It has been increasingly recognized that ROP differs worldwide and tailored screening and treatment approaches are needed to reduce aberrant vasoproliferation and facilitate physiologic retinal vascular development in infants . N-3 PUFAs are essential for normal retinal development and appear to play a protective role against retinal neovascularization and visual damage, if provided with n-3 PUFA-enriched formulas in preterm neonates . DHA and its substrate eicosapentaenoic acid (EPA) (20:5n-3), being regulators for transcription factor, and parent fatty acids for neuroprotectin D1 and a family of eicosanoids, have beneficial effects on ischemia, oxidative stress, inflammation and cellular signaling mechanisms, influencing retinal cell gene expression and cellular differentiation, as well as activating molecules implicated in the pathogenesis of vasoproliferative and neurodegenerative retinal diseases such as ROP . In our study, we found that intravenous fish oil containing lipid emulsions increased erythrocyte DHA content with no changes in EPA content and reduced the incidence of severe ROP in preterm infants, compared to the traditional soy oil lipid emulsions.
Concerning the effects of n-3 PUFA supplementation on ROP in preterm infants, no final conclusions have yet been reached. In a prospective cohort study, it is found that a time-dependent accumulation of AA at the expense of DHA seems to occur in utero in erythrocytes of preterm infants who will develop ROP, thus reinforcing the beneficial properties of DHA on this disease . In other observational or prospective randomized studies, the use of intravenous fish oil-containing lipid emulsions is associated with a lower incidence of ROP or severe ROP and decreased need for laser or bevacizumab treatment in preterm infants [24–26], which is in keeping with our findings. Inconsistently, preterm infants treated with fish oil containing emulsions did not differ for any or severe ROP, as well as for bronchopulmonary dysplasia, NEC, PDA, or sepsis, and the incidence of cholestasis in extremely premature infants [27, 28]. Therefore, evidence is insufficient to determine with any certainty if fish oil emulsions offer advantage in prevention or resolution of ROP or in any other clinical outcome, and a large multicenter randomized clinical trial is required [29, 30]. Inconsistencies between studies may be ascribed to baseline differences in body n-3 PUFAs, different dosages used and duration, other nutrient deficiencies and lack of investigating interaction effects of gender and age, etc. .
The accretion of PUFAs including n-3 series as well as n-6 series in the fetus increases exponentially from the 30th to the 38th week during pregnancy, and continues during the first 3 years after birth, and thus preterm infants may be in more disadvantage compared to term infants if n-3 PUFAs provided insufficiently after birth . It has been reported that preterm infants fed milk with a DHA content 2–3 times higher than the current concentration in infant formulas have better neurologic outcomes in early life, and thus suggesting that human milk and preterm formula should contain approximately 1.5% of fatty acid as DHA to compensate for the early DHA deficiency [33, 34]. Herein, our results showed that the erythrocyte DHA content was increased with parenteral administration of the fish oil containing emulsions to preterm infants, instead of the soy oil lipid emulsions, which caused an increase in LA and total n-6 PUFA content in erythrocytes. Similarly, providing a target dose of 3 to 3.5 g/kg/day of lipid emulsions containing 15% of fish oil beneficially modulates the DHA profile, but providing lipid emulsions containing 10% fish oil at a dose of ≤ 2 g/kg/day fails to increase circulating DHA .
In addition to DHA, EPA is found to be beneficial for body health by antagonizing arachidonic acid (AA) derived eicosanoids, which is associated with retinal neurovascular impairment . The n-3 index, the percentage of EPA plus DHA in erythrocytes, represents a human body’s status in EPA and DHA. The compiling recent data supports the target range for the omega-3 index of 8–11% in adults and pregnant mothers . In children and adolescents, daily supplementation of ≥ 450 mg DHA + EPA and an increase in the n-3 index to > 6% makes it more likely to show efficacy on cognitive development . In the current study, the n-3 index was elevated to 4.79% by the use of fish oil containing lipid emulsions with no changes in erythrocyte EPA content, but it was still less than the idea value (6%) for children. This might be resulted from the daily supplementation of less DHA + EPA (< 320 mg per day) in the lipid emulsions used. In consistency, other reports demonstrated that extremely premature infants on the same fish oil containing lipid emulsions with ours had significantly elevated fraction of EPA and slightly increased DHA fraction with the n-3 index of 4.03% at 14 days . Next, supplementation of higher quantities of DHA + EPA using new lipid emulsion formulas and the optimal n-3 index need to be focused to elucidate their effects on the growth and development of infants including preterm babies.
To be noteworthy, evaluating postnatal AA status after birth and correcting its deficiency in addition to EPA and DHA need to be strengthened for ROP prediction and prevention, because AA is indispensable in the vasculature and in specific aspects of immunity, being functioned as a precursor for leukotrienes, prostaglandins, and thromboxanes, collectively known as eicosanoids in infant development . In term infant formula, ratios of n-6 to n-3 PUFAs around 7:1 have been most commonly used, and preterm formulas usually have the ratios ranging between 5:1 and 15:1 . Several expert groups recommend that infants receive at least 0.3% DHA and at least 0.3% AA, with a ratio of AA to DHA from 1:1 to 2:1 in infant feedings, is associated with improved visual and cognitive outcomes . The low postnatal AA levels has been proved to be strongly associated with the development of ROP (any stage of ROP and severe ROP) . Furthermore, a randomized clinical trial study found that, compared with standard of care, enteral simultaneous supplementation of AA and DHA lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA . In this study, erythrocyte AA content was not altered by parenteral administration of either soy oil or fish oil lipid emulsions, because body AA content is usually stable owing to the higher ability for AA synthesis from its precursor LA . Nonetheless, the best clinical approach to PUFA supplementation and n-6 to n-3 PUFA (or AA to DHA) ratios are still far from evident, and requires in-depth investigation on specific fatty acid supplementation in the context of other fatty acids .
In conclusion, administration of fish oil containing lipid emulsions increased erythrocyte DHA content with an increased AA/DHA ratio and reduced n-3 index, even though EPA and AA content in erythrocytes was not changed, and consequently had beneficial effects on severe ROP in preterm infants. In order to provide a more conclusive picture, future trials should employ larger sample sizes in prospective randomized studies with long-term follow-up and should focus on supplementation of higher quantities of DHA + EPA.