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Background & aims
The purpose of the study was to compare the effects of the parenteral emulsion SMOFlipid®, with 15% fish oil, with Clinoleic® on retinopathy of prematurity (ROP) and other morbidities and growth, and to compare their impact on longitudinal serum levels of fatty acids. Retinopathy of prematurity, other morbidity and growth were cor...
Contexts in source publication
Context 1
... infants received parenteral and enteral nutrition according to clinical routine. Daily intakes of fatty acids AA, eicosapentaenoic acid (EPA) and DHA (mg/ kg/d) were prospectively registered from birth during the first 2 weeks of life (Table 2). ...
Context 2
... from 74 infants gave breastmilk at 7 and 14 days postnatal age, these samples were analyzed and used in calculation. Total amount of LCPUFA from breastmilk and donor milk was calculated ( Table 2). The type of lipid emulsion given was not blinded. ...
Context 3
... the 90 infants recruited for the study, 78 (87%) survived the study period, 41 of whom were randomized to receive SMO- Flipid ® and 37 to Clinoleic ® (Fig. 1). The clinical characteristics of the study infants are reported in Table 1, Supplemental Table 2. ...
Context 4
... nutritional intake during the time period in which a ma- jority received parenteral nutrition (days 1e14) was similar in the treatment groups (Table 2). Infants on Clinoleic ® received a median (minemax) of 72 (15e1558) mL fat given for a median (minemax) of 12 (2e92) days. ...
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OBJECTIVES: We aimed to investigate the relationship between cord 25-hydroxyvitamin D level and bronchopulmonary dysplasia and other neonatal morbidities (sepsis, necrotizing enterocolitis, intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, retinopathy of prematurity) in preterm neonates. STUDY DESIGN: Infants age...
Citations
... A large number of preterm infants born < 1,500 g require parenteral nutrition until full enteral feeds are established (20) . However, as soon as the preterm infant achieves full enteral feeding, the parenteral diet is stopped, a fact that limits the administration of DHA by this route (17) . On the other hand, if DHA is administered directly into the mouth using oral drops, treatment can be continued even after hospital discharge until retinal vascularization is completed. ...
Retinopathy of prematurity (ROP) is a leading cause of blindness in premature infants. The condition is associated with docosahexaenoic acid (DHA) deficiency. This study aimed to investigate the effect of DHA supplementation on the occurrence of ROP in infants receiving oral oil drops. It is part of the Joinville DHA study (JoiDHA Study), a non-parallel-group cohort study conducted from March 2020 to January 2023 at a public maternity hospital in Brazil. Infants born before 33 weeks of gestational age or with a birth weight ≤1,500 g were recruited. Among 155 infants, 81 did not receive and 74 received DHA supplementation until complete vascularization of the peripheral retina. There was a higher incidence of infants with ROP in the unsupplemented group (58·6%) compared to the DHA group (41·4%), but this difference was not significant ( P =0·22). Unadjusted logistic regression analysis showed that patent ductus arteriosus and neonatal corticosteroids were significantly ( P <0·05) associated with ROP in both groups. In the DHA group, surfactant use was also associated with ROP ( P =0·003). After adjusting for important covariates, patent ductus arteriosus and neonatal corticosteroids continued to be significant for infants in the unsupplemented group (OR=3·99; P =0·022 and OR=5·64; P =0·019, respectively). In the DHA group, only surfactant use continued to be associated with ROP (OR=4·84; P =0·015). In summary, DHA supplementation was not associated with ROP. Further studies are necessary to better understand the relationship between DHA supplementation, ROP, and associated comorbidities.
... 53,54 In extremely preterm infants with a median parenteral nutrition duration of 8 days no effect of fish oil on ROP incidence was observed. 55 A systematic review and metaanalysis in 2017 concluded that the use of fish-oil lipid emulsions may reduce the incidence of severe ROP or the need for laser therapy in preterm infants. 56 However, in 2019 a Cochrane review found no support for the use of fish oil containing lipid emulsions compared to non-fish oil emulsions to reduce ROP. ...
... Administering omega-3 LCPUFAs to extremely preterm infants has resulted in increased levels of circulating DHA and EPA but also in reduced ArA levels. 55,59 In a trial comparing PN with and without fish oil, lower serum fractions of ArA were associated with ROP. 60 Interestingly, it has been demonstrated in one cohort, that higher mean daily serum levels of DHA during the first 28 postnatal days were associated with lower frequency of severe ROP even after adjustment for known risk factors, but only in those infants with sufficiently high ArA levels (mean daily minimum level of 7.8 to 8.3 molar percent). 61 In the Mega Donna Mega trial, infants with GA < 28 weeks were randomized to receive enteral ArA (100 mg/kg/d) and DHA (50 mg/kg/d) or no supplementation from within 3 days after birth until 40 weeks' PMA. ...
Very preterm infants are at high risk of growth failure. Poor weight gain is a prominent risk factor for retinopathy of prematurity (ROP) and optimizing nutrition could potentially promote growth and reduce ROP. Most infants at risk of ROP need parenteral nutrition initially and studies of enhanced parenteral provision of lipids and amino acids have suggested a beneficial effect on ROP. Higher amino acid intake was associated with lower incidence of hyperglycemia, a risk factor for ROP. For very preterm infants, providing unpasteurized fortified raw maternal breast milk appears to have a dose-dependent preventive effect on ROP. These infants become deficient in arachidonic acid (ArA) and docosahexaenoic acid (DHA) after birth when the maternal supply is lost. Earlier studies have investigated the impact of omega-3 fatty acids on ROP with mixed results. In a recent study, early enteral supplementation of ArA 100 mg/kg/d and DHA 50 mg/kg/d until term equivalent age reduced the incidence of severe ROP by 50%.
Impact
Previous reviews of nutritional interventions to prevent morbidities in preterm infants have mainly addressed bronchopulmonary dysplasia, brain lesions and neurodevelopmental outcome. This review focusses on ROP.
Neonatal enteral supplementation with arachidonic acid and docosahexaenoic acid, at levels similar to the fetal accretion rate, has been found to reduce severe ROP by 50% in randomized controlled trials.
... This suggests a promising avenue for enhancing angiogenesis in the early phase of ROP. However, preclinical trials involving supplementation of IGF-1, DHA, and ARA have shown limited efficacy and failed to replicate the effective results observed in animal studies [91][92][93][94]. Moreover, the boundaries between different stages of human ROP are not as distinctive as those in animal models. ...
Retinopathy of prematurity (ROP) continues to pose a significant threat to the vision of numerous children worldwide, primarily owing to the increased survival rates of premature infants. The pathologies of ROP are mainly linked to impaired vascularization as a result of hyperoxia, leading to subsequent neovascularization. Existing treatments, including anti-vascular endothelial growth factor (VEGF) therapies, have thus far been limited to addressing pathological angiogenesis at advanced ROP stages, inevitably leading to adverse side effects. Intervention to promote physiological angiogenesis during the initial stages could hold the potential to prevent ROP. Adenosine A2A receptors (A2AR) have been identified in various ocular cell types, exhibiting distinct densities and functionally intricate connections with oxygen metabolism. In this review, we discuss experimental evidence that strongly underscores the pivotal role of A2AR in ROP. In particular, A2AR blockade may represent an effective treatment strategy, mitigating retinal vascular loss by reversing hyperoxia-mediated cellular proliferation inhibition and curtailing hypoxia-mediated neovascularization in oxygen-induced retinopathy (OIR). These effects stem from the interplay of endothelium, neuronal and glial cells, and novel molecular pathways (notably promoting TGF-β signaling) at the hyperoxia phase. We propose that pharmacological targeting of A2AR signaling may confer an early intervention for ROP with distinct therapeutic benefits and mechanisms than the anti-VEGF therapy.
... According to the literature, few studies have been performed in vivo with extremely preterm infants. Some studies have not found a correlation between ROP development and DHA supplementation [15,16], whereas others have [17][18][19]. According to Berbade-Garcia and colleagues, it seems that LC-PUFA supplementation is correlated with a lower occurrence of severe ROP [20]. ...
Background
Incomplete vascularization of the retina in preterm infants carries a risk of retinopathy of prematurity (ROP). Progress in neonatal resuscitation in developing countries has led to the survival of an increasing number of premature infants, resulting in an increased rate of ROP and consequently in visual disability. Strategies to reduce ROP involve optimizing oxygen saturation, nutrition, and normalizing factors such as insulin-like growth factor 1 and n-3 long-chain polyunsaturated fatty acids (LC-PUFA). Our previous study, OmegaROP, showed that there is an accumulation or retention of docosahexaenoic acid (DHA) in mothers of infants developing ROP, suggesting abnormalities in the LC-PUFA placental transfer via fatty acid transporting proteins. The present study aims to better understand the LC-PUFA transport dysfunction in the fetoplacental unit during pregnancy and to find a novel target for the prevention of ROP development.
Methods
The study protocol is designed to evaluate the correlation between the expression level of placental fatty acid receptors and ROP occurrence. This ongoing study will include 100 mother-infant dyads: mother-infant dyads born before 29 weeks of gestational age (GA) and mother-infant dyads with full-term pregnancies. Recruitment is planned over a period of 46 months. Maternal and cord blood samples as well as placental tissue samples will be taken following delivery. ROP screening will be performed using wide-field camera imaging according to the International Classification of ROP consensus statement.
Discussion
The results of this study will have a tangible impact on public health. Indeed, if we show a correlation between the expression level of placental omega-3 receptors and the occurrence of ROP, it would be an essential step in discovering novel pathophysiological mechanisms involved in this retinopathy.
Trial registration
NCT04819893.
... However, an analysis of circulating fatty acid levels in postnatal period for infants receiving these lipid emulsions early in life revealed increasing circulating amounts of those fatty acids but continued deficits of AA and DHA [134], as predicted by the low capacity of preterm infants to transform these precursors into the downstream fatty acids AA and DHA adequately [135]. In contrast to soy-based emulsions, those based on fish oil (either 100% or the newer emulsions based on mixtures with other oils), provide EPA and DHA to increase postnatal circulating levels of these LCPUFAs, but also increase the levels of LA less dramatically than soybean oil emulsions [136]. However, fish-oil-containing emulsions could produce a decrease in circulating levels of AA [136,137] as well as in the n-6/n-3 ratio in preterm infants, when compared with those found in breastfed neonates born at term to mothers consuming western diets. ...
... In contrast to soy-based emulsions, those based on fish oil (either 100% or the newer emulsions based on mixtures with other oils), provide EPA and DHA to increase postnatal circulating levels of these LCPUFAs, but also increase the levels of LA less dramatically than soybean oil emulsions [136]. However, fish-oil-containing emulsions could produce a decrease in circulating levels of AA [136,137] as well as in the n-6/n-3 ratio in preterm infants, when compared with those found in breastfed neonates born at term to mothers consuming western diets. In fact, it has been suggested that rather than the type of lipid emulsion used, the decrease in AA may be behind the adverse effects associated with these formulations [135], such as an increased risk of premature retinopathy [138] or late-onset sepsis [139]. ...
Certain limitations exist for animals to modify fatty acid changes. Besides the role of arachidonic acid (AA), docosahexaenoic acid (DHA) and other 20-carbon long-chain polyunsaturated fatty acids (LCPUFAs) for the synthesis of inflammatory mediators as eicosanoids, different LCPUFAs have many other effects, including their abilities to regulate gene expression and downstream events. LCPUFAs are susceptible to autoxidation, which is prevented by the action of antioxidants in the form of enzymes like superoxide dismutases, catalases and peroxidases, as well as antioxidant compounds that protect against oxidation or repair the damage caused. Under normal conditions, the fetus needs both essential fatty acids (EFAs) and LCPUFAs, which are obtained from its mother by placental transfer. In early pregnancy, dietary derived fatty acids are accumulated in maternal adipose tissue. However, during late pregnancy, corresponding to the period of the highest fetal growth, maternal adipose tissue becomes catabolic and LCPUFAs are released into the circulation by adipose lipolytic activity. The released LCPUFAs are taken up by maternal liver to be esterified and released back to the circulation as triacylglycerides (TAGs) in very-low-density lipoprotein (VLDL) that become available to the placenta to be transferred to the fetus in the form of non-esterified fatty acids (NEFAs). An enhanced adipose tissue lipolysis is maintained around parturition and esterified LCPUFAs are diverted to mammary glands thanks to an increased activity of lipoprotein lipase for milk production. Throughout this process, LCPUFAs become available to the newborn during suckling. The important role of both DHA and AA for the development of the nervous system and for growth has motivated their dietary supplement during different postnatal stages. This has been especially important in preterm infants both because under normal conditions, the fetus acquires most of these fatty acids during late pregnancy, and because the immaturity of the enzyme systems for the synthesis of AA and DHA from their respective EFAs.
... Some studies have demonstrated a more pronounced ARA deficit with SO,MCT,OO,FO ILE compared with SO ILE. [36][37][38] It remains to be determined what the parenteral and enteral ARA, DHA, and EPA requirements for infants in the NICU are, and if remedying these deficits will improve outcomes. ...
Intravenous lipid emulsions (ILEs) are a source of nonprotein calories and fatty acids and help promote growth in preterm infants and infants with intestinal failure. An ILE dose and oil source determines its fatty acid, phytosterol, and vitamin E delivery. These factors play a role in the infant's risk for essential fatty acid deficiency and cholestasis, and help modulate inflammation, immunity, and organ development. This article reviews different ILEs and their constituents and their relationship with neonatal health.
... Fortification of intravenous lipid emulsions and enteral supplementation have been assessed as ways to improve LCPUFA status in preterm infants [11][12][13][14][15][16][17][18][19]. Supplementation has primarily focused on DHA, but DHA together with AA, has also been evaluated [12,16,[18][19][20]. ...
... Fish oilcontaining intravenous lipid emulsions, now widely used in neonatal intensive care units, have a high DHA and eicosapentaenoic acid (EPA, 20:5 n−3) content but are relatively low in AA [21]. Consequently, these emulsions increase infant DHA and EPA but reduce their AA levels, resulting in an AA:DHA ratio that may be non-physiological [11,14,17]. Enteral supplementation with fish oil or human milk with high DHA concentration has a similar effect on circulating LCPUFA levels in the preterm infant, i.e. ...
... Details of the nutritional strategy have been described [17,23]. The parenteral nutrition was initiated as early as possible after birth and was provided either via 3-in-1 (Numeta G13E, Baxter Medical AB, Kista, Sweden) or by individually composed parenteral nutrition consisting of glucose (monohydrate 50 g 100 ml −1 ), amino acids (2 g 100 ml −1 Vaminolac®, Fresenius Kabi, Uppsala, Sweden or 3.1 g 100 ml −1 Primene, Baxter Medical AB, Kista, Sweden), and lipids. ...
Background and aim:
Preterm infants risk deficits of long-chain polyunsaturated fatty acids (LCPUFAs) that may contribute to morbidities and hamper neurodevelopment. We aimed to determine longitudinal serum fatty acid profiles in preterm infants and how the profiles are affected by enteral and parenteral lipid sources.
Methods:
Cohort study analyzing fatty acid data from the Mega Donna Mega study, a randomized control trial with infants born <28 weeks of gestation (n=204) receiving standard nutrition or daily enteral lipid supplementation with arachidonic acid (AA):docosahexaenoic acid (DHA) (100:50 mg/kg/day). Infants
received an intravenous lipid emulsion containing olive oil:soybean oil (4:1). Infants were followed from birth to postmenstrual age 40 weeks. Levels of 31 different fatty acids from serum phospholipids were determined by GC-MS and reported in relative (mol%) and absolute concentration (μmol l-1) units.
Results:
Higher parenteral lipid administration resulted in lower serum proportion of AA and DHA relative to other fatty acids during the first 13 weeks of life (p<0.001 for the 25th vs the 75th percentile). The enteral AA:DHA supplement increased the target fatty acids with little impact on other fatty acids. The absolute
concentration of total phospholipid fatty acids changed rapidly in the first weeks of life, peaking at day 3, median (Q1-Q3) 4452 (3645-5466) μmol l-1, and was positively correlated to the intake of parenteral lipids. Overall, infants displayed common fatty acid trajectories over the study period. However, remarkable differences in fatty acid patterns were observed depending on whether levels were expressed in relative or absolute units. For example, the relative levels of many LCPUFAs, including DHA
and AA, declined rapidly after birth while their absolute concentrations increased in the first week ofJournal Pre-proof
4 life. For DHA, absolute levels were significantly higher compared to cord blood from day 1 until postnatal week 16 (p<0.001). For AA, absolute postnatal levels were lower compared to cord blood from week 4 throughout the study period (p<0.05).
Conclusions:
Our data show that parenteral lipids aggravate the postnatal loss of LCPUFAs seen in preterm infants and that serum AA available for accretion is below that in utero. Further research is needed to establish optimal postnatal fatty acid supplementation and profiles in extremely preterm infants to promote development and long-term health.
... The mean GA for preterm infants with non-severe and severe neovascular ROP was 26.8 (SD ± 1.0) vs 24.2 (SD ± 1.0) (P = 0.004), mean birthweight was 984.3 (SD ± 218.9) vs. 592.1 (SD ± 136.6) (P = 0.006), and mean BW standard deviation score was − 0.54 (SD ± 0.8) vs. − 1.3 (SD ± 1.9) (P = 0.949). Blood samples were taken on postnatal days (PNA) 1, 7, 14, and 28, and at postmenstrual age (PMA) at 32 weeks according to study protocol [42]. Nutritional intake, total, enteral and parenteral energy (kcal/kg/day), and lipids (g/kg/day) were presented as mean values for the following time periods: first PNA week (PNA days 2-7), second PNA week (PNA days [8][9][10][11][12][13][14], and PNA weeks 3 and 4 (PNA days [15][16][17][18][19][20][21][22][23][24][25][26][27][28], details previously presented [42]. ...
... Blood samples were taken on postnatal days (PNA) 1, 7, 14, and 28, and at postmenstrual age (PMA) at 32 weeks according to study protocol [42]. Nutritional intake, total, enteral and parenteral energy (kcal/kg/day), and lipids (g/kg/day) were presented as mean values for the following time periods: first PNA week (PNA days 2-7), second PNA week (PNA days [8][9][10][11][12][13][14], and PNA weeks 3 and 4 (PNA days [15][16][17][18][19][20][21][22][23][24][25][26][27][28], details previously presented [42]. International guidelines for ROP classification and ROP treatment were followed [43,44]. ...
Hyperglycemia in early postnatal life of preterm infants with incompletely vascularized retinas is associated with increased risk of potentially blinding neovascular retinopathy of prematurity (ROP). Neovascular ROP (Phase II ROP) is a compensatory but ultimately pathological response to the suppression of physiological postnatal retinal vascular development (Phase I ROP). Hyperglycemia in neonatal mice which suppresses physiological retinal vascular growth is associated with decreased expression of systemic and retinal fibroblast growth factor 21 (FGF21). FGF21 administration promoted and FGF21 deficiency suppressed the physiological retinal vessel growth. FGF21 increased serum adiponectin (APN) levels and loss of APN abolished FGF21 promotion of physiological retinal vascular development. Blocking mitochondrial fatty acid oxidation also abolished FGF21 protection against delayed physiological retinal vessel growth. Clinically, preterm infants developing severe neovascular ROP (versus non-severe ROP) had a lower total lipid intake with more parenteral and less enteral during the first 4 weeks of life. Our data suggest that increasing FGF21 levels in the presence of adequate enteral lipids may help prevent Phase I retinopathy (and therefore prevent neovascular disease).
... According to the literature, few studies have been performed in vivo with extremely preterm infants. Some studies have not found a correlation between ROP development and DHA supplementation [15][16], whereas others have [17][18][19]. According to Berbade-Garcia and colleagues, it seems that LC-PUFA supplementation is correlated with a lower occurrence of severe ROP [20]. ...
Background
Incomplete vascularization of the retina in preterm infants carries a risk of retinopathy of prematurity (ROP). Progress in neonatal resuscitation in developing countries has led to the survival of an increasing number of premature infants, resulting in an increased rate of ROP and consequently in visual disability. Strategies to reduce ROP involve optimizing oxygen saturation, nutrition, and normalizing factors such as insulin-like growth factor 1 and n-3 long-chain polyunsaturated fatty acids (LC-PUFA). Our previous study, OmegaROP, showed that there is an accumulation or retention of docosahexaenoic acid (DHA) in mothers of infants developing ROP, suggesting abnormalities in the LC-PUFA placental transfer via fatty acid transporting proteins. The present study aims to better understand the LC-PUFA transport dysfunction in the fetoplacental unit during pregnancy and to find a novel target for the prevention of ROP development.
Methods
The study protocol is designed to evaluate the correlation between the expression level of placental fatty acid receptors and ROP occurrence. This ongoing study will include 100 patients: patients giving birth before 29 weeks of gestational age (GA) and patients with full-term pregnancies. Recruitment is planned for over 46 months. Maternal and cord blood samples as well as placental tissue samples will be taken following delivery. ROP screening will be performed using wide-field camera imaging according to the International Classification of ROP consensus statement.
Discussion
The results of this study will have a tangible impact on public health. Indeed, if we show a correlation between the expression level of placental omega-3 receptors and the occurrence of ROP, it would be an essential step in discovering novel pathophysiological mechanisms involved in this retinopathy.
Trial registration: 2020-A03253-36
... Our data are quite interesting, considering that most studies about the use of SMOFlipid ® were related only to short-term neonatal outcomes [8,[18][19][20]. Furthermore, only one study by Thanhaeuser et al. previously analyzed the outcomes of preterm infants receiving MLE or SLE after randomization. ...
Background:
Few studies in the literature have analyzed the long-term neurodevelopmental outcomes of the administration of a multicomponent versus a soybean-based lipid emulsion (LE) in preterm infants receiving parenteral nutrition (PN). A recent randomized controlled trial conducted in our unit provided evidence of better growth in head circumference during the hospital stay in those who received a multicomponent LE.
Methods:
This is a 24 month follow-up study of preterm infants, previously enrolled in a randomized trial, who received a multicomponent LE (SMOFlipid®) or a standard soybean-based one (Intralipid®). We evaluated neurodevelopmental outcomes at 24 months of corrected age (CA) in the two groups.
Results:
Ninety-three children were followed up to the age of 24 months CA. Due to the peculiar time frame of the SARS-CoV-2 pandemic, neurodevelopmental outcomes were evaluated only in 77 children: 37 in the SMOFlipid® group and 40 in the Intralipid® group. No differences in major disability rates or in Griffith's evaluation were found between the two groups.
Conclusions:
In our population study, the administration of a multicomponent LE containing fish oil, compared to a soybean-based LE, had no significant effects on neurodevelopmental outcomes in preterm infants at 24 months CA.
