Nutritional Support

Number: 0061

(Replaces CPB 144)

Policy

Notes:

1. For members with such a plan benefit, specific nutritional support is considered to be a medical item only when it is administered enterally (i.e., by feeding tube) or parenterally (i.e., by intravenous administration) where the member has either

   1. a permanent Footnotes^* non-function or disease of the structures that normally permit food to reach the small bowel; or
   2. disease of the small bowel that impairs digestion and absorption of an oral diet, either of which requires enteral or parenteral feedings to provide sufficient nutrients to maintain weight and strength commensurate with the member's overall health status. 

   Note: Not all benefit plans cover nutritional support even in the circumstances stated above.  Please check benefit plan descriptions.

2. Aetna does not cover nutritional support that is taken orally (i.e., by mouth), unless mandated by state law.  Oral nutrition is not considered a medical item.  See section on Special Medical Foods below.

3. Regular food products are not considered medical items.  Regular food products include food thickeners, baby food, gluten-free food products, high protein powders and mixes, low carbohydrate diets, normal grocery items, nutritional supplement puddings, weight-loss foods and formula (products to aid weight loss), or other regular grocery products that can be mixed in blenders and used with an enteral system regardless of whether these regular food products are taken orally or parenterally.  

Determinants of the route of administration of nutritional support include the functional status of the gastrointestinal tract and the anticipated duration of therapy.

1. Enteral Tube Feedings

   Enteral nutrition is the provision of nutritional requirements through a tube into the stomach or small intestine.

   The short-term methods of enteral tube feedings include nasogastric, nasoduodenal and, less frequently, nasojejunal tubes.  Long-term enteral feedings are best administered by a percutaneous gastrostomy or jejunostomy tube.

   Aetna considers enteral tube feedings medically necessary when the member has either 

   1. permanent Footnotes^* non-function or disease of the structures that normally permit food to reach the small bowel; or  
   2. disease of the small bowel that impairs digestion and absorption of an oral diet,

   either of which requires tube feedings to provide sufficient nutrients to maintain weight and strength commensurate with the member's overall health status.

   The member's condition could be either an anatomic abnormality (e.g., obstruction due to head and neck cancer or reconstructive surgery, etc.) or a motility disorder (e.g., severe dysphagia following a stroke, neuromuscular or disease of the central nervous system that interferes with the ability to chew or swallow, etc.).  Enteral nutrition is not considered medically necessary for members with a functioning gastrointestinal tract whose need for enteral nutrition is due to reasons such as anorexia or nausea associated with mood disorder, end-stage disease, etc.

   The member must require tube feedings to maintain weight and strength commensurate with the member's overall health status.  Adequate nutrition must not be possible by dietary adjustment and/or oral supplements.  Enteral nutrition may be considered medically necessary for members with partial impairments (e.g., a member with dysphagia who can swallow small amounts of food or a member with Crohn's disease who requires prolonged infusion of enteral nutrients to overcome a problem with absorption).

   Note: Enteral nutrition products that are administered orally and related supplies are not covered.

   Footnotes^* Note: The member must have a permanent impairment.  Permanence does not require a determination that there is no possibility that the member's condition may improve sometime in the future.  If the judgment of the doctor, substantiated in the medical record, is that the impairment can reasonably be expected to exceed 3 months (90 days), the test of permanence is considered met.  This is consistent with Center for Medicare and Medicaid Services (CMS) guidelines.

   Formulas consisting of semi-synthetic intact proteins or protein isolates (e.g., Enrich, Ensure, Ensure HN, Ensure Powder, Isocal, Lonalac Powder, Meritene, Meritene Powder, Osmolite, Osmolite HN, Portagen Powder, Renu, Sustacal, Sustagen Powder, Travasorb) are considered medically necessary for enteral feeding of the majority of older members who meet criteria for enteral feeding.  Formulas consisting of natural intact proteins or protein isolates (e.g., Compleat B, Compleat B Modified, Vitaneed) are considered medically necessary for enteral feeding of members with an allergy or intolerance to semi-synthetic formulas.  Calorically dense formulas are also considered medically necessary for enteral feedings if they are indicated.  The medical necessity for special formulas for enteral feedings must be justified in each member.

   Infant Formula

   Note: Infant formulas  are only covered if administered via the tube-feeding route and the criteria for coverage of enteral feedings are met.  Infant formulas given orally are not covered.  In addition, breast milk additive to prevent necrotizing enterocolitis in premature infants is only covered if administered via the tube-feeding route and the criteria for coverage of enteral feedings are met.

   Equipment

   Appropriate nutrients, administration supplies, and equipment are considered medically necessary for persons who meet criteria for enteral feedings.  Tube feedings are usually given by gravity feedings or syringe.  Pumps are considered medically necessary durable medical equipment (DME) only where gravity feedings or syringe feedings have caused complications or are otherwise not indicated (e.g., gravity feeding is not satisfactory due to reflux and/or aspiration, severe diarrhea, dumping syndrome, administration rate less than 100 ml/hr, blood glucose fluctuations, circulatory overload, gastrostomy/jejunostomy tube used for feeding).  More than 3 nasogastric tubes or 1 gastrostomy/jejunostomy tube every 3 months is rarely considered medically necessary.

   Note: Some Aetna plans exclude coverage of DME and supplies.  Please check benefit plan descriptions.

2. Relizorb

   Relizorb is considered experimental and investigational for use with enteral tube feedings due to insufficient evidence in the peer-reviewed literature.

3. Parenteral Nutrition/Total Parenteral Nutrition (TPN)

   Parenteral nutrition involves the delivery of micronutrients and macronutrients through catheters in central or peripheral veins.  In most instances, the central venous route is utilized; for long-term total parenteral nutrition (TPN), a central catheter (e.g., Hickman, Broviac, PIC) is burrowed through a subcutaneous tunnel on the anterior chest.

   Generally, the parenteral approach is considered medically necessary only if adequate nutritional intake is not possible via the oral or tube-feeding route.

   Aetna considers parenteral nutrition medically necessary for members who meet any of the following criteria:

   1. Documentation of a failure of enteral (i.e., oral or tube feeding) nutrition, as defined by either of the following:

      1. A non-edematous or post-dialysis documented loss of greater than 10 % of body weight over a 3-month period; or

      2. Total protein less than 6 g/dL or serum albumin less than 3.4 g/dL;

   2. A condition in which it is necessary for the gastrointestinal tract to be totally non-functioning for a period of time;
   3. Evidence of structural or functional bowel disease that makes oral and tube feedings inappropriate;
   4. Hyperemesis gravidarum (only in cases of failed medical management or when used in a step-therapy program);
   5. Member is peri-operative (regardless of disease state) and unable to tolerate oral or tube feedings.

   Parenteral nutrition may be either “self-mixed” (i.e., the member or family caregiver is taught to prepare the nutrient solution aseptically) or “pre-mixed”.  The doctor must justify the need for pre-mixed parenteral nutritional solutions.

   Parenteral nutrition is not considered medically necessary for members with a functioning gastrointestinal tract whose need for parenteral nutrition is only due to:

   1. A physical disorder impairing food intake such as the dyspnea of severe pulmonary or cardiac disease;
   2. A psychological disorder impairing food intake such as depression;
   3. A side effect of a medication;
   4. A swallowing disorder;
   5. A temporary defect in gastric emptying such as a metabolic or electrolyte disorder;
   6. Disorders inducing anorexia such as cancer;
   7. Renal failure and/or dialysis. Footnotes^*

   Footnotes^*Members receiving intra-dialytic parenteral nutrition must meet the criteria for total parenteral nutrition set forth above.

   Aetna considers intra-peritoneal nutrition experimental and investigational.  Aetna considers intra-peritoneal amino acid (IPAA) supplementation medically necessary for members on peritoneal dialysis when all of the following criteria are met:

   1. Inability to administer or tolerate adequate oral protein nutrition, including food supplements, or enteral tube feeding; and
   2. The combination of some oral or enteral intake that, when combined with IPAA, will meet the individual's nutritional goals; and
   3. There is evidence of inadequate dietary protein intake and protein malnutrition.

   Equipment

   If the criteria for parenteral nutrition are met, medically necessary nutrients, administration supplies, and equipment are considered medically necessary.

4. Special Medical Foods Taken Orally

   Note: Aetna covers special medical foods only when mandated by state law.

   Special medical foods are used for the treatment of inborn errors of metabolism (histidinemia, homocystinuria, maple syrup urine disease [MSUD], phenylketonuria [PKU], and tyrosinemia).  The special oral formulas are designed to restrict intake of one or more amino acids.  Some states now have mandates requiring coverage of these dietary formulas.

   Aetna does not cover banked breast milk, food supplements, specialized infant formulas, vitamins and/or minerals taken orally (i.e., by mouth).

   Food supplements, specialized infant formulas (e.g., Alimentum, Elecare, Neocate, and Nutramigen), lactose-free foods, vitamins and/or minerals may be used to replace intolerable foods, for lactose intolerance, to supplement a deficient diet, or to provide alternative nutrition in the presence of such conditions as allergies, gastrointestinal disorders, hypoglycemia, and obesity.  Food supplements, lactose-free foods, specialized infant formulas, vitamins and/or minerals taken orally are not covered, even if they are required to maintain weight or strength and regardless of whether these are prescribed by a physician.

   Most Aetna plans do not specifically include coverage of infant formulas when taken orally.  In the absence of a specific inclusion or state mandate, specialized infant formulas are not covered.

5. Enteral Nutrition/Enteral Feeding

   Aetna considers enteral nutrition for induction and maintenance of remission in adults with Crohn's disease experimental and investigational because of insufficient evidence in the peer-reviewed literature.

Background

Parenteral nutrition involves the delivery of micronutrients and macronutrients through catheters in central or peripheral veins.  In most instances, the central venous route is utilized, and for long-term total parenteral nutrition a central catheter (e.g., Hickman, Broviac, PIC) is burrowed through a subcutaneous tunnel on the anterior chest.

Enteral nutrition can be administered via a small catheter placed through the nose into the stomach or by a surgically placed catheter into the stomach or intestines.  Enteral nutrition therapy may supplement protein and calories in a variety of situations where oral nutrition is not adequate, with the intention of providing part or all of the daily requirements.  Specialized diets for specific diseases or pathophysiologic situations may be administered via enteral nutrition.  These specialized diets may involve restricting a particular element of the diet (e.g., fat, lactose), adding a particular nutrient that may be required in larger amounts than are available from a regular diet (e.g., calcium, potassium), or altering the consistency of the diet (e.g., high-fiber, full-liquid).

The need for specialized foods is very common, and for most conditions, the specialized food is needed for the person's entire lifetime.  For example, in Europe and the United States, the prevalence of lactose intolerance is 7 to 20 % in Caucasians, and is as high as 80 to 95 % among Native Americans, 65 to 75 % among Africans and African Americans, and 50 % in Hispanics (Scrimshaw et al, 1988).  The prevalence exceeds 90 % in some populations in eastern Asia.

Another example of a common medical condition requiring a specialized diet is celiac disease (also called gluten-sensitive enteropathy and non-tropical sprue), with a prevalence of almost 1 % of the population (Fasano et al, 2003).  There are many other examples where specialized diets are prescribed, which could extend to specialized diets for hypertension, diabetes, or cardiovascular disease.

Aetna's policy on parenteral and enteral nutrition is similar to Medicare policy.  Medicare provides reimbursement under the part-B prosthetic-device benefit for parenteral and enteral nutrition.  Consistent with its policy of covering supplies necessary for use of prosthetics, Medicare will generally cover medically necessary supplies, equipment, and nutrients associated with parenteral and enteral nutrition if the coverage requirements for enteral or parenteral nutritional therapy are met under the prosthetic device benefit provision.

Sullivan et al (2010) evaluated the health benefits of an exclusively human milk-based diet compared with a diet of both human milk and bovine milk-based products in extremely premature infants.  Infants fed their own mothers' milk were randomized to 1 of 3 study groups.  Groups HM100 and HM40 received pasteurized donor human milk-based human milk fortifier (HMF) when the enteral intake was 100 and 40 ml/kg/day, respectively, and both groups received pasteurized donor human milk if no mother's milk was available.  Group BOV received bovine milk-based HMF when the enteral intake was 100 ml/kg/day and preterm formula if no mother's milk was available.  Outcomes included duration of parenteral nutrition, morbidity, and growth.  The 3 groups (total n = 207 infants) had similar baseline demographic variables, duration of parenteral nutrition, rates of late-onset sepsis, and growth.  The groups receiving an exclusively human milk diet had significantly lower rates of necrotizing enterocolitis (NEC; p = 0.02) and NEC requiring surgical intervention (p = 0.007).  The authors concluded that for extremely premature infants, an exclusively human milk-based diet is associated with significantly lower rates of NEC and surgical NEC when compared with a mother's milk-based diet that also includes bovine milk-based products.

Ganapathy et al (2012) evaluated the cost-effectiveness of a 100 % human milk-based diet composed of mother's milk fortified with a donor human milk-based HMF versus mother's milk fortified with bovine milk-based HMF to initiate enteral nutrition among extremely premature infants in the neonatal intensive care unit (NICU).  A net expected costs calculator was developed to compare the total NICU costs among extremely premature infants who were fed either a bovine milk-based HMF-fortified diet or a 100 % human milk-based diet, based on the previously observed risks of overall NEC and surgical NEC in a randomized controlled study that compared outcomes of these 2 feeding strategies among 207 very low birth-weight infants.  The average NICU costs for an extremely premature infant without NEC and the incremental costs due to medical and surgical NEC were derived from a separate analysis of hospital discharges in the state of California in 2007.  The sensitivity of cost-effectiveness results to the risks and costs of NEC and to prices of milk supplements was studied.  The adjusted incremental costs of medical NEC and surgical NEC over and above the average costs incurred for extremely premature infants without NEC, in 2011 US$, were $74,004 (95 % confidence interval [CI]: $47,051 to $100,957) and $198,040 (95 % CI: $159,261 to $236,819) per infant, respectively.  Extremely premature infants fed with 100 % human-milk based products had lower expected NICU length of stay and total expected costs of hospitalization, resulting in net direct savings of 3.9 NICU days and $8,167.17 (95 % CI: $4,405 to $11,930) per extremely premature infant (p < 0.0001).  Costs savings from the donor HMF strategy were sensitive to price and quantity of donor HMF, percentage reduction in risk of overall NEC and surgical NEC achieved, and incremental costs of surgical NEC.  The authors concluded that compared with feeding extremely premature infants with mother's milk fortified with bovine milk-based supplements, a 100 % human milk-based diet that includes mother's milk fortified with donor human milk-based HMF may result in potential net savings on medical care resources by preventing NEC.

Relizorb

Fat malabsorption is most common in individuals who cannot produce or secrete adequate amounts of digestive enzymes because of compromised pancreatic function. According to current United European Gastroenterology guidelines (Lohr, et al., 2018), "enteral nutrition is indicated with PERT [pancreatic enzyme replacement therapy] administered alongside where necessary (GRADE 2C, strong agreement)" in persons with pancreatic insufficiency who are unable to achieve adequate intake with oral nutrition.

There is little evidence to support how PERT is best administered and optimised in people with CF receiving enteral nutrition (van der Haak & Kench, 2017). In the absence of sufficient evidence, a number of techniques have been described including oral administration, PERT suspended in juice, PERT dissolved in bicarbonate and administered via an enteral feeding tube, and administration of crushed microspheres via an enteral feeding tube.

According to the manufacturer, Relizorb is considered a first of it's kind enzyme cartridge.  It is designed to mimic the action of pancreatic lipase for use in adults receiving enteral tube feedings (Medscape, 2015). Relizorb is an enzyme packed cartridge indicated for use in adults to hydrolyze fats in entral formula. The cartridge fits in line with enteral feeding systems, and is connected between the infusion pump and the feeding tube. The active ingredient is the digestive enzyme lipase, attached to polymetric carriers together called iLipase. As the formula passes through Relizorb, it makes contact with the iLipase, and fats in the formula are modified to more absorbable forms prior to ingestion. It was cleared for marketing by the Food and Drug Administration (FDA) for this indication.  However, efficacy data are limited and Relizorb has not been compared to other methods of administration of PERT. Therefore, there is an insufficient evidence base to support its use at this time.

Schwarzenberg and associates (2016) stated that nutrition is integral to the care of individuals with cystic fibrosis (CF).  Better nutritional status is associated with improved pulmonary function.  In some individuals with CF, enteral tube feeding can be useful in achieving optimal nutritional status.  Current nutrition guidelines do not include detailed recommendations for enteral tube feeding.  The Cystic Fibrosis Foundation convened an expert panel to develop enteral tube feeding recommendations based on a systematic review of the evidence and expert opinion.  These guidelines addressed when to consider enteral tube feeding, assessment of confounding causes of poor nutrition in CF, preparation of the patient for placement of the enteral feeding tube, management of the tube after placement and education about enteral feeding.  These recommendations are intended to guide the CF care team, individuals with CF, and their families through the enteral tube feeding process.  The guideline stated that an inline cartridge enzyme (lipase) delivery system for enteral feeds was approved by the FDA for adults during the development of these guidelines; evaluation of its benefits and limits should be considered before use.

In a multi-center, randomized, double-blind, cross-over, open-label clinical trial, Freedman and colleagues (2017) evaluated the safety, tolerability, and fat absorption of a new in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula provided to patients with CF.  Plasma omega-3 fatty acid (FA) concentrations were measured and used as markers of fat absorption.  Gastro-intestinal symptoms were recorded to evaluate safety and tolerability.  Information regarding the effect of enteral nutrition (EN) on appetite and breakfast consumption was also collected.  Before study entry, participants had received EN for a mean of 6.6 years at a mean volume of approximately 800 ml, yet had a mean body mass index (BMI) of only 17.5 kg/m and omega-3 FA plasma concentrations were only 60 % of levels found in normal healthy subjects.  Compared with placebo, cartridge use resulted in a statistically significant 2.8-fold increase in plasma omega-3 FA concentrations.  There were no adverse experiences associated with cartridge use, and a decrease in the frequency and severity of most symptoms of malabsorption was observed with cartridge use.  Participants reported increased preservation of appetite and breakfast consumption with cartridge use compared with their pre-study regimen.  The authors concluded that the use of this in-line digestive cartridge was safe and well-tolerated, and resulted in significantly increased levels of plasma omega-3 FA used with enteral formula, suggesting an overall increased fat absorption. 

The authors of this manufacturer-sponsored study stated that the main drawback of this study was the small sample size (n = 34).  Despite the relatively small sample size, the study, however, included approximately 1 % of the population of patients with CF who receive EN.  In addition, the age range of the study population is representative of the population of patients with CF in the United States.  The authors stated that these study results should be generalizable to the larger population of patients with CF and exocrine pancreatic insufficiency who receive supplemental EN.  Only 1 feeding through digestive cartridge was, however, used to measure its effect on fat absorption, and only 7 days of digestive cartridge use were used to measure its safety.  They stated that a longer-term study is currently ongoing to assess the effects of sustained digestive cartridge use, particularly without concomitant pancreatic enzyme replacement therapy.

Alkaade and Vareedayah (2017) stated that exocrine pancreatic insufficiency (EPI) is characterized by a deficiency of exocrine pancreatic enzymes, resulting in deficits in digestion of all macronutrients, with deficiencies in digestion of fats being the most clinically relevant.  The leading cause of EPI is chronic pancreatitis.  However, many other causes and conditions may be implicated, including CF, pancreatic duct obstruction, gastric and pancreatic surgery, diabetes mellitus and other conditions.  Physical and biochemical causes of EPI include decreased production and secretion of lipase, increased lipase destruction, pancreatic duct obstruction, decreased lipase stimulation and degradation, as well as gastro-intestinal (GI) motility disorders.  Exocrine pancreatic insufficiency is largely diagnosed clinically, and is often identified by symptoms such as steatorrhea, weight loss, abdominal discomfort, and abdominal bloating.  Lifestyle modifications (e.g., smoking cessation, limiting or avoiding alcoholic drinks, and reducing dietary fat intake) and exogenous pancreatic enzyme supplements are commonly used to help restore normal digestion and absorption of dietary nutrients in patients with EPI.  The authors noted that approximately 44 % of patients with CF require oral supplemental nutrition, and 11 % require enteral tube feeding.  Nutrient utilization may be improved using semi-elemental or elemental enteral products or dosing pancreatic enzyme replacement therapy (PERT) with enteral feedings.  Additionally, a recently approved in-line medical device with immobilized lipase (Relizorb) has been developed to hydrolyze fats in enteral formula.

Nguyen (2017) noted that EN is preferred over parenteral nutrition (PN) as a result of the greater safety of EN therapy and comparative convenience.  A wide variety of EN products have been developed, including disease-specific products to help manage the nutritional needs of patients with kidney failure, liver failure, lung disease, diabetes, and other conditions.  An assessment of each patient's nutritional needs and digestive function should be conducted prior to initiation of EN therapy.  Other considerations in determining the appropriate route and method of EN administration include the time and nursing involvement required for administration, potential complications of medication administration, and concerns related to pancreatic dysfunction in certain groups.  The author noted that (i) a recently approved in-line medical cartridge with immobilized lipase (Relizorb) hydrolyzes fats in enteral formulas just prior to delivery into the patient with an enteral feeding tube; and (ii) to eliminate the challenges of PERT administration, the Cystic Fibrosis Foundation indicates Relizorb may be used to deliver enteral formula in this population.

Freedman (2017) stated that patients with EPI have suboptimal secretion of pancreatic digestive enzymes and experience a range of clinical symptoms related to the malabsorption of fat.  In patients with EPI unable to meet their nutritional requirements, EN support is used to augment nutritional status.  In addition to protein and carbohydrate, EN formulas contain fats as a calorie source, as well as vitamins and minerals to help prevent nutritional deficiencies related to malabsorption.  Semi-elemental EN formulas are advantageous as they contain hydrolyzed protein, shorter chain carbohydrates, and may contain medium chain triglycerides as a fat source.  However, severely pancreatic insufficient patients may be unable to absorb complex long-chain triglycerides provided by EN formulas due to insufficient pancreatic lipase; replacement pancreatic enzyme products are recommended for these patients.  The author stated that currently, none of the FDA-approved PERT products are indicated for use in patients receiving EN and administration of enzymes by mixing into EN formula is not supported by guidelines as this route is associated with risks.  Relizorb (immobilized lipase) is a novel in-line digestive cartridge that has been designed to address the unmet need for PERT in patients receiving EN.  Relizorb efficacy and compatibility with a range of commercially available polymeric and semi-elemental formulas with varying nutrient, caloric content, and triglyceride chain lengths have been demonstrated.  In most formulas, Relizorb efficiently hydrolyzed greater than 90 % of fats within the formula into absorbable FAs and monoglycerides.

Freedman and colleagues (2018) noted that PI and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased GI symptoms; thus, EN is used in patients with CF and poor nutritional status. In an industry-sponsored study, these researchers evaluated safety, tolerability and improvement of FA status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula.  Patients with CF receiving EN participated in a multi-center, 90-day open-label study during which Relizorb was used with overnight EN.  The primary end-point was change over time in RBC uptake of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); GI symptoms were collected to evaluate safety and tolerability.  Several clinical and anthropometric parameters were also assessed throughout the study.  A total of 36 subjects completed the study with a mean age of 13.6 years, BMI of 17.7 and 6.2 years mean use of over-night EN.  Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA; Relizorb use was not associated with any unanticipated adverse events (AEs).  The authors concluded that this study established the safety and tolerability of Relizorb and showed its potential to normalize fat absorption, improve symptoms commonly associated with fat mal-absorption and enhance nutritional status in patients with CF receiving EN feedings.  They stated that this was the 1st prospective study to show EN can improve FA abnormalities in CF.  Since improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, Relizorb may have important long-term therapeutic benefits in patients with CF.  Moreover, these investigators stated that it is not possible to draw definitive conclusions from the current and previous Relizorb studies regarding the influence of Relizorb use on changes in patient anthropometric measurements.

The authors stated that this study had several drawbacks.  It was a relatively small study (n = 36).  In addition, the study was strictly open-label and was not intended to compare outcomes between participants who did and did not use Relizorb.  Furthermore, other than enteral nutrition, dietary intake was not recorded during the study, limiting the ability to determine if oral caloric intake was adequate to lead to weight gain.  Additionally, the study may not have been long enough to observe an increase in body weight or BMI for patients in a relatively fat-starved condition.  Furthermore, because the current study did not measure body tissue composition, it is unknown whether subjects improved their tissue composition without changing body weight or size.  It may turn out that nutritional health may be more accurately measured using biomarkers other than the traditional body weight and BMI.  Body tissue composition, including fat mass, fat-free mass, and lean body mass may be more important to overall health than body size or mass.  It is likely that body tissue composition is an indirect measure of important cellular and molecular processes that may be directly measured using molecules such as long-chain polyunsaturated FAs (LCPUFAs), which are essential building blocks of cell membranes and play important roles in cell and tissue function throughout the body.

Formula versus Donor Breast Milk for Feeding Preterm or Low Birth Weight Infants

Quigley and colleagues (2018) noted that when sufficient maternal breast milk is not available, alternative forms of EN for preterm or low birth weight (LBW) infants are donor breast milk or artificial formula.  Donor breast milk may retain some of the non-nutritive benefits of maternal breast milk for preterm or LBW infants.  However, feeding with artificial formula may ensure more consistent delivery of greater amounts of nutrients.  Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or LBW infants.  In a Cochrane review, these investigators determined the effect of feeding with formula compared with donor breast milk on growth and development in preterm or LBW infants.  They used the Cochrane Neonatal search strategy, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 6), Ovid Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (until June 8, 2017), as well as conference proceedings and previous reviews.  Randomized or quasi-randomized controlled trials (RCTs) comparing feeding with formula versus donor breast milk in preterm or LBW infants were selected for analysis.  Two review authors assessed trial eligibility and risk of bias and extracted data independently.  They analyzed treatment effects as described in the individual trials and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data, and mean differences (MDs) for continuous data, with respective 95 % CIs.  These researchers used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in subgroup analyses.  They assessed the quality of evidence for the main comparison at the outcome level using "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methods.  A total of 11 trials, in which 1,809 infants participated in total, fulfilled the inclusion criteria; 4 trials compared standard term formula versus donor breast milk; and 7 compared nutrient-enriched preterm formula versus donor breast milk.  Only the 4 most recent trials used nutrient-fortified donor breast milk.  The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in 4 trials and lack of blinding in most of the trials.  Formula-fed infants had higher in-hospital rates of weight gain (MD 2.51, 95 % CI: 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95 % CI: 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95 % CI: 0.47 to 1.23 mm/week).  These researchers did not find evidence of an effect on long-term growth or neurodevelopment.  Formula feeding increased the risk of necrotizing enterocolitis (typical RR 1.87, 95 % CI: 1.23 to 2.85; RD 0.03, 95 % CI: 0.01 to 0.06).  The GRADE quality of evidence was moderate for rates of weight gain, linear growth, and head growth (down-graded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all-cause mortality, and necrotizing enterocolitis (down-graded for imprecision).  The authors concluded that in preterm and LBW infants, feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, resulted in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotizing enterocolitis.  The trial data did not show an effect on all-cause mortality, or on long-term growth or neurodevelopment.

Enteral Nutrition for Induction / Maintenance of Remission in Crohn's Disease

Narula and associates (2018) noted that corticosteroids are often preferred over EN as induction therapy for Crohn's disease (CD).  Prior meta-analyses suggested that corticosteroids are superior to EN for induction of remission in CD.  Treatment failures in EN trials are often due to poor compliance, with drop-outs frequently due to poor acceptance of a naso-gastric (NG) tube and unpalatable formulations.  This systematic review was an update of a previously published Cochrane review.  These investigators evaluated the safety and effectiveness of exclusive EN as primary therapy to induce remission in CD and examined the importance of formula composition on effectiveness.  They searched Medline, Embase and CENTRAL from inception to July 5, 2017.  They also searched references of retrieved articles and conference abstracts; RCTs involving patients with active CD were considered for inclusion.  Studies comparing one type of EN to another type of EN or conventional corticosteroids were selected for review.  Data were extracted independently by at least 2 authors.  The primary outcome was clinical remission; secondary outcomes included adverse events (AEs), serious adverse events (SAEs) and withdrawal due to AEs.  For dichotomous outcomes, these researchers calculated the RR and 95 % CI.  A random-effects model was used to pool data.  They performed intention-to-treat (ITT) and per-protocol analyses for the primary outcome.  Heterogeneity was explored using the Chi-2 and I2 statistics.  The studies were separated into 2 comparisons: one EN formulation compared to another EN formulation; and EN compared to corticosteroids.  Subgroup analyses were based on formula composition and age.  Sensitivity analyses included abstract publications and poor quality studies.  These investigators used the Cochrane risk of bias tool to assess study quality.  They used the GRADE criteria to assess the overall quality of the evidence supporting the primary outcome and selected secondary outcomes.  A total of 27 studies (1,011 participants) were included; 3 studies were rated as low risk of bias; 7 studies were rated as high risk of bias, and 17 were rated as unclear risk of bias due to insufficient information; 17 trials compared different formulations of EN, 13 studies compared 1 or more elemental formulas to a non-elemental formula, 3 studies compared EN diets of similar protein composition but different fat composition, and 1 study compared non-elemental diets differing in glutamine enrichment.  Meta-analysis of 11 trials (378 subjects) demonstrated no difference in remission rates; 64 % (134/210) of patients in the elemental group achieved remission compared to 62 % (105/168) of patients in the non-elemental group (RR 1.02, 95 % CI: 0.88 to 1.18; GRADE very low quality).  A per-protocol analysis (346 participants) produced similar results (RR 1.04, 95 % CI: 0.91 to 1.18).  Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no differences in remission rates.  An analysis of 7 trials including 209 patients treated with EN formulas of differing fat content (low fat: less than 20 g/1,000 kCal versus high fat: greater than 20 g/1,000 kCal) demonstrated no difference in remission rates (RR 1.03; 95 % CI: 0.85 to 1.26).  Very low fat content (less than 3 g/1,000 kCal) and very low long chain triglycerides demonstrated higher remission rates than higher content EN formulas.  There was no difference between elemental and non-elemental diets in AEs rates (RR 1.00, 95 % CI: 0.63 to 1.60; GRADE very low quality), or withdrawals due to AEs (RR 1.29, 95 % CI: 0.80 to 2.09; GRADE very low quality).  Common AEs included nausea, vomiting, diarrhea and bloating.  A total of 10 trials compared EN to steroid therapy.  Meta-analysis of 8 trials (223 participants) demonstrated no difference in remission rates between EN and steroids; 50 % (111/223) of patients in the EN group achieved remission compared to 72 % (133/186) of patients in the steroid group (RR 0.77, 95 % CI: 0.58 to 1.03; GRADE very low quality).  Subgroup analysis by age showed a difference in remission rates for adults but not for children.  In adults, 45 % (87/194) of EN patients achieved remission compared to 73 % (116/158) of steroid patients (RR 0.65, 95 % CI: 0.52 to 0.82; GRADE very low quality).  In children, 83 % (24/29) of EN patients achieved remission compared to 61 % (17/28) of steroid patients (RR 1.35, 95 % CI: 0.92 to 1.97; GRADE very low quality).  A per-protocol analysis produced similar results (RR 0.93, 95 % CI: 0.75 to 1.14).  The per-protocol subgroup analysis showed a difference in remission rates for both adults (RR 0.82, 95 % CI: 0.70 to 0.95) and children (RR 1.43, 95 % CI: 1.03 to 1.97).  There was no difference in AEs rates (RR 1.39, 95 % CI: 0.62 to 3.11; GRADE very low quality).  However, patients on EN were more likely to withdraw due to AEs than those on steroid therapy (RR 2.95, 95 % CI: 1.02 to 8.48; GRADE very low quality).  Common AEs reported in the EN group included heartburn, flatulence, diarrhea and vomiting, and for steroid therapy acne, moon facies, hyperglycemia, muscle weakness and hypoglycemia.  The most common reason for withdrawal was inability to tolerate the EN diet.

The authors concluded that very low quality evidence suggested that corticosteroid therapy may be more effective than EN for induction of clinical remission in adults with active CD.  Very low quality evidence also suggested that EN may be more effective than steroids for induction of remission in children with active CD.  Protein composition did not appear to influence the effectiveness of EN for the treatment of active CD.  EN should be considered in pediatric CD patients or in adult patients who can comply with NG tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided.  These researchers stated that further research is needed to confirm the superiority of corticosteroids over EN in adults; and further research is needed to confirm the benefit of EN in children.  Furthermore, they stated that more effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a NG tube as this may lead to increased patient adherence with this therapy.

Akobeng and colleagues (2018) stated that prevention of relapse is a major issue in the management of quiescent CD.  Current therapies (e.g., methotrexate, biologics, 6-mercaptopurine and azathioprine) may be effective for maintaining remission in CD, but these drugs may cause significant AEs.  Interventions that are safe and effective for maintenance of remission in CD are desirable.  These investigators evaluated the safety and efficacy of EN for the maintenance of remission in CD and examined the impact of formula composition on effectiveness.  They searched Medline, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and clinicaltrials.gov from inception to July 27, 2018.  They also searched references of retrieved studies and reviews; RCTs including participants of any age with quiescent CD were considered for inclusion.  Studies that compared EN with no intervention, placebo or any other intervention were selected for review.  Two authors independently screened studies for inclusion, extracted data and assessed methodological quality using the Cochrane risk of bias tool.  The primary outcome was clinical or endoscopic relapse as defined by the primary studies.  Secondary outcomes included anthropometric measures (i.e., height and weight), quality of life (QOL), AEs, serious AEs (SAEs) and withdrawal due to AEs.  These researchers calculated the RR and 95 % CI for dichotomous outcomes.  For continuous outcomes, they calculated the MD and 95 % CI.  A random-effects model was used for the statistical analysis.  These researchers used the GRADE criteria to assess the overall certainty of the evidence supporting the primary outcome and selected secondary outcomes.  A total of 4 RCTs (262 adult participants) met the inclusion criteria; 1 study (n = 33) compared an elemental diet to a non-elemental (polymeric) diet; 1 study (n = 51) compared a half elemental diet to a regular free diet.  Another study (n = 95) compared an elemental diet to 6-mercaptopurine (6-MP) or a no treatment control group; 1 study (n = 83) compared a polymeric diet to mesalamine; 2 studies were rated as high risk of bias due to lack of blinding or incomplete outcome data.  The other 2 studies were judged to have an unclear risk of bias.  The studies were not pooled due to differences in control interventions and the way outcomes were assessed.  The effect of an elemental diet compared to a polymeric diet on remission rates or withdrawal due to AEs was uncertain; 58 % (11/19) of participants in the elemental diet group relapsed at 12 months compared to 57 % (8/14) of participants in the polymeric diet group (RR 1.01, 95 % CI: 0.56 to 1.84; very low certainty evidence); 32 % (6/19) of participants in the elemental diet group were intolerant to the enteral nutritional formula because of taste or smell and were withdrawn from the study in the first 2 weeks compared to zero participants (0/14) in the polymeric diet group (RR 9.75, 95 % CI: 0.59 to 159.93; low certainty evidence).  Anthropometric measures, QOL, AEs and SAEs were not reported as outcomes.  The effect of an elemental diet (half of total daily calorie requirements) compared to a normal free diet on relapse rates was uncertain; 35 % (9/26) of participants in the elemental diet group relapsed at 12 months compared to 64 % (16/25) of participants in the free diet group (RR 0.54, 95 % CI: 0.30 to 0.99; very low certainty evidence).  No AEs were reported.  This study reported no differences in weight change between the 2 diet groups.  Height and QOL were not reported as outcomes.  The effect of an elemental diet compared to 6-MP on relapse rates or AEs was uncertain; 38 % (12/32) of participants in the elemental diet group relapsed at 12 months compared to 23 % (7/30) of participants in the 6-MP group (RR 1.61; 95 % CI: 0.73 to 3.53; very low certainty evidence); 3 % (1/32) of participants in the elemental diet group had an AE compared to 13 % (4/30) of participants in the 6-MP group (RR 0.23, 95 % CI: 0.03 to 1.98; low certainty evidence); AEs in the elemental diet group included surgery due to worsening CD; AEs in the 6-MP group included liver injury (n = 2), hair loss (n = 1) and surgery due to an abscess (n = 1).  No SAEs or withdrawals due to AEs were reported.  Weight, height and QOL were not reported as outcomes.  The effect of a polymeric diet compared to mesalamine on relapse rates and weight was uncertain; 42 % (18/43) of participants in the polymeric diet group relapsed at 6 months compared to 55 % (22/40) of participants in the mesalamine group (RR 0.76; 95 % CI: 0.49 to 1.19; low certainty evidence).  The MD in weight gain over the study period was 1.9 kg higher in the polymeric diet group compared to mesalamine (95 % CI: -4.62 to 8.42; low certainty evidence); 2 participants in the polymeric diet group experienced nausea and 4 had diarrhea.  It was unclear if any participants in the mesalamine group had an AE.  Height, QOL, SAEs and withdrawal due to AEs were not reported as outcomes.

The authors concluded that the findings of this review were uncertain and no firm conclusions regarding the safety and efficacy of EN in quiescent CD could be drawn.  They stated that more research is needed to determine the safety and efficacy of using EN as maintenance therapy in CD.  Currently, there are 4 ongoing studies (estimated enrolment of 280 participants).  This review will be updated when the results of these studies are available.

Guidelines on clinical nutrition in inflammatory bowel disease from the European Society for Parentaral and Enteral Nutrition (Forbes, et al., 2017) state that "there is no 'IBD diet' that can be generally recommended to promote remission in IBD patients with active disease." The guidelines noted that, due to strong concerns over corticosteroid use and aiming for optimal growth in children, enteral nutrition is often first-line therapy for pediatric patients with active Crohn's disease. The guidelines noted that, although enteral nutrition as primary therapy in adults with Crohn's disease has also repeatedly been considered to be effective "the data are not robust." The guidelines note that "meta-analyses do not support the use of EN as primary treatment for acute exacerbations of CD in adults. Patchy clinical conviction and the data, which appear better than might be expected with placebo, ensure continuing controversy over its role in adults."

The above policy is based on the following references: