface area

• Prone to hyperglycemia due to poor insulin response

• Lower brown fat reserves and glycogen stores

• Immature thyroid control of metabolic rate VLBW,Very low-birth-weight.

given small volumes, 10 to 20 mL/kg/day, in the first few days of life to continue for 3 to 7 days before advancing the feeds. Clinical stability is required before advancing the feeds. These volumes are com- patible with the volume of mother’s milk of a mother of a premature infant (Boxes 15-3and15-4). In a randomized trial of GI priming and the tube-feeding method, bolus feeding was found to be superior, the major outcome being time required to attain full oral feedings. GI priming was not associated with adverse effects. Feeding intolerance was less and the rate of weight gain was greater. The greater the amount of human milk fed, the lower the morbidity.

Although early enteral feedings are not univer- sally accepted, a number of randomized controlled studies support the concept. Berseth12reports 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 as well as higher plasma concentrations of gas- trin and gastric inhibitory peptide. From a manage- ment 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 less than 24 hours of age at 1 mL/h to infants who were fed full feeds starting at days 2 to 7 com- pared with infants on usual delayed protocols. All

showed an advantage to early feeds85(Table 15-2 andBox 15-5).

Requirements of ELBW infants begin with water, the first great need, followed by energy requirements of 120 kcal/kg/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 pro- tein accretion, Brumberg and LaGamma21 recom- mend 3.5 to 4 g/kg/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 American Academy of Pediatrics (AAP),4 WHO, and the Institute of Medicine.

Human milk is better than formula in early feeds in establishing enteral tolerance and discontinua- tion of parenteral nutrition, in long-term improved neurodevelopmental outcome, and in the psycho- logical 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 advan- tages of human milk, however.

Many investigators have concluded that mini- mal enteral feedings with human milk can optimize growth, development, and progress for small pre- mature infants, even if ventilator dependent.85 In most studies, the incidence of NEC has been similar with and without early feeds.83The presence of an umbilical catheter has long been a contraindication to feeding because of the risk for NEC. When Davey et al.30 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 and less photo- therapy. Benefits from early feeds were measurable with raw maternal milk, pasteurized premature milk, and even to some extent whey-dominant infant formula (Figure 15-3).

Low Birth Weight (LBW) Infants

All premature infants are not the same. Infants who are born weighing less than 2500 g are referred to as being low birth weight (LBW). If the infants are less than 37 weeks’ gestation, they are premature; if they are full term and LBW, they are SGA.

Very LBW(VLBW) refers to an infant weighing less than 1500 g. The probability of survival has changed dramatically in all weight ranges. With the availability of surfactant for respiratory distress, BOX 15-3. Advantages of Gastrointestinal

Priming

• Shortened time to regain birth weight

• Improved feeding tolerance

• Reduced duration of parenteral nutrition

• Enhanced enzyme maturation

• Reduced intestinal permeability

• Improved gastrointestinal motility

• Matured hormone responses

• Improved mineral absorption, mineralization

• Lowered incidence of cholestasis

• Reduced duration of phototherapy

BOX 15-4. Advantages of Priming with Mother’s Milk

• Earlier use of mother’s milk

• Mothers begin milk expression earlier

• Infants receive more mother’s milk

• Psychological advantage for mother’s safety Modified with permission from Schanler RJ, Anderson D: The

low-birth weight infant in patient care. In Duggan C, Watkins JB, Walker WA, editors:Nutrition in pediatrics,ed 4, Hamilton, 2008, BC Decker.

infants between 500 and 1000 g are surviving in greater numbers. The problems of nutrition, how- ever, pose new challenges to the neonatologist.

The feedings appropriate for a 2000-g premature infant vary only in volume and frequency from full-term infants in most cases. Feedings for VLBW infants must address the advantages and disadvan- tages 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 15-6).

The advantages of human milk for LBW infants include the physiologic amino acid and fat profile, the digestibility and absorption of these proteins

TABLE 15-2 Nutritional Milestones Prime-Continuous

(n539) Prime-Bolus

(n543) NPO-Continuous

(n544) NPO-Bolus

(n545) Duration of parenteral

nutrition (days) 3432∗ 3632 3221 3219

Milk start (days)† 62 63 163 164

Regain birth weight

(days) 125 135 125 137

Complete tube-feeding (days),{Gestation 26-27 weeks (days),} Gestation 28-30 weeks (days)

331940163019 29192673123 2993411275 2992973011

First successful oral

feeding (days) 5119 5026 4914 5218

Full oral feeding (days) 6420 6121 6418 6520

Duration of hospitalization (days)

8141 8745 8040 8124

*MeanSD.

†Different by study design.

{Interaction between gestational age and feeding method,pẳ0.001.

}Continuous versus bolus,pẳ0.001.

NPO,Nothing by mouth.

From Schanler RJ, Shulman RN, Lau C, et al: Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method,Pediatrics103:434, 1999.

BOX 15-5. Published and Putative Effects of Early Enteral Intake of Infants Weighing Less Than 1500 g

• No change in necrotizing enterocolitis incidence

• Less cholestatic jaundice

• Less osteopenia

• Less physiologic jaundice

• Increased glucose tolerance

• Better weight gain

• Earlier tolerance of full oral nutrient intake

• Increased gut hormones: gastric inhibitory peptide, enteroglucagon, gastrin, motilin, neurotension

• Induction of digestive enzyme synthesis and release

• Improved antral-duodenal coordination of peristalsis

• Allows gut colonization (vitamin K production) and avoids germ-free gut complications

• Earlier maturation of brush border barrier qualities

• Prevents atrophy and attendant effects of starvation

0 2 4 6 8 10

Pre-TPT feeds Post-TPT feeds

Apnea (1 day) (P = 0.10)

Apnea (3 days) (P = 0.02)

Brady (1 day) (P < 0.01)

Brady (3 days) (P < 0.001)

Figure 15-3. Episodes of apnea and bradycardia before and after initiation of transpyloric tube feedings especially when limited to human milk. (From Malcolm WF, Smith PB, Mears S, et al: Transpyloric tube feeding in very low birthweight infants with suspected gastroesophageal reflux: impact on apnea and bradycardia,J Perinatol29:372, 2009.)