A Neonatologist’s Perspective: Is the Quest for an “Ideal” Lipid Emulsion Over?

Soybean oil-based lipid emulsions (SOLE, Intralipid®, Fresenius Kabi, Uppsala, Sweden) are the primary parenteral fat source in American neonatal intensive care units (NICUs). However, SOLE is not the ideal lipid emulsion for neonates. First, SOLE’s high content of phytosterols, low vitamin E concentration, and skewed ω-6: ω-3 fatty acid ratio (7:1) contributes to intestinal failure-associated liver disease (IFALD). Second, while SOLE is a source of essential fatty acids (linoleic and α-linoleic acid), it is devoid of arachidonic acid (AA) and docosahexaenoic acid (DHA), 2 critical fatty acids that modulate inflammation, growth, and brain development¹. Because of low stores and increased needs, premature neonates are at risk for AA and DHA deficiencies.

In infants, dose-reduction strategies for SOLE (≤1g/kg/d) have shown a modest benefit with respect to IFALD prevention and treatment^2,3. The potential benefit of lipid sparing must be weighed against risks (fatty acid deficiencies, growth failure, and neurodevelopmental impairment)³. Since SOLE is the only lipid emulsion approved by the Food and Drug Administration (FDA) in the United States for children, neonatologists are faced with a lack of better options.

The use of a non-FDA approved 100% fish oil-based lipid emulsion (FOLE, Omegaven®, Fresenius Kabi, Bad Homburg, Germany) has gained popularity as a rescue treatment for IFALD^2,4. In contrast to SOLE, FOLE contains a negligible amount of phytosterols and a higher Vitamin E content. FOLE has a skewed ω-6: ω-3 fatty acid ratio (1:8); it is rich in DHA and eicosapentaenoic acid (EPA); and it provides some linoleic acid and AA¹. FOLE was designed for adults and intended to complement SOLE as an ω-3 supplement with a recommended dose of 0.2 g/kg/d. Despite the lack of large, well-powered randomized controlled trials, many studies have concluded that low-dose FOLE effectively and safely treats IFALD^1,2,4. Following IFALD resolution, some clinicians continue FOLE as the sole source of parenteral fat. Contrary to prior concerns, studies have not reported essential fatty acid deficiencies or growth restriction with FOLE⁴.

Because of economic and administrative barriers, many U.S. clinicians and patients lack access to FOLE. As a result, clinicians may feel forced to resort to SOLE dose restriction. This conundrum highlights the need for a new lipid emulsion that is nutritionally appropriate and safe. The ideal lipid emulsion would provide sufficient energy, fatty acids, and a balanced ω-6:ω-3 fatty acid ratio and would be phytosterol-free.

The FDA recently approved a mixed oil-based lipid emulsion (MOLE; SMOFlipid®, Fresenius Kabi) for adults. This has opened up opportunities for the off-label use of MOLE in U.S. NICUs. MOLE (30% soybean oil, 30% medium chain triglycerides, 25% olive oil, and 15% fish oil) has been prescribed outside the United States to adults and children. In comparison to SOLE, MOLE provides DHA and AA, a higher concentration vitamin E, and lower phytosterol content¹. MOLE’s most obvious advantage is that it improves DHA status and can be given as single lipid source dosed at 3 g/kg/d. Some studies suggest that MOLE may be less hepatotoxic than SOLE and has anti-inflammatory and antioxidant properties^5,6.

While MOLE appears to be an attractive lipid emulsion for the NICU patients, we would like to highlight some potential concerns. First, MOLE contains a lower concentration of the essential fatty acids than SOLE. In contrast to FOLE, MOLE supplies less AA and DHA and more EPA than DHA^1,9. High DHA/EPA intakes, without sufficient AA provisions, may down-regulate ω-6 fatty acid synthesis. It has yet to be determined if fatty acid profiles will be adversely affected in neonates receiving prolonged MOLE courses. Second, 3 g/kg/d of MOLE provides a phytosterol load comparable with 1 g/kg/d of SOLE. Studies continue to report IFALD in infants who receive MOLE, and meta-analyses comparing MOLE with SOLE for IFALD prevention are inconclusive^2,8,9. In an attempt to minimize phytosterol exposure, neonatologists may dose-restrict MOLE, which may compromise growth and cause an essential fatty acid deficiency.

So where does this leave a neonatologist practicing in the United States? Should MOLE replace SOLE as the lipid of choice? Clinicians should note that the “ideal” lipid emulsion for infants does not exist. Let us reflect upon the lessons learned from FOLE. In 2017, many clinicians and patients believe that a randomized controlled trial comparing FOLE to SOLE for the treatment of advanced IFALD is unethical. However, because such large-scale studies were not conducted during a period of equipoise, there are still camps of FOLE “believers” and “non-believers.” If we adopt an unregulated, off-label use of MOLE in our NICUs, without well-designed studies, we may never answer if MOLE is a superior lipid emulsion when compared to SOLE.

While considering the off-label use of MOLE, neonatologists should consider the following:

• There is some encouraging data to support the replacement of SOLE with MOLE as a nutrition product^5,6.

• MOLE will not prevent IFALD entirely. IFALD surveillance must continue^2,5,6.

• There is a lack of data comparing MOLE to FOLE for IFALD treatment. Studies continue to suggest that FOLE plays a key role in IFALD treatment⁴.

• There may be a risk for fatty acid deficiencies with long-term MOLE, and dose restriction may exacerbate this risk. Fatty acid status may warrant monitoring.

• Information regarding long-term growth and neurodevelopment for neonates receiving MOLE, low-dose SOLE, and FOLE is scant and requires investigation.

In conclusion, let us balance optimism with reason. While it is enticing to adopt new clinical practices, we must remember that our goal is to provide evidence-based clinical care. Continued collaboration amongst clinicians, investigators, industry, regulatory bodies, and patients will help fill in these knowledge gaps as we continue our quest for an “ideal” lipid emulsion.

Abbreviations:

AA

arachidonic acid

DHA

docosahexaenoic acid

EPA

eicosapentaenoic acid

FOLE

fish oil-based lipid emulsion

IFALD

intestinal failure-associated liver disease

NICU

neonatal intensive care unit

MOLE

mixed oil-based lipid emulsion

SOLE

soybean oil-based lipid emulsion