Introduction and Summary
Necrotizing enterocolitis (NEC) was first described in 1965 and today is one of the most common life-‐threatening gastrointestinal problems associated with prematurity (Duthie & Lander, 2013). Necrotizing enterocolitis (Necrotizing-‐ causes tissue death, Enterocolitis-‐ inflamed small intestine and colon (Seattle Children's Hospital Research Foundation, 2014)) is a condition characterized by ischemic necrosis of the intestinal mucosa which is
associated with inflammation, increases in enteric gas forming organisms, and dissection of gas into the muscularis and portal venous system (Department of Pediatrics, University of Florida College of Medicine, Gainesville, USA, 1996). While the exact cause of the disease is unknown it is believed that the following factors appear to play a role:
• The infant’s gastrointestinal tract is not mature enough to properly move food when the baby is fed, resulting in irritated and inflamed intestines.
• Intestinal bacteria reproduce and the infant’s immune system is unable to protect the intestines from the bacteria, causing the intestines to become infected. The infant’s immature immune system overreacts to the infection, inflammation increases and may result in blister formation inside the intestines.
• Blood flow to the infant’s intestines is poor; this may be due to bacteria within the intestines. Improper blood flow can damage the tissue and lead to tissue death. Dead tissue increases the risk of perforation, which can lead to intestinal leakage of stool and bacteria into the abdomen, causing infections (peritonitis) (Seattle
Children's Hospital Research Foundation, 2014).
very low birth weight infants (birth weight below 1500 g) (Schanler, 2014b). The
treatment of NEC is dependent upon the severity of the illness as determined by the Bell staging criteria (Table 1).
Table 1
perforation (stage IIB) (Department of Pediatrics, University of Florida College of Medicine, Gainesville, USA, 1996). Surgical interventions are necessary in almost 20-‐40% of preterm infants with NEC (Yee et al., 2012) and 1 in 4 infants with NEC die from the disease
(Maheshwari & Waldemar, 2011).
Cost of Care
Premature infants experience a variety of medical problems, leading to an increased number of doctor’s visits and hospitalizations, which in turn results in increased monetary costs. Having a premature infant is both emotionally and financially challenging on
who required surgical intervention to treat NEC incurred the highest cost of ~$405,000 and longest average hospital stay, 108 days(Ganapathy et al., 2011).
Pathology
The pathology of NEC is primarily due to changes associated with intestinal infarction (Ballance, Dahms, Shenker, & Kliegman, 1990). The findings will vary and depend on the stage of the disease and the presence of underlying pathogenic factors. In most cases, the ileum and colon are involved, however, in more severe cases the entire gastrointestinal tract is affected (Ballance et al., 1990). Upon examination, the bowel
appears distended and hemorrhagic. Occasionally, subserosal collections of gas will present along the mesenteric border (Schanler, 2014c). Gangrenous necrosis is typically found on the antimesenteric border, and bowel perforations may be present (Schanler, 2014c). As the gastrointestinal tract heals, the bowel wall thickens, fibrous adhesions appear and areas of stenosis form(Schanler, 2014c). The common findings with NEC include mucosal edema, hemorrhage, transmural bland necrosis, acute inflammation, secondary bacterial infiltration and collections of gas(Schanler, 2014c).
Pathogenesis
The pathogenesis of NEC is unknown, however, it is believed to be a heterogeneous multifactorial disease that causes mucosal injury in a susceptible host (Schanler, 2014c). The following factors are associated with the pathogenesis of NEC:
• Prematurity
• Impaired mucosal defense
• Milk feeding
• Circulatory instability of the intestinal tract
• Medications that result in intestinal mucosal injury or enhance microbial overgrowth.
Current epidemiologic studies have identified prematurity and milk feeding as consistent risk factors for NEC (Schanler, 2014c).
Primary Risk Factors for NEC: Prematurity and Milk Feeding
A premature infant is an infant who is born at or before 37 weeks of gestation (Lee & Zieve, 2011). According to the Centers for Disease Control and Prevention (CDC), in 2012 preterm delivery affected over 450,000 infant in the United States, accounting for ~ 1 of every 9 infants born. In 2010, 35% of all infant deaths were related to preterm delivery (Centers for Disease Control and Prevention, 2014). Preterm infants often have lower birth weights than infants born at term (Lee & Zieve, 2011). Infants who are born at low birth weights (<2,500 g), and particularly infants born at very low birth weights (<1,500 g), are more likely to die within the first year of life and suffer from long-‐term physical and
The term “milk fed” refers to enteral feeds of human milk, commercially produced infant formulas or a combination of both. Over 90% of infants who develop NEC have received milk feeding, however, NEC can occurs in infants who have never been fed
(Berseth, 2005). Enteral feeding may contribute to the pathogenesis of NEC because human milk and commercial infant formulas act as substrates needed for bacterial proliferation in the gut (Berseth, 2005).
Newborns, particularly premature infants, are unable to completely digest and absorb nutrients. As a result, bacterial fermentation products of partially digested carbohydrates and lipids within the intestine of preterm infants may result in mucosal injury (Berseth, 2005). Delayed transit time due to an immature gastrointestinal tract in the premature infant further exacerbates this issue (Berseth, 2005). While NEC is
associated with enteral feeds, it remains unclear whether feeding-‐related factors such as rate of advancement and timing of initial feeding are directly linked to NEC.
slow progression of enteral feeds was not associated with a reduced risk (Morgan, Young, & McGuire, 2011b).
Human Milk and Lowering the Risk of NEC
When compared to formula, human milk is more protective against NEC in
premature infants. Infant diets that consist of exclusive human milk, appropriately fortified, have resulted in lower incidences of NEC (Cristofalo, Schanler, & Blanco, 2011; Lucas, 1990; Meinzen-‐Derr et al., 2009; Quigley & McGuire, 2014). A prospective study found that NEC was 6 to 10 time less common in preterm infants who received human milk compared to those who received formula(Lucas, 1990). This study also found that NEC was 3 times less common in those infants who received a combination of formula and human milk than those fed only formula (Lucas, 1990).
A meta-‐analysis of randomized controlled trials found that the risk of developing NEC was 2.8 times higher in formula fed infants versus infants feed human milk (Quigley & McGuire, 2014). Another study found that the risk of developing NEC decreased by a factor of 0.8 for every 10% increase in the proportion of enteral feeds that consisted of human milk (Meinzen-‐Derr et al., 2009). In another trial of 207 premature infants with birth
weights of 500 to 1250g, the rate of NEC was lower in the two groups randomly assigned to the exclusively human milk based diet compared with the group receiving mother’s milk fortified with bovine milk-‐based fortifiers and preterm formula when mothers milk was not available (Cristofalo et al., 2011). The exclusively human milk diet consisted of
out of the eight infants with NEC who received the exclusively human milk diet required surgery, while seven of the eleven infants who received the bovine milk-‐based diet required surgery (Cristofalo et al., 2011). This study demonstrated the benefits of
providing an exclusively human milk diet compared with a diet that consists of bovine-‐milk based products for EP infants (Cristofalo et al., 2011).
Factors found in human milk may play a part in protecting against NEC by reducing inflammation or the introduction of foreign antigens in the gastrointestinal tract (Schanler, 2014c). These protective factors include platelet activating factor acetylhydrolase,
secretory Immunoglobulin A, cytokines (IL-‐10, IL-‐11), epidermal growth factor, nucleotides, glutamine, and antioxidants such as Vitamin E, carotene and glutathione (Schanler, 2014c). Mechanism described in Figure 1.
(Image Reprinted from Hunter, Upperman, Ford, & Camerini, 2008)
2014c). Human milk improves digestive motility, which helps prevent milk pooling within the intestines and decreases intestinal permeability (Schanler, 2014c). Human milk has also been found to activate the mucosal defense system so that localized immune activation is prevented (Schanler, 2014c).
Benefits of Breastfeeding
The American Academy of Pediatrics (AAP) and the World Health Organizations (WHO) recognize human milk as the optimal feeding for all newborns because of the proven health benefits to infants and their mothers(American Academy of Pediatrics, 2012). Advantages of human milk include:
• Improved gastrointestinal function, digestion and absorption of vital nutrients. • Enhanced visual and cognitive development.
• Improved maternal psychological well-‐being and promotes maternal-‐infant bonding.
• Enhanced immune system with lower risk of infections such as sepsis, urinary tract infections, and necrotizing enterocolitis.
One of the most beneficial impacts of human milk in infants, particularly premature infants, is the enhanced immune system.
Barriers to Providing Exclusive Breast Milk to the Preterm Infant
establish and maintain a milk supply and transitioning from gavage feeding to nursing at the breast (Callen & Pinelli, 2005).
A major barrier to providing exclusive milk feedings to premature infants is the difficulty many mothers experience in producing sufficient quantities of milk (Schanler, 2014a). Maternal stress and/or illness, difficulty establishing and maintaining a milk supply without a suckling infant, and the biological immaturity of the mammary gland of mothers of preterm infants all negatively impact a mothers milk supply (Schanler, 2014a). Additionally, mothers of premature infants may have difficulties maintaining their milk supply due to prolonged hospitalization and separation from their newborn (Callen & Pinelli, 2005). Immediately after delivery, very low birth weight infants do not have the ability to nurse at the breast and stimulate milk production due to their immaturity and weak, ineffective suck (Callen & Pinelli, 2005). Mothers of premature infants must begin pumping to establish their milk supply and must continue pumping multiple times a day for weeks or months until their infant is able to nurse at the breast (Callen & Pinelli, 2005). When the baby is developed enough to attempt nursing at the breast, establishing an effective latch and suck can be extremely difficult. In the United States approximately 70% of term infants and mothers initiate partial or exclusive breastfeeding, while only 50% of preterm infants are breastfeeding upon hospital discharge (Callen & Pinelli, 2005).
maternal drug abuse) or where the mother chooses not to breastfeed. If exclusive human milk feedings are to be achieved in NICU’s, pasteurized donor human milk is often used (Carroll & Herrmann, 2013), however, not all hospitals have access to donor human milk. In the United States milk donors are not paid and human milk banks incur costs associated with screening, testing, pasteurizing and shipping human milk; this cost in turn is passed along to the purchaser (Carroll & Herrmann, 2013). In 2008, the average price of donor human milk in the United States was $4.077 per ounce (30mL) (Carroll & Herrmann, 2013). There are instances in which the hospital will incur the cost of donor human milk for
preterm infants based on the severity of prematurity and other medical conditions that may exist (Carroll & Herrmann, 2013; Updegrove, 2005). In many states Medicaid programs will cover some portion of the cost for the donor milk if the infant’s diagnosis warrants the use of donor human milk (Updegrove, 2005). In some cases, private insurance companies will cover the cost, and in other situations the family is responsible (Updegrove, 2005). The high cost associated with donor breast milk is often a deterrent in situations where families have to pay out-‐of-‐pocket costs.
Improving the overall health of mothers and their children is a primary goal for the Centers for Disease Control and Prevention’s Division of Nutrition, Physical Activity and Obesity (Centers for Disease Control and Prevention, 2013). Supporting and promoting breastfeeding is a key part to achieving this goal (Centers for Disease Control and
Prevention, 2013). Supporting breastfeeding is a public health priority because breast milk promotes a variety of health benefits, such as protecting against the development of NEC. Offering the necessary emotional, physical and financial support to nursing mothers,
particularly mothers of EP infants, can aid in providing an exclusive human milk-‐based diet to those infants who need it the most. For mothers unable to provide sufficient amounts of breast milk, for those that are unable to breastfeed or for those that choose not to
breastfeed, donor human milk is a necessity in protecting against the development of NEC and other complications that can arise in EP infants. Given the recent shortages of donor human milk, it is vital that efforts be made to help grow the supply of donor human milk so that premature infants are given the best nutrition possible to improve their quality of life.
Future Efforts
of new donors (Weaver, 2013). This is due to a number of factors: increased publicity and media interest in milk banking, the work of UKAMB to educate the public and potential donors on the donation process, and word-‐of-‐mouth advertising by former donors (Weaver, 2013). Increasing exposure to and awareness of milk banking has helped the UKAMB in their efforts to supply infants in the UK with needed breast milk.
transportation to donation centers can still discourage milk donors. The Human Milk Bank in Milan, at Macedonio Melloni Maternity Hospital, offers electric pumps, sterile bottles and at home pick-‐up services at regular intervals completely free of charge to donor mothers (Grovslien, Torng, Moro, Simpson, & Barnett, 2013). This eliminates a majority of the up-‐ front out of pocket costs for donors and may act as an incentive to donate expressed breast milk.
Another step to increasing supply of donor human milk would be reforming maternity leave policies in the United States. Maternity leave is the period of time that a new mother can take off from work after the birth of her baby. Maternity leave is typically created from a variety of benefits such as sick leave, vacation/holiday time, personal days, short-‐term disability and unpaid leave time (American Pregnancy Association, 2011). The Family and Medical Leave Act (FMLA) is a law requiring most companies to provide their employees up to 12 weeks of unpaid family leave time after the birth of a child (American Pregnancy Association, 2011). However, there are exceptions to the FMLA in which the business is not legally required to provide unpaid leave (American Pregnancy Association, 2011). These exceptions include the number of employees (< 50), time of employment (minimum of 1250 hours of work in past 12 months), and level of wages (top 10%)
thus hinder her ability to provide an exclusive human milk diet to her infant as well as her ability to produce extra breast milk for donation. The NGO Save the Children reports that in countries with longer periods of parental leave, children were breastfed longer and had higher life expectancy (Save the Children, 2012). Countries such as Sweden and Norway have some of the most generous parental leave policies in the world, providing more than a year of paid leave for the mother and father combined (Hurt, Killian, & Straley, 2011). The United States is the only industrialized nation that does not mandate paid parental leave (Hurt et al., 2011). Revamping the policies concerning parental leave in the United States, maternity leave in particular, to provide some financial assistance could help extend the amount of time the mother is able to spend with her infant thus increasing the duration of breast feeding. Ogbuanu et al. (2011) conducted a study to investigate the effects of
maternity leave length and time of first return to work on breastfeeding duration in United States mothers. This study concluded that if new mothers delay their return to work then breastfeeding duration is likely to lengthen (Ogbuanu, Glover, Probst, Liu, & Hussey, 2011). Providing new moms with financial assistance during this time can alleviate stress and promote breastfeeding as well as her ability to produce excess breast milk for donation.
lower the risk of NEC as well as other health conditions and in turn reduce healthcare costs in both the short term and long term.
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