Association of fish oil containing lipid emulsions with retinopathy of prematurity: a retrospective observational study

Retinopathy of prematurity (ROP) is a potentially sight-threatening neurovascular disease which affects the retina in infants, especially in preterm infants [1‐3]. During the past two decades, the accomplishment of neonatal health care system supports a higher survival rate of preterm infants than ever before, leading to an increased incidence of ROP worldwide. Although there has been considerable improvement on ROP with respect to etiology, pathogenesis and treatment, it remains a leading cause of childhood blindness worldwide [4]. Prematurity and long-term high oxygen supplementation have been demonstrated to be the major risk factors; whereas, maternal diseases (hypertension, diabetes mellitus and infection), caesarean section, premature rupture of membranes, respiratory distress syndrome (RDS), low Apgar score, patent ductus arteriosus (PDA), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH) and sepsis are considered as alternative risk factors [4, 5].

It is clear that docosahexaenoic acid (DHA) (20:6n-3), belonging to the series of n-3 polyunsaturated fatty acids (n-3 PUFAs), is an important component of retinal cell membrane and is required for photoreceptor cell development. The highest body concentration of DHA per unit area is found in the retinal disc membranes with a percentage of 30% of total retinal fatty acids [6‐8]. Compared with full-term infants, preterm infants have lower plasma concentration and less body DHA storage, because they have missed important intrauterine accretion of nutrients including DHA in the third trimester. Furthermore, several investigations have found that preterm infants have capacity to synthesize DHA from precursor α-linolenic acid (ALA) (18:3n-3), but this endogenous synthesis may not be sufficient to cover the needs of the infant [9‐11]. Consistent evidence demonstrates that n-3 PUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathogenesis of vasoproliferative and neurodegenerative retinal diseases such as ROP [8, 12‐14].

Lipids are important components of parenteral nutrition to meet the requirements for essential fatty acids and high energy in preterm infants, who have limited endogenous lipid storage [15, 16]. Lipid emulsions are available for use as part of parenteral nutrition, including conventional lipid emulsions consisting of pure soybean oil, mixed lipid emulsions consisting of soybean oil plus medium-chain triglycerides (MCT) and/or olive oil, and most recently, a multicomponent lipid emulsion comprising 30% soybean oil, 30% MCT, 25% olive oil, and 15% fish oil [16]. Soybean oil-based lipid emulsions containing primarily n-6 PUFAs, have been demonstrated to contribute to increased body levels of proinflammatory cytokines and oxidative stress [16]. Multicomponent lipid emulsions comprising fish oil n-3 PUFAs, growingly accepted during the past decades, may be beneficial for paediatric patients by supplying a balanced ratio of n-6 to n-3 PUFAs [16‐18], but more evidence is needed particularly for preterm infants, regarding changes in blood fatty acid levels and potential health risk without strong evidence of benefit [19‐21]. Therefore, in this retrospective observational study, we investigated the effects of fish oil n-3 PUFA containing lipid emulsions on body accumulation of DHA, and their associations with ROP in preterm infants.

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 [4]. 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 [14]. 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 [14]. 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. Meanwhile, the beneficial effects of administration of lipid emulsions containing fish oil on retina has also been associated with the higher vitamin E/α-tocopherol levels compared with other lipid emulsions [27].

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 [28]. 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 [29‐31], 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 [32, 33]. 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 [18, 34]. 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 [35]. In addition, our study presented that cesarean section is significantly higher in the soy oil group than that in the fish oil group. Recently, it is reported that babies delivered by caesarean section had a reduced risk of developing ROP compared with those delivered vaginally [16]. Thus, it was sensible for the lower incidence of severe ROP in the fish oil group with a lower cesarean section.

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 [36]. 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 [37, 38]. 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 [39]. To note, intake or supplementation of either the quantity of n-3 PUFAs or the ratio of n-6/n-3 PUFAs determines the concentration of DHA in erythrocytes and tissues, and its health effects. In the current study, the ratio of n-6/n-3 PUFAs for the soy oil emulsions and fish oil emulsions was 8:1 and 4:1 respectively. 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 [40]. 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 [41].

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 [8]. 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 [42]. 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 [43]. 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 [43]. This might be resulted from the daily supplementation of less DHA+EPA (<157 mg/kg/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 [27]. 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 [44]. The low postnatal AA levels has been proved to be strongly associated with the development of ROP (any stage of ROP and severe ROP) [45]. 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 [46]. 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 [40]. Nonetheless, the best clinical approach to PUFA supplementation and n-6 to n-3 PUFA (or AA to DHA) ratio are still far from evident, and requires in-depth investigation on specific fatty acid supplementation in the context of other fatty acids [40].

Administration of fish oil emulsions to preterm infants reduced the incidence of severe ROP with increased erythrocyte DHA concentration. Unfortunately, the current study was a retrospective observational study with a smaller sample size. To provide a more conclusive picture, future trials should employ larger sample size in prospective randomized studies with long-term follow-up and should focus on supplementation of higher quantities of DHA+EPA. Meanwhile, the contribution of enteral feeding to fatty acid concentrations in erythrocyte was not investigated. Finally, the averaged gestational age for preterm infants was 31 weeks, meaning more mature babies included in this study. Thus, study on preterm infants with gestational age less than 28 weeks should be highlighted as a future research perspective.

In summary, administration of fish oil containing lipid emulsions increased erythrocyte DHA content with a reduction in AA/DHA ratio and an increase of n-3 index, even though EPA and AA content in erythrocytes was not changed, and consequently had beneficial effects on incidence of severe ROP in preterm infants.