Fish-Oil Fat Emulsion Supplementation May Reduce the Risk of Severe Retinopathy in VLBW Infants

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1 ARTICLES Fish-Oil Fat Emulsion Supplementation May Reduce the Risk of Severe Retinopathy in VLBW Infants AUTHORS: Dorota Pawlik, MD, PhD, a Ryszard Lauterbach, MD, PhD, a and Ewa Turyk, MD b Departments of a Neonatology and b Ophthalmology, Jagiellonian University Medical College, Kraków, Poland KEY WORDS retinopathy of prematurity, docosahexaenoic acid, DHA, n-3 PUFA, very low birth weight infant, parenteral nutrition ABBREVIATIONS DHA docosahexaenoic acid ROP retinopathy of prematurity CRIB Clinical Risk Index for Babies BPD bronchopulmonary dysplasia VEP visual evoked potential Mr Lauterbach designed the experiment and conducted the study, contributed significantly to the analytic methods and data analysis, and contributed significantly to the writing of the manuscript; Ms Pawlik contributed to the collection and analysis of data, provided significant advice on the study design, and contributed to subject recruitment; and Ms Turyk contributed significantly to the ophthalmologic assessment and contributed to the writing of the manuscript. doi: /peds Accepted for publication Oct 13, 2010 Address correspondence to Ryszard Lauterbach, MD, Department of Neonatology, Jagiellonian University Medical College, P Kraków, Kopernika, Poland. ryszard@ lauterbach.pl PEDIATRICS (ISSN Numbers: Print, ; Online, ). Copyright 2011 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. WHAT S KNOWN ON THIS SUBJECT: Docosahexaenoic acid is important for fetal brain development and visual acuity in infants. Infants born prematurely are at particular risk for docosahexaenoic acid insufficiency because they may not have benefited from a full trimester of the mother s lipid stores. WHAT THIS STUDY ADDS: This is the first study in which the administration of fish-oil lipid emulsion in very low birth weight infants from the first day of life is described. The influence of fish-oil lipid emulsion on the regression of retinopathy seems to be worthy of further investigation. abstract OBJECTIVE: The retina contains rods and cones that have membranes highly enriched with docosahexaenoic acid (DHA). Infants born prematurely are at risk of DHA insufficiency, because they may not have benefited from a full third trimester of the mother s lipid stores. Moreover, within the first 2 to 3 weeks of life, the main sources of lipids for premature infants are fat emulsions, which do not contain DHA. PATIENTS AND METHODS: This observational study was designed to compare the safety and efficacy outcomes of an intravenous fat emulsion that consists of fish-oil emulsion (contains DHA) with soybean and olive oil, administered from the first day of life to 40 infants who weighed 1250 g; results were obtained from a historical cohort of 44 preterm neonates who were given an emulsion of soybean and olive oil. The primary study outcomes were the occurrence of retinopathy and need for laser therapy and cholestasis. Infants in the 2 groups were comparable with regard to demographic and clinical characteristics and were subjected to the same conventional therapy. RESULTS: There was a significantly lower risk of laser therapy for infants who received an emulsion of soybean, olive oil, and fish oil (P.023). No significant differences were found in acuity and latency of visual evoked potentials between infants in the 2 groups. There was no infant with cholestasis among those who received fish-oil emulsion, and there were 5 subjects with cholestasis in the historical group (P.056). CONCLUSION: Fish-oil based fat emulsion administered from the first day of life may be effective in the prophylaxis of severe retinopathy. Pediatrics 2011;127: PEDIATRICS Volume 127, Number 2, February

2 Docosahexaenoic acid (DHA) has been shown to be particularly important for fetal brain development and visual acuity in infants. 1,2 Infants born prematurely are at special risk for DHA insufficiency because they may not have benefited from a full trimester of the mother s lipid stores. 3 In addition, preterm infants have a very limited ability to synthesize DHA from the -linoleic acid. 4 The exclusive source of DHA after birth for preterm newborns is breast milk or DHA-enriched formula. However, within the first 2 to 3 weeks of life, the main sources of lipids for most prematurely delivered infants are fat emulsions, administered as components of total parenteral nutrition. These comprise soybean oils, with or without safflower; olive oils; or medium-chain triglyceride oil, which are rich in n-6 fatty acids and do not contain DHA. Consequently, supply of DHA is interrupted for a relatively long period of time, which depends either on the immaturity of infants or the incidence of feeding complications. On the other hand, a fish-oil emulsion contains -3 fatty acids, DHA. Recently, Gura et al 5 showed the safety and efficacy of a fish-oil based fat emulsion, administered in a maintenance dosage of 1 g/kg per day in the treatment of parenteral nutrition-associated liver disease in infants. Our trial was designed to replace partially a soybean and olive oil emulsion with a fish-oil emulsion in a total daily lipid requirement. We hypothesized that preterm infants who received a fish-oil emulsion in an amount equal to one-third of their total daily intravenous lipid intake, administered from the first day of life, would exhibit lowered risk of severe retinopathy of prematurity (ROP) and cholestasis compared with infants who received a conventional soybean and olive oil emulsion. PATIENTS AND METHODS All infants who weighed 1250 g, delivered prematurely before the 32nd week of gestation and admitted to the NICU of the Medical College of the Jagiellonian University in Cracow, Poland, between April 1 and September 30, 2008 (sixth months), were candidates for the study. Infants who needed total parenteral nutrition were treated with a volume composition of lipid emulsions that consisted of 50% of soybean and olive oil emulsion (20% Clinoleic [Baxter SA, Norfolk, United Kingdom]) and 50% of fish-oil emulsion (10% Omegaven [Fresenius Kabi AG, Bad Homburg, Germany]). The comparison of parenteral fat emulsions is presented in Table 1. The treatment protocol was approved by Jagiellonian University s ethical committee, and informed written consent was obtained from parents of all treated infants. However, for additional investigation and analysis only, infants without major congenital malformation or inborn metabolic errors and symptoms of congenital infection were enrolled. Finally, 40 of the 63 admitted infants were enrolled and prospectively followed (experimental group). A historical cohort of 44 infants who weighed 1250 g, who were delivered prematurely before the 32nd week of pregnancy and hospitalized in the ICU, was reviewed for comparison purposes TABLE 1 Comparison of Parenteral Fat Emulsions: 10% Omegaven and 20% Clinoleic Variable Omegaven, g/ml Clinoleic, g/ml Oil Soybean 4 Olive 16 Fish 10 Glycerol Egg phospholipids Linoleic a-linoleic DHA Eicosapentaenoic acid Arachidonic acid (historical group). The exclusion criteria were identical in both groups of infants. Patients in the historical group were separated from 68 infants who were born and admitted to the neonatal department between October 1, 2007, and March 31, 2008 (sixth months). A source of lipid emulsion, administered parenterally in infants in the historical group, was a 20% soybean and olive oil emulsion (20% Clinoleic). The following data were collected in infants of both groups: birth weight, gestational age, Apgar score, Clinical Risk Index for Babies (CRIB) score, gender, and antenatal steroid administration. The diagnosis and routine medical management of respiratory insufficiency and/or sepsis in the 2 groups was comparable. Also, the criteria either for ventilatory support or weaning from the ventilator were comparable in infants of both groups. Both in the experimental and historical group of infants, the lipid emulsions were administered from the first day of life as a continuous infusion for 24 hours per day. The initial daily dose for infants with a birth weight of 1000 g was 0.5 g of lipids per kg of body weight (0.15 g of Omegaven and 0.35 g of Clinoleic). Respectively, the initial dose for infants with birth weight of 1000 g was 1.0 g of lipids per kg of body weight (0.35 g of Omegaven and 0.65 g of Clinoleic). It was increased by 0.5 to 1.0 g of lipids per kg body weight every 24 hours to a maximum of 3.0 to 3.5 g of lipids per kg of body weight/d ( g of Omegaven and g of Clinoleic). With regard to enteral feeding, infants in both groups were fed initially and advanced at 20 ml of breast milk (an average content of lipids ranged from g per 100 ml) and/or formula (Bebilon Nenatal Premium [Nutricia, Opole, Poland]; 4.4 g of lipids per 100 ml) enriched with -3 long-chain polyunsaturated fatty acids 224 PAWLIK et al

3 ARTICLES per kg per day, according to feeding tolerance. Thirty-nine infants in the experimental group (87%) and 41 infants in the historical group (91%) received their own mother s breast milk. The intravenous lipid infusion as a component of total parenteral nutrition was progressively replaced with enteral intake so as to maintain the total daily lipid dose at 3.0 to 3.5 g of lipids per kg of body weight. The dosages and schedule of lipid administration were identical in both groups. The primary study outcomes were development of ROP and the need for laser photocoagulation, as well as the occurrence of cholestasis during hospitalization. Cholestasis was defined as a serum direct bilirubin value of 1.0 mg/dl if the total bilirubin level was 5 mg/dl or a direct bilirubin value of 20% of the total bilirubin if the total bilirubin level was 5 mg/dl, found in 2 consecutive measurements. 6 Laboratory values were prospectively measured approximately biweekly. The historical group had all the bilirubin tests available, recorded retrospectively. Secondary outcomes, including bloodstream infections, treatment for patent ductusp arteriosus pharmacological or surgical, the occurrence of intraventricular hemorrhage, bronchopulmonary dysplasia (BPD), length of hospitalization, and total parenteral nutrition, were analyzed in both groups. BPD was defined as an oxygen requirement and/or respiratory support at 36 weeks corrected gestational age. The intraventricular hemorrhage was defined as ultrasonographic evidence for intraventricular blood. Ophthalmologic Assessment In infants of both groups, the monitoring of level of oxygen saturation with pulse oximetry was initiated within the first minutes after birth and was continued until the infant was breathing ambient air and did not require ventilatory support (ventilator or continuous positive airway pressure) for 48 hours. Adjustments in supplemental oxygen to maintain the target level of oxygen saturation between 88 and 93 (ranges identical for both groups) were performed by the clinical nurses. All infants either in the experimental or historical group were screened for ROP (screening criteria of 32 weeks gestational age or 1500 g) by 1 ophthalmologist (blinded of intervention) trained in the diagnosis of ROP. Examinations continued until the study outcome was reached or resolution occurred. In infants of both groups who developed ROP (all stages), the visual acuity and functional integrity of the visual pathways were assessed at 18 to 24 months corrected age. Visual acuity was evaluated using the Preferential Looking Test with the use of the Teller acuity cards. Integrity of the visual pathways was assessed by the visual evoked potential (VEP) examination obtained by pattern and flash stimulation using EP-1000 apparatus (Tomey, Tokyo, Japan). Pattern VEP was elicited by checkerboard stimuli with large 1 (60 minutes of arc) and small 0.3 checks. The standard pattern stimulus is a high-contrast black and white checkerboard. Flash VEP was elicited by a brief flash that subtends a visual field of at least 20 presented in a dimly illuminated room. Statistical Analyses Statistical analyses were performed with the use of Statistica 8.0 for Windows (StatSoft Inc., Tulsa, OK). Statistical significance of differences in categorical values was analyzed by the 2 test with 2 degrees of freedom. Fisher s exact probability test was applied when examining variables of low incidence. The unpaired Student s t or the Mann-Whitney U test was performed to examine the differences between demographic and clinical characteristics in the groups. The logistic regression analysis was used to estimate possible correlations between analyzed factors and the incidence of ROP. RESULTS The overall mortality rate in the group of 63 infants (40 of them comprised the experimental group) admitted to the NICU between April 1 and September 30, 2008, was 25.3% and did not differ significantly from respective data (27.9%) obtained in the group of 68 infants (44 of them comprised the historical group) who were born and admitted to the neonatal department between October 1, 2007, and March 31, Table 2 shows that patients in the experimental and historical group were similar with regard to the birth weight, gestational age, Apgar score, CRIB score, and the frequency of antenatal steroid administration. Cholestasis was diagnosed in 5 of 44 infants in the historical group, whereas it did not occur in patients in the experimental group (P.056). The rate of secondary outcomes (bloodstream infections, treatment for patent ductus arteriosus [pharmacological or surgical], and the occurrence of BPD, intraventricular hemorrhage, a length of hospitalization or total parenteral nutrition [in days]) did not differ between the 2 groups. Although the rates of retinopathy among infants of the 2 groups were similar (13 infants [32.5%] in the experimental group versus 16 infants [36.3%] in the historical group), in 10 of 13 patients in the experimental group the spontaneous regression of disease was observed. Laser therapy was performed only in 3 patients. In fact, for 12 of 16 infants with retinopathy in the historical group, laser therapy was needed, and for 2 of them laser therapy had to be repeated within the next 2 weeks. The difference in rates of ophthalmologic interventions PEDIATRICS Volume 127, Number 2, February

4 TABLE 2 Demographic and Clinical Characteristics of Patients in the Experimental and Historical Groups Variables among infants between the 2 groups was significant (P.023; 2-tailed Fisher s exact test). The comparison of demographic (birth weight, gestational age) and clinical characteristics (Apgar score, CRIB score, neonatal sepsis in general [bacterial or fungal], BPD, and intraventricular hemorrhage according to number and grades) of patients who developed ROP in the experimental and historical group did not show significant differences between infants in the 2 groups. Among patients with ROP in the historical group, the only factors that significantly increased risk of laser therapy were gestational age and the severity (stage) of retinopathy (gestational age, odds ratio: 0.27 [95% confidence interval: ]; P.047) (stage of ROP, odds ratio: 9.86 [95% confidence interval: ]; P.046) However, similar correlations were not found in the experimental group. Of the 29 infants who developed ROP, in 26 visual acuity was assessed and the results obtained in 22 of them were within the normal ranges ( ) Experimental Group (N 40) Historical Group (N 44) Demographic Birth weight, median (range), g 920 ( ) 940 ( ).72 Gestational age, median (range), wk 28 (25 32) 28 (24 32).81 Female gender, n (%) 23 (57.5) 28 (63.5).46 SGA infant, n (%) 8 (20) 7 (15).21 Clinical Apgar score, median (range) 7.0 (1 9) 7.0 (1 9).73 CRIB score, mean; median (range) 3.77; 2.0 (0.0 11) 3.72; 3.0 (1 13).43 Antenatal steroids, n (%) 21 (52) 19 (43).28 Mechanical ventilation, mean; median (range), d 9.9; 8.0 (1 30) 13.2; 6.0 (1 52).31 n-cpap ventilation, mean; median (range), d 16.5; 15.0 (1 43) 15.7; 16.0 (2 34).35 PDA closure, N/n nonsurgical/n surgical 20/11/9 23/13/10.50 Sepsis, N/n Gram-positive/n Gram-negative) 22/20/3 19/16/3.38 IVH, n Cholestasis, n TPN, mean; median (range), d 21.7; 21 (5 55) 22.3; 18.5 (7 91).23 Hospitalization, mean; median (range), d 63.1; 61.5 (25 115) 64.9; 61.5 (26 120).28 BPD, n ROP stage 1 to 3, n ROP laser therapy SGA indicates small for gestational age; n-cpap, nasal continuous positive airway pressure; IVH, intraventricular hemorrhage; TPN, total parenteral nutrition. with respect to the age of patients. In 4 infants (1 in the experimental group and 3 in the historical group), evaluated data were below the lower range of normal values. The families of the 3 infants could not be contacted. Integrity of the visual pathways was evaluated by the VEP examination. However, because of poor cooperation of the patients, only in 16 of the 26 infants was the assessment of integrity of visual pathways performed. The results of pattern VEP evaluations were the following: the mean values of amplitude of P100 for 1 pattern were 12.4 and 14.2 V in the experimental and historical groups, respectively; the mean values of latency were milliseconds and 94.5 milliseconds, respectively. For 0.3 pattern, the mean amplitudes of P100 were 11.2 and 10.5 V in the experimental and historical groups, respectively; the mean latencies were 95.4 milliseconds and 94.1 milliseconds, respectively. Respectively, the results of flash VEP evaluations were as follows: the mean P value of amplitude of P100 in the experimental group was 24.3 V and in the historical group 22.9 V. The mean latencies of P100 were and milliseconds, respectively. None of the differences concerning data obtained during the assessment of integrity of the visual pathways between the 2 groups of infants were significant. In all infants of both groups, the intravenous lipid emulsion was introduced from the first day of life. The occurrence of undesirable safety effects in infants who received fish-oil emulsion was similar with that found in historical group. Two patients in experimental group and 3 infants in historical group developed hypertriglyceridemia (triglyceride level: 350 mg/dl). No patient in either group developed coagulopathy (international normalized ratio: 2); the mean platelet count as well as central venous catheter infection and new infection rates were comparable in the 2 groups of infants during the intravenous administration of both types of lipid emulsion. On average, the total intravenous intake of DHA in infants in the experimental group was from 2.0 to 4.0 g per infant. The daily doses ranged from 30 mg/kg per day (total intravenous lipid intake: 0.5 g/kg per day) to 200 mg/kg per day (total intravenous lipid intake: 3.5 g/kg per day). DISCUSSION In this observational study, we found significantly lower risk of laser therapy in infants with retinopathy who received a fish-oil emulsion in an amount equal to one-third of their total daily intravenous lipid intake from the first day of life. Although there was no infant with cholestasis among patients who received fish-oil emulsion and there were 5 subjects with cholestasis in historical group, the number of subjects in the studied groups was probably insufficient for that tendency to 226 PAWLIK et al

5 ARTICLES achieve statistical significance. As shown in Table 2, demographic and clinical characteristics of the patients in 2 groups were comparable. Thus, differences in severity of clinical condition of patients in the experimental and historical group could be ruled out. It seems to us that intravenous intake of DHA was the most important difference between the 2 groups of infants, which might influence the spontaneous regression of retinopathy in infants of experimental group. It is well known that between the 23rd and 40th week of pregnancy, the weight of brain increases from 75 to 400 g. DHA is 1 nutrient absolutely required for the development of the sensory, perceptual, cognitive, and motor neural system during the brain growth spurt. 7 The retina, functionally an extension of the brain, contains rods and cones that have membranes highly enriched with DHA. It was established that DHA comprises 20% of total fatty acid content of the infant retina. In the outer segments of rod photoreceptors, DHA comprises 35% of total fatty acids. 8 Rodents, primates with experimentally induced DHA deficiency, show a deficit in retinal structure, visual acuity development, and cognitive performance. On the other hand, a higher dose of DHA in the neonatal period improves visual acuity of preterm infants. 9,10 In vitro studies demonstrate that DHA inhibits the expression of inflammatory markers such as pro-inflammatory cytokines, monocytes adhesion to endothelial cells and cell-adhesion molecules, particularly vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin. 11 Recently, the role of an inflammatory reaction in the pathophysiology of ROP has been suggested. 12 Also, the results of experimental data obtained by Connor et al 13 indicate that DHA, eicosapentaenoic acid, and their potent bioactive products at physiologic levels reduce pathologic neovascularization through enhanced vessel regrowth after vascular loss and injury, and that enriching the sources of -3 polyunsaturated fatty acids may be an effective approach to help prevent proliferative retinopathy. We speculate that there may have been several reasons why we found no significant differences in acuity and latency of VEPs between infants of the 2 groups. First is the limited sample size of the subjects (only 16 of 29 infants) recruited for assessment for visual integrity of the visual pathways. With regard to acuity, no differences between infants in the experimental and historical group could result from the relatively advanced age of patients. It was shown that acuity significantly improves in the first few months of life and probably at 18 to 24 months of age, most infants achieve an acuity considered to be normal. 10 However, studies with infants born at term have shown that lower -3 long-chain polyunsaturated fatty acid status in early life was related to poorer stereo acuity and to poorer attentional control, which together indicates that the effects of early long-chain polyunsaturated fatty acid nutrition may persist over time and influence multiple areas of development. 14 Also, Innis and Friesen 15 presented a significant correlation between VEP peak latencies and red blood cells DHA concentrations at birth. Lapillonne and Jensen 16 demonstrated that enterally fed premature infants (below 1250 g) exhibit daily DHA deficit of 20 mg/kg per day, which represents 44% of DHA that should have been accumulated. In addition, DHA content of human milk and current preterm formulas cannot compensate for an early deficit that may occur during the first month of life. In 2008, Koletzko et al 17 recommended use of an infant formula that provides DHA at levels between 0.2 and 0.5 weight percent of total fat. Then, Makrides et al 18 suggested supplementation of DHA as 1.0% of total fatty acids in premature infants born before 33 weeks gestational age. Recently, Lapillonne and Jensen 16 suggested that human milk and preterm formula should contain 1.5% of fatty acid as DHA to prevent the appearance of a DHA deficit and to compensate for the early DHA deficit. Our patients in the experimental group had received different dosages of DHA, depending on the daily intravenous lipid intake. The total intravenous intake of DHA in infants in the experimental group ranged from 2.0 to 4.0 g of DHA per infant. However, because the concentration of DHA in breast milk was not evaluated routinely we were not able to establish the total intake of DHA, supplemented either intravenously or enterally. On the basis of our findings, it was impossible to calculate the precise dose of DHA (mg/kg per day) that an infant should receive to avoid ROP. The aim of our clinical investigation was to reach the root cause of the deficit of DHA in infants with a birth weight of 1250 g. The fact that they are minimally fed by enteral route and receive routine parenteral nutrition that does not contain DHA might be the major causative factor of different pathologies, including cholestasis and retinopathy. CONCLUSIONS This is the first study, to our knowledge, in which the intravenous administration of fish-oil based lipid emulsion in very low birth weight infants from the first day of life is described. Whether this is an optimal dosage or preferential fish-oil emulsion, it should be assessed in blind controlled, multicenter studies. PEDIATRICS Volume 127, Number 2, February

6 REFERENCES 1. Kidd PM. Omega-3 DHA and EPA for cognition, behavior and mood: clinical findings and structural-functional synergies with cell membrane phospholipids. Altern Med Rev. 2007;12(3): Farooqui AA, Horrocks LA, Farooqui T. Modulation of inflammation in brain: a matter of fat. J Neurochem. 2007;101(3): Haggarty P. Placental regulation of fatty acid delivery and its effect on fetal growth: a review. Placenta. 2002;23(suppl A): S28 S38 4. SanGiovanni JP, Parra-Cabrera S, Colditz GA, Berkey CS, Dwyer JT. Meta-analysis of dietary essential fatty acids and long-chain polyunsaturated fatty acids as they relate to visual resolution acuity in healthy preterm infants. Pediatrics. 2000;105(6): Gura MK, Lee S, Valim C, et al. Safety and efficacy of a fish-oil based fat emulsion in the treatment of parenteral nutritionassociated liver disease. Pediatrics. 2008; 121(3). Available at: cgi/content/full/121/3/e Moyer V, Freese DK, Whitington PF, et al. Guidelines for the evaluation of cholestatic jaundice in infants: recommendation of the North American Society for Pediatric, Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39(2): McCann JC, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in human and animals. Am J Clin Nutr. 2005; 82(2): SanGiovanni JP, Berkey CS, Dwyer JT, Colditz GA. Dietary essential fatty acids, long chain polyunsaturated fatty acids and visual resolution acuity in healthy fullterm infants: a systematic review. Early Hum Dev. 2000;57(3): Greenberg JA, Bell SJ, Van Ausdal W. Omega-3 fatty acid supplementation during pregnancy. Rev Obstet Gynecol. 2008;1(4): Smithers LG, Gibson RA, McPhee A, Makrides M. Higher dose of docosahexaenoic acid in the neonatal period improves visual acuity of preterm infants: results of a randomized controlled trial. Am J Clin Nutr. 2008;88(4): De Caterina R, Liao JK, Libby P. Fatty acid modulation of endothelial activation. Am J Clin Nutr. 2000;71(1 suppl):213s 223S 12. Dammann O. Inflammation and retinopathy of prematurity. Acta Paediatr. 2010;99(7): Connor KM, SanGiovanni JP, Lofqvist C, et al. Increased dietary intake of -3- polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. 2007; 13(7): Williams C, Birch EE, Emmett PM, Northstone K; Avon Longitudinal Study of Pregnancy and Childhood Study Team. Stereoacuity at age 3.5 y in children born full-term is associated with prenatal and postnatal dietary factors: a report from a population-based cohort study. Am J Clin Nutr. 2001;73(2): Innis SM, Friesen RW. Essential n-3 fatty acids in pregnant women and early visual acuity maturation in term infants. Am J Clin Nutr. 2008;87(3): Lapillonne A, Jensen CL. Reevaluation of the DHA requirement for the premature infant. Prostaglandins Leukot Essent Fatty Acids. 2009;81(2 3): Koletzko B, Lien E, Agostoni C, et al. The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations. J Perinat Med. 2008;36(1): Makrides M, Gibson RA, McPhee AJ, et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA. 2009;301(2): PAWLIK et al

7 Fish-Oil Fat Emulsion Supplementation May Reduce the Risk of Severe Retinopathy in VLBW Infants Dorota Pawlik, Ryszard Lauterbach and Ewa Turyk Pediatrics 2011;127;223; originally published online January 3, 2011; DOI: /peds Updated Information & Services References Citations Post-Publication Peer Reviews (P 3 Rs) including high resolution figures, can be found at: /content/127/2/223.full.html This article cites 17 articles, 6 of which can be accessed free at: /content/127/2/223.full.html#ref-list-1 This article has been cited by 14 HighWire-hosted articles: /content/127/2/223.full.html#related-urls One P 3 R has been posted to this article: /cgi/eletters/127/2/223 Subspecialty Collections Permissions & Licensing Reprints This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant /cgi/collection/fetus:newborn_infant_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: Online ISSN:

8 Fish-Oil Fat Emulsion Supplementation May Reduce the Risk of Severe Retinopathy in VLBW Infants Dorota Pawlik, Ryszard Lauterbach and Ewa Turyk Pediatrics 2011;127;223; originally published online January 3, 2011; DOI: /peds The online version of this article, along with updated information and services, is located on the World Wide Web at: /content/127/2/223.full.html PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: Online ISSN: