Premature neonates are at high risk for growth failure and a host of morbidities including sepsis, chronic lung disease, necrotizing enterocolitis, retinopathy of prematurity, cholestasis, and neurodevelopmental impairment. Nutrition plays an important role in modulating disease. Virtually all extremely low birth weight neonates (birth weight less than 1 kg) receive parenteral nutrition and intravenous lipids in order to promote optimal nutrition and growth. Intravenous lipids provide nonprotein calories and the essential fatty acids linoleic acid (an omega-6 fatty acid) and alpha-linoleic acid (an omega-3 fatty acid). High omega-6:omega-3 fatty acid ratios promote inflammation and have been associated with various adult-onset diseases, including cardiovascular disease, diabetes, and cancer.
Currently, the only Food and Drug Administration–approved lipid emulsion is entirely soybean based (Intralipid). This lipid emulsion contains a high omega-6:omega-3 fatty acid ratio, high concentrations of linoleic and alpha-linoleic acid, and lacks arachidonic acid (ARA, an omega-6 fatty acid) and docosahexaenoic acid (DHA, an omega-3 fatty acid). Moreover, soybean oil contains a small amount of vitamin E, an antioxidant which helps prevent lipid peroxidation and oxidative stress. A non–FDA approved lipid emulsion (SMOFlipid) is currently being prescribed to children, including preterm neonates, in Europe. SMOFlipid contains a “mix” of various oils (30% soy, 15% fish, 30% coconut, and 25% olive oil) and a higher concentration of Vitamin E (48 mg/dL vs. 38 mg/dL). In comparison with soybean oil, SMOFlipid’s fatty acid content more closely resembles breast milk with a more physiologically appropriate omega-6:omega-3 fatty acid ratio. As a result, SMOFlipid theoretically may have the capability to modulate disease by decreasing systemic inflammation and tissue injury.
In small retrospective and randomized controlled trials, preterm neonates who received SMOFlipid have increased ARA, DHA, and vitamin E concentrations and decreased markers of oxidative stress, compared with neonates who received standard soybean oil1-3. Improving the DHA and ARA status in preterm neonates has several theoretical advantages. DHA and ARA are preferentially transferred to the fetus during the third trimester of pregnancy, and found in significant quantities in the brain, retina, and breast milk. Under normal physiological conditions, linoleic and alpha-linoleic acid, which cannot be synthesized de novo, are metabolized to ARA and DHA. Despite being provided with linoleic and alpha-linoleic acid in intravenous soybean oil, preterm neonates develop ARA and DHA deficiencies. Preterm neonates lack the necessary enzymatic machinery (due to immature livers) to convert these essential fatty acids into their downstream products. ARA and DHA deficiencies have been linked to the development of bronchopulmonary dysplasia and retinopathy of prematurity. Infant formulas now contain DHA and ARA, and have been associated with improved visual and cognitive outcomes. Because very low birth weight neonates are at high risk for growth failure and neurological impairment along with other comorbidities, many people believe that intravenous lipids should contain pre-formed ARA and DHA. However, it remains to be determined if an improved fatty acid profile in this population translates into better long-term outcomes.
Soybean-based lipids also have been heavily criticized for their high concentrations of hepatotoxic phytosterols, which have been linked to parenteral nutrition associated liver disease (PNALD). Neonates are at high risk for PNALD because of immature livers and the need for prolonged courses of parenteral nutrition. Twenty percent to 60% of premature neonates and children with gastrointestinal disorders will develop PNALD. In neonates with short bowel syndrome, the highest-risk subgroup, 70% will develop PNALD and 20% will progress to liver failure. Once end-stage liver disease develops, an isolated liver or combined small bowel-liver transplant may be the only life-saving measure. Due to the high mortality of end-stage PNALD, small size of transplant candidates, and shortage of organ donors, 50% of children awaiting a transplant will not survive. Five-year post-transplant survival is 60%-70% and fraught with a complex lifestyle. Transplants also carry a high price tag with an estimated cost of $1.5-$1.9 million in the first year.
In comparison with soybean oil, SMOFlipid has a reduced concentration of phytosterols (48 mg/L vs. 343 mg/L). Phytosterols are only found in plant food sources and approximately 5%-10% of phytosterols are absorbed in the intestine. As a result, in a healthy child, they are present at minimal concentrations in the bloodstream. Children receiving parenteral nutrition and with PNALD have higher concentrations of phytosterols, compared with controls. High concentrations of phytosterol reduce the expression of hepatic bilirubin and bile acid transporters. As a result, as phytosterol concentrations rise, bile acids and bilirubin are retained in the liver, causing cholestasis. Like phytosterols, cytokines cause a decrease in biliary flow. Hence, soybean oil’s high concentration of phytosterols and omega-6 fatty acids, which causes a shift toward a proinflammatory state, act synergistically to promote liver injury. SMOFlipid’s reduced phytosterol content potentially may have important implications with regards to the development and progression of PNALD. In randomized controlled trials, neonates who received SMOFlipid had decreased phytosterol concentrations and improved liver function tests, compared with neonates who received soybean oil. Larger studies are needed to determine if SMOFlipid reduces the incidence or severity of PNALD.
In children with advanced PNALD, low dose fish oil monotherapy (Omegaven) has been shown to biochemically reverse cholestasis4,5. Like SMOFlipid, Omegaven is not FDA approved and its use is restricted throughout the United States. Omegaven is dosed at 1 g/kg per day, lacks phytosterols, and contains high concentrations of the anti-inflammatory omega-3 fatty acids DHA and eicosapentaenoic acid, and vitamin E. Based on the assumption that reducing the liver’s exposure to phytosterols and omega-6 fatty acids treats PNALD, it has now become common clinical practice in many neonatal intensive care units to prescribe low dose soybean oil for PNALD prevention. While observational data suggests low dose soybean oil (1 g/kg per day or less) reduces the incidence of PNALD, randomized controlled trials have not demonstrated a change in cholestasis. Lipid sparing (fish or soy) is not without risks, particularly in high-risk populations such as preterm neonates. Inadequate lipid intake during a period of rapid growth and development could cause a fatty acid deficiency and impair growth and neurodevelopment. The central nervous system contains high concentrations of lipids, which are important for cell structure and function and gene transcription. One of the advantages of SMOFlipid is that it can be dosed at 3 g/kg per day, unlike Omegaven, and may be more likely to meet the lipid requirement of neonates.
In summary, the current FDA-approved soy-based lipid product was not designed to meet the nutritional needs of the preterm infant. An ideal lipid emulsion would provide adequate concentrations of polyunsaturated fatty acids, promote growth, be free of phytosterols, and minimize inflammation and other adverse sequelae. SMOFlipid may be more likely to meet the DHA and ARA requirement of the premature neonate. A mixed lipid emulsion dosed at 3 g/kg per day may improve growth and long-term neurodevelopment and reduce the incidence of parenteral nutrition associated liver disease along with other common neonatal diseases. In turn, this may reduce health care related costs. Appropriately powered, well-designed randomized controlled trials with long-term follow-up are needed to evaluate this new lipid emulsion.
References
1. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):514-21 .
2. Nutr Clin Pract. 2012 Dec;27(6):817-24 .
3. J Pediatr Gastroenterol Nutr. 2014 Apr;58(4):417-27 .
4. JPEN J Parenter Enteral Nutr. 2016 Mar;40(3):374-82 .
5. JPEN J Parenter Enteral Nutr. 2014 Aug;38(6):682-92 .
Dr. Calkins is an assistant professor of pediatrics in the division of neonatology at the University of California, Los Angeles. She receives research funding from Fresenius Kabi, the German manufacturer of the products described in this article. The terms of this arrangement have been reviewed by UCLA in accordance with its conflict of interest policy. Because there is only one manufacturer for some of the products discussed in this article, for clarity we have chosen to use brand names rather than generic names. Email Dr. Calkins at pdnews@frontlinemedcom.com.
