Although SMOFlipid® is associated with neonatal growth rates and a reduction on the risk of cholestasis, reports on its effects on ROP and the need for ROP treatment are inconsistent.

We show no beneficials effects for SMOFlipid® on ROP incidence and the need for ROP treatment and no beneficials effects on weekly weight gain from birth to 6 weeks of life.

It is desirable that clinical trials be designed to investigate new strategies capable of preventing ROP or progression to more severe disease.

Retinopathy of prematurity (ROP) is a multifactorial disease associated with preterm birth. Its incidence and severity are directly proportional to the degree of prematurity.1 Prevention of ROP is of utmost importance to avoid retinal detachment and blindness.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for the development of the brain. It accounts for 20% of all fatty acids in the retina. Endogenous DHA synthesis from the α-linoleic acid is inadequate to meet the neurodevelopment requirements of preterm infants, who in addition have practically no reserves as the acid accumulates in adipose tissue during the third trimester of pregnancy. The main source of DHA after birth for premature newborns is breast milk, but it is well known that many of them must be artificially nourished through parenteral nutrition in the first weeks of life.

Preventing progression to more severe disease is the best way to reduce associated morbidity in patients with ROP. Nutritional supplementation with omega-3 fatty acids contained in fish oil may modify the course of ROP. Nonetheless, while some studies have shown that intravenous fish oil-containing lipid emulsions have a protective effect against ROP incidence and severity,2,3 others have shown no such benefits.4–7

The main aim of this study is to compare the effects of ClinOleic® and SMOFlipid® as part of parenteral nutrition (PN) on ROP incidence, severity, and need for treatment. ClinOleic® is a lipid emulsion that contains 20% soybean oil and 80% olive oil, and SMOFlipid® contains 30% soybean oil, 30% MCT, 25% olive oil and 15% fish oil. The decision to switch from ClinOleic® to SMOFlipid® was based on the composition of the products. SMOFlipid® has an optimal omega-6/omega-3 ratio and contains the appropriate amount of alpha-tocopherol (200 mg/L), which acts as an antioxidant. Several studies have reported faster growth rates and a lower incidence of cholestasis with solutions containing SMOFlipid®.8–10

Secondary aims are to compare the effects of the 2 emulsions on weekly weight gain in the first 6 weeks of life and common clinical outcomes.

Of the 214 infants identified, 34 were excluded: 31 because they had not undergone a fundus examination, 2 because of congenital malformations, and 1 because of a missing clinical record. Thus, after application of the inclusion and exclusion criteria, 180 infants remained: 90 in the ClinOleic® group and 90 in the SMOFlipid® group.

Mean GA was lower in infants who had received SMOFlipid® compared with ClinOleic® (26.9 vs 27.4 weeks, p=.04). Differences in lung maturation with antenatal corticosteroids were also significant, with 74% of patients in the ClinOleic® group achieving full maturation compared with 90% in the SMOFlipid® group (p=.013). Apgar scores at 1 and 5 min were significantly higher for ClinOleic® (p=.019 and p=.006, respectively). The differences observed for the rest of the biodemographic and obstetric variables were non-significant (Table 1).

Mean duration of PN was 8.9 days in the ClinOleic® group and 9.2 in the SMOFlipid® group. In the former, PN was administered for more than 7 days in 55 infants and for more than 14 days in 4 infants. Four infants in this group also required PN at some other point during admission. In the SMOFlipid® group, 46 and 7 infants received PN for more than 7 and 14 days, respectively. Twelve of the infants in this group required PN at another moment of hospitalization.

This is the first study conducted in Spain to compare the effects of the lipid emulsions ClinOleic® and SMOFlipid® on ROP incidence, severity, and need for treatment in preterm infants receiving PN.

ROP incidence was practically identical in the 2 treatment groups, and most cases were stage 2. Stage 3 ROP was more common in the SMOFlipid® group (9 cases vs 5 in the ClinOleic® group), but the difference was non-significant. Thirteen infants required treatment for ROP: 4 in the ClinOleic® group and 9 in the SMOFlipid® group. A trend towards a higher proportion of infants with stage 3 ROP and ROP requiring treatment was observed in those administered SMOFlipid®.

The clinical profile of the 2 treatment groups differed. Compared with infants in the ClinOleic® group, those who had received SMOFlipid® had a lower GA, were more likely to receive antenatal corticosteroid therapy, and had worse CRIB and Apgar scores. The nutritional profile suggests that patients in the SMOFlipid® group had worse clinical status and a greater risk of mortality or severe illness than those in the ClinOleic® group. The different patient profiles could explain the higher incidence of stage 3 ROP and greater need for treatment in patients who received SMOFlipid®.

Two studies by Pawlik and colleagues attributed the beneficial effects of fish oil on ROP to DHA.2,3 Fetal DHA requirements are estimated to be in the range of 40–60 mg/kg BW/d.12,13 SMOFlipid® 20% contains about 2% (w/w) DHA. A dosage of 2.5 g/kg BW/d of lipids thus would provide 50 mg of DHA/kg BW/d, which would cover practically all the requirements of preterm infants. The amount of DHA provided by SMOFlipid®, however, is lower in the first few days of life, and the potential effects of this insufficiency on morbidity are unknown.14

Just 4 studies have compared the effects of PN including SMOFlipid® and ClinOleic® on ROP and ROP requiring treatment in preterm infants. Unal et al.4 reported a lower, albeit non-significant, incidence of ROP (29.5% vs 32.5%) and stage ≥2 ROP (9.4% vs 11.7%) in infants administered SMOFlipid®. Zübariouglu et al.7 observed a higher, but non-significant, incidence of stage ≥2 ROP in infants administered ClinOleic® (34% vs 20.5%, p=.147). Two studies5,6 found no differences in the incidence and severity of ROP in preterm infants that received SMOFlipid® or ClinOleic®. None of these 4 studies found significant differences in the incidence of ROP, stage ≥2 ROP, or ROP requiring treatment between infants administered ClinOleic® or SMOFlipid®. Our results are consistent with these findings.

The effects of SMOFlipid® and soybean oil emulsions on ROP and the need for ROP treatment have been analyzed in more studies but the findings are inconsistent. Several studies have reported a lower incidence of ROP in patients administered SMOFlipid®, but no differences in ROP requiring treatment or stage ≥3 ROP.14–16 Three other studies17–19 reported lower ROP incidence in the SMOFlipid® group, however, might be due to the longer PN duration in the soybean oil emulsions group or the older GA in SMOFlipid® group.

In the clinical trial by Vlaardingerbroek et al.,8 stage ≥3 ROP was more common in patients who received Intralipid® (4% vs 0% for SMOFlipid®, p=.494). D'Ascenzo et al.20 compared plasma fatty acids in preterm infants who received SMOFlipid® and Intralipid®. Infants administered SMOFlipid® had higher plasma concentrations of DHA and eicosapentaenoic acid, but there were no cases of stage ≥3 ROP in any of the groups. Another 2 studies also found non-significant differences in the incidence of stage ≥3 ROP according to the use of PN including SMOFlipid® or Intralipid®.12,21 Similar findings for ROP and ROP requiring treatment have been reported in several clinical trials.22–24 On the other hand, Gharehbaghi et al.25 reported a significantly lower incidence of stage 3 ROP in patients who received SMOFlipid®.

Choudhary et al.,26 on comparing 2 periods like us, found a higher incidence of ROP among preterm infants who received SMOFlipid® compared with Intralipid® (54% vs 39%, p=.03). Qian et al.27 observed higher rates of ROP in preterm infants who received SMOFlipid® versus Lipofundin® (60.1% vs 47.4%, p=.19). ROP rates were also higher in infants on SMOFlipid® compared with Intralipid® in the studies by Uberos et al.28 and by Jackson et al.29 Finally, Thanhaeuser et al.30 reported that preterm infants on SMOFlipid® with a birth weight <750 g at 12 months of corrected GA had a higher incidence of ROP than infants with the same profile on Intralipid® (85.7% vs 70%). The need for treatment, however, was higher in the Intralipid® group (20% vs 17%).

Our study compares the effects of different types of lipid emulsions in PN on weekly weight gain from birth to 6 weeks of life. Our results are consistent with those reported in the clinical trial by Hsiao et al.,24 where infants on SMOFlipid® gained a mean of 18.42 g/d. Other 2 studies8,26 reported a greater weight gain for SMOFlipid® compared with Intralipid®.

The main limitation of this study is its single-center, observational, retrospective design. Furthermore, the DHA provided by the enteral diet has not been quantified, which could modify the results obtained. Our findings may also have been influenced by improvements to neonatal care over the study period.

In conclusion, this retrospective study showed the lack of beneficial effects of SMOFlipid® compared with ClinOleic® on ROP incidence and severity. Multiple factors influence clinical outcomes in preterm infants, making it very difficult to discern the effects of different types of nutritional lipid emulsions using observational data from retrospective cohorts. A beneficial effect for SMOFlipid® on other clinical outcomes in preterm infants cannot be ruled out based on our findings.

The study was approved by the hospital's ethics and clinical research committee and the Spanish Agency for Medicines and Medical Devices (code: MJC-LIP-2017-01).

Mª José Cabañas Poy: data collection, study design, interpretation of analysis and manuscript writing; Bruno Montoro Ronsano: analysis and interpretation; Félix Castillo Salinas: data collection; remaining authors: manuscript revision. All the authors approved the final version of the manuscript.

No specific funding was received for this study from agencies in the public, commercial, or not-for-profit sectors.

The authors declare that they followed their institutions' protocols to access to the patients data and that was done with the unique purpose of the scientific investigation and scientific disclosure.

Mª José Cabañas Poy: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. José Bruno Montoro Ronsano: Writing – original draft, Methodology, Formal analysis. Félix Castillo Salinas: Writing – original draft, Formal analysis, Data curation. Nieves Martín-Begué: Writing – original draft, Formal analysis, Data curation. Susana Clemente Bautista: Writing – original draft, Formal analysis, Conceptualization. Mª Queralt Gorgas Torner: Writing – review & editing, Writing – original draft, Methodology.