Early Human Development 90 (2014) 27–31

Contents lists available at ScienceDirect

Early Human Development

journal homepage: www.elsevier.com/locate/earlhumdev

The influence of fish-oil lipid emulsions on retinopathy of prematurity in

very low birth weight infants: A randomized controlled trial☆
Serdar Beken a,⁎, Dilek Dilli a, Nurdan Dinlen Fettah a, Emrah Utku Kabataş b,
Ayşegül Zenciroğlu a, Nurullah Okumuş a
a
Neonatal Intensive Care Unit, Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey
b
Pediatric Ophthalmology Unit, Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To compare the effect of two lipid emulsions on the development of retinopathy of prematurity in very
Received 19 September 2013 low birth weight infants.
Received in revised form 7 November 2013 Design: Randomized controlled study.
Accepted 16 November 2013 Patients and methods: Eighty very low birth weight infants receiving parenteral nutrition from the first day of life
were evaluated. One of the two lipid emulsions were used in the study infants: Group 1 (n = 40) received fish-
Keywords:
oil based lipid emulsion (SmofLipid®) and Group 2 (n = 40) soybean oil based lipid emulsion (Intralipid®).
Lipid emulsion
Parenteral nutrition
Main outcome measures: The development of retinopathy of prematurity and the need for laser photocoagulation
Retinopathy of prematurity were assessed.
Results: The maternal and perinatal characteristics were similar in both groups. The median (range) duration of
parenteral nutrition [14 days (10–28) vs 14 (10–21)] and hospitalization [34 days (20–64) vs 34 (21–53)] did
not differ between the groups. Laboratory data including complete blood count, triglyceride level, liver and kid-
ney function tests recorded before and after parenteral nutrition also did not differ between the two groups. In
Group 1, two patients (5.0%) and in Group 2, 13 patients (32.5%) were diagnosed with retinopathy of prematurity
(OR: 9.1, 95% CI 1.9–43.8, p = 0.004). One patient in each group needed laser photocoagulation, without signif-
icant difference. Multivariate analysis showed that only receiving fish-oil emulsion in parenteral nutrition
decreased the risk of development of retinopathy of prematurity [OR: 0.76, 95% CI (0.06-0.911), p = 0.04].
Conclusions: Premature infants with very low birth weight receiving an intravenous fat emulsion containing fish
oil developed less retinopathy of prematurity.
© 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction transferred from mother to fetus in the third trimester of pregnancy

Advances in neonatal care have led to increased survival of infants
born prematurely. Total parenteral nutrition (TPN) is initiated in very
low birth weight (VLBW) infants to achieve the postnatal growth at a
rate that approximates the intrauterine growth of a normal fetus at
the same postconceptional age. In these infants, full enteral feedings
are generally delayed because of the severity of medical problems asso-
ciated with prematurity, such as feeding intolerance or necrotizing en-
terocolitis (NEC).
The importance of ω − 3 polyunsaturated fatty acids (PUFAs) has
been shown in fetal and neonatal development, especially for brain
and retinal tissues which are highly dependent on ω-3 PUFAs especially
docosahexaenoic acid (DHA) [1]. However, preterm infants are often
deficient of ω − 3 PUFAs because the most of ω − 3 PUFAs are
☆ Clinical trials registration number: NCT01875510.
⁎ Corresponding author at: Dr. Sami Ulus Hastanesi, Babür Caddesi, Altındağ, Ankara,
Turkey. Tel.: +90 532 671 31 96; fax: +90 312 317 03 53.
E-mail address: serbeken@yahoo.com (S. Beken).
[2,3]. Moreover, preterm infants have a very limited ability to synthesize
DHA from the α-linoleic acid. The major source of DHA after birth for
preterm newborns is breast milk or DHA-enriched formula [4]. It is
well known that the main sources of lipids for VLBW infants are fat
emulsions given as components of TPN within the first two to three
weeks of life.
Intravenous lipid emulsions are important components of TPN. They
contain essential fatty acids and provide a key source of calories which is
critical for growth and development of infants not receiving enteral
feedings. Conventional lipid emulsions derived from soybean oil contain
a high share of ω − 6 PUFAs (mainly linoleic acid). The lack of ω − 3
PUFAs might cause major problems on growing infant and can be ad-
justed by ω− 3 PUFAs containing lipid emulsions which are the main
sources of lipid in infants born prematurely. A new generation lipid
emulsion SMOFlipid contains a mixture of soybean oil, medium chain
triglycerides (MCT), olive-oil, fish-oil (ω− 3 PUFA) and α-tocopherol
[5]. The routine use of SMOFlipid within a TPN regimen is shown to be
well tolerated, safe and beneficially modulating the fatty acid profile
in preterm infants [6]. In a recent research, Gura et al. showed the safety

0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.earlhumdev.2013.11.002
28 S. Beken et al. / Early Human Development 90 (2014) 27–31
and efficacy of a fish-oil-based fat emulsion on parenteral nutrition-
associated liver disease in infants [7].
There are limited data on retinal effects of ω−3 PUFA supplementa-
tion on preterm infants [8,9]. Therefore, in this study, we investigated
whether VLBW infants who received a fish-oil emulsion administered
from the first day of life would exhibit or not lowered risk of ROP com-
pared with infants who received a soybean oil emulsion.
2. Patients and methods
2.1. Design and setting
From 01 January, 2013 to 31 July, 2013, a prospective, blinded, single
center, randomized controlled trial was conducted in the neonatal in-
tensive care unit (NICU) of Ankara Dr. Sami Ulus Maternity and Children
Research and Training Hospital, a level III neonatal center in Turkey.
2.2. Patients and study protocol
During the study period, preterm infants admitted to NICU were in-
cluded. Infants who weighed b1500 g and delivered prematurely before
the 32nd week of gestation were eligible for the study. Infants with
major congenital anomalies, congenital infections and inborn metabolic
errors were excluded from the study.
Informed and written parenteral consents were obtained before ran-
domization. Infants who needed TPN were treated with a volume com-
position of lipid emulsions that were both supplied by Fresenius Kabi AB
(Uppsala, Sweden). Study infants were randomly assigned to one of the
two groups by balanced blocks using sealed envelopes. Stratification
was not included in the block design.
➣ Group 1: Fish-oil emulsion (20% SMOFlipid: soybean oil 60 g/dL,
MCT 60 g/dL, olive oil 50 g/dL, fish oil 30 g/dL, egg phospholipids
12 g/dL, glycerol 25 g/dL, vitamin E 200 mg α-TE/L).
➣ Group 2: Soybean oil emulsion (20% Intralipid: soybean oil 200 g/dL,
egg phospholipids 12 g/dL, glycerol 22,5 g/dL, vitamin E 57 mg
α-TE/L).
Group assignment was made by the investigator (last author) who
was not involved in the care of the infants. A member of the TPN team
who was blinded and not involved in the care of infants followed orders
from the sealed envelope prepared by the investigators. Nurses and
doctors responsible for the infants were also blinded to the group
assignment.
TPN was started with intravenous glucose and amino acid solution
(1 g/kg) in the first day of life. In both groups, the lipid emulsions
were administered from the first day of life as a continuous infusion
for 24 h per day. The initial daily dose for infants with a birth weight
of b 1000 g was 0.5 g of lipids per kg of body weight. Respectively, the
initial dose for infants with birth weight of N 1000 g was 1.0 g of lipids
per kg of body weight. It was increased by 0.5 to 1.0 g of lipids per kg
body weight every 24 h to a maximum of 3.0 g of lipids per kg of
body weight/day. Infants also received trace elements, water and lipid
soluble vitamins as standard part of TPN protocol.
With regard to enteral feeding, infants in both groups were fed ini-
tially and advanced at 20 mL of breast milk (an average content of lipids
ranged from 3.8 to 4.3 g per 100 mL) and/or preterm formula
(Prematil-LCP®, Milupa, GmbH, Friedrichsdorf, Germany; 3.9 g of lipids
per 100 mL) enriched with ω − 3 long-chain polyunsaturated fatty
acids per kg per day, according to feeding tolerance. Thirty-two infants
in Group 1 (80%) and 30 infants in Group 2 (75%) received their own
mother's breast milk. The intravenous lipid infusion as a component of
TPN was progressively replaced with enteral intake so as to maintain
3.0 g of lipids per kg of body weight/day. The dosages and schedule of
lipid administration were similar in both groups.
Demographic and clinical data including the patients' gender,
gestational age, birth weight, APGAR score, severity of disease score
(SNAPPE-II; The Score for Neonatal Acute Physiology Perinatal Exten-
sion), the presence of associated disorders such as respiratory distress
syndrome (RDS), intraventricular hemorrhage (IVH) (grade ≥ 2),
necrotizing enterocolitis (NEC) (grade ≥ 2), and CLD (oxygen depen-
dency beyond 36 weeks of corrected age) with diuretic or steroid, cho-
lestasis (defined as serum direct bilirubin value of 1.0 mg/dL, if the total
bilirubin level was b 5.0 mg/dL or direct bilirubin value of N 20% total bil-
irubin if the total bilirubin level was N5.0 mg/dL), ROP and need for
laser photocoagulation, metabolic disturbances such as hypoglycemia/
hyperglycemia and culture proven sepsis were recorded. The number
of red blood cell (RBC) transfusion, duration of mechanical ventilation,
duration of oxygen, duration of TPN and length of hospitalization
were noted. Laboratory data including whole blood count, creatinine,
triglyceride, total/direct bilirubin, alanine amino transferase (ALT) and
gamma-glutamyl transpeptidase (GGT). Laboratory values were pro-
spectively measured biweekly.
2.3. Outcomes
Primary outcomes were the development of ROP and the need for
laser photocoagulation. Secondary outcomes including cholestasis, nos-
ocomial infections, NEC, intraventricular hemorrhage, and chronic lung
disease were analyzed in both groups.
2.4. Ophtalmological assessment
In both groups, the level of oxygen saturation was monitored by
pulse oximetry within the first minutes of life and continued until the
infant was breathing ambient air and did not require respiratory sup-
port. Adjustments in supplemental oxygen to maintain the target level
of oxygen saturation between 90 and 95 (ranges identical for both
groups) were performed by the clinical nurses.
The initial ROP examinations were performed when corrected age
was 31 weeks in infants with gestational age of ≤27 weeks, while the
infants born at or beyond 28 weeks were examined by the postnatal
fourth to fifth weeks. All fundus examinations were performed by the
same pediatric ophthalmologist who was blinded to the group assign-
ment. The follow-up examinations were performed once a fortnight in
patients with low-risk pre-threshold disease, and at least once a week
for ones with high-risk pre-threshold disease. Infants with normal
vascularization of the retina to the periphery were not re-examined.
The patients were treated with indirect ophthalmoscopic argon LP
[OcuLight GL (532 nm) Laser Photo-coagulator] of the entire avascular
retina with near confluent burns when type 1 ROP developed, as deter-
mined by the Early Treatment for Retinopathy of Prematurity (ETROP)
study [10].
2.5. Ethics
The study protocol was approved by the Local Ethics Committee. All
parents were fully informed about the investigational nature of this
study as well as its aim. A written consent was obtained from all parents.
This trial has been registered at www.clinicaltrials.gov (identifier
NCT01875510).
2.6. Sample size calculation and statistics
According to our previous research the incidence of ROP among
VLBW infants was ~30%. We hypothesized that fish-oil lipid emulsion
in VLBW might decrease the rate of ROP. A power analysis showed
that setting the error 0.05 with 72.9% power and an absolute reduction
of the incidence of ROP by 20%, the total number needed to verify our
hypothesis was 80 (40 in each group).
SPSS 17.0 (SPSS, Chicago, IL) was used for statistical analysis.
The Kolmogorov–Smirnov test was used to determine the shapes of
the distribution of variables. Data are expressed as the arithmetic
 S. Beken et al. / Early Human Development 90 (2014) 27–31 29

mean ± standard deviation (SD) or median (range; min–max), as ap- Table 1

propriate. Differences among two groups were analyzed by the Student Demographic and clinic characteristics of the infants.

t-test or the Mann–Whitney U test, where appropriate. Chi-square test Group 1 (n = 40) Group 2 (n = 40) p
was performed for categorical variables. The Pearson or Spearman test
Maternal age (years) a 27.3 ± 4.8 26.8 ± 6.6 0.67
was used to analyze correlation between variables. The level of signifi- Antenatal steroid, (n,%) 28 (70) 26 (65)
cance was set at 5% for all comparisons. Multivariate analysis was con- Cesarean section, (n,%) 32 (80) 30 (75) 0.78
ducted by entering possible confounding variables (gestational week, Male, (n,%) 24 (60) 22 (55%) 0.23
Gestational age (week)b 30 (28–31) 30 (27–31) 0.83
RDS, sepsis, NEC, hyperglycemic events, number of transfusions, dura-
Birth weight (grams)a 1092 ± 224 1160 ± 251 0.43
tion of oxygen, and type of lipid emulsion in TPN) to analyze the influ- APGARb 6 (5–8) 6 (5–8) 0.91
ence of lipid emulsions on the outcome variable (ROP). Odds ratios SNAPPE-II scoreb 37 (33–65) 40 (32–71) 0.28
(ORs) are presented with 95% confidence intervals (CIs). SNAPPE-II: The Score for Neonatal Acute Physiology Perinatal Extension.
a
Mean ± standard deviation.
b
Median (minimum, maximum).
3. Results
There was no difference for the rate of RDS, duration of oxygen
There were 85 infants with a gestational age below 32 weeks admit- therapy, duration of mechanical ventilation, number of RBC transfusion,
ted to our NICU during the 6 months of study period. Of these infants, number of hyperglycemic events between the groups, but number of
five were not included in the study; one had esophageal atresia, hypoglycemic events were higher in Group 2 (p = 0.039). When
one had diaphragmatic hernia and three were without parental consent. groups are compared according to neonatal morbidities and mortality,
Finally, 80 infants (40 in each arm) enrolled the study (Fig. 1). no difference was noted (Table 3).
The maternal and perinatal characteristics were similar in both Two patients (5.0%) in Group 1 and 13 patients (32.5%) in Group 2
groups (Table 1). Laboratory data recorded in the first day of life (before were diagnosed with ROP (OR: 9.1, 95% CI 1.9–43.8, p = 0.004). In
TPN) and after cessation of TPN (after TPN) also did not differ between Group 1, one patient (2.5%) was stage 2 and one patient (2.5%) was
the two groups (Table 2). Table 3 shows infants' clinical characteristics. stage 3 plus-ROP. In Group 2, six patients (15.0%) were stage 1, six
The median (range) duration of TPN [14 days (10–28) vs 14 (10–21)] patients (15.0%) were stage 2, and one patient (2.5%) was stage 3
and hospitalization [34 days (20–64) vs 34 (21–53)] did not differ plus-ROP. In each group only one patient needed laser photocoagula-
between the groups (p = 0.53 and p = 0.77, respectively) (Table 3). tion, without significant difference (Table 3).
When gestational age, RDS, sepsis, NEC, number of hyperglycemic
Assessed for eligibility events, number of transfusions, duration of oxygen, and type of lipid
(n=85) emulsion in TPN were assigned as possible risk factors, multivariate
analysis showed that only receiving fish-oil lipid emulsion in TPN de-
creased the risk of ROP development [OR: 0.76, 95% CI (0.06–0.911),
Excluded (n=5): had
esophagial atresia (n=1);
p = 0.04].
Enrollment
had diaphragmatic hernia
(n=1); without parental 4. Discussion
consent (n=3)

Lipid emulsions are an integral element of TPN regimens for critically

Randomly assigned
ill preterm infants. In this randomized controlled study, it was seen that
(n=80)
both intravenous lipid emulsions were well tolerated and infants who
received fish-oil emulsions have less ROP. There were no differences
in other neonatal morbidities between groups. We can't say that fish-
oil emulsions reduce the risk of cholestasis as its rate did not differ in
groups. There were only two infants with cholestasis in each group.
Allocated to SMOFLipid Allocated to IntraLipid
Allocation group group
Lower proportion of VLBW infants in the study group might be the rea-
son for this low rate of cholestasis. Early enteral feeding and timely
(n=40) (n=40)
control of infections may also be more effective preventive strategies
for cholestasis.
DHA is a nutrient which is required for the development of the retina
and brain [11]. It was established that DHA comprises 20% of total fatty
acid content of the infant retina. Although DHA represents a small per-
centage of the fatty acids in most human tissues, it is the most abundant
PUFA in the retina which modulates capillary integrity, neovasculariza-
tion, visual function and inflammation in the retina [4,12,13]. Higher
dose of DHA in the neonatal period was shown to improve visual acuity
Analysis Final number analysed:40 Final number analysed:40 of preterm infants [8,9]. Recently, the role of an inflammatory reaction
Outcomemeasurements: Outcome measurements: in the pathophysiology of ROP has been suggested. The results of an ex-
Retinopathy of prematurity: 2 Retinopathy of prematurity: 13
perimental data obtained by Connor et al. [14] indicated that DHA,
eicosapentaenoic acid, and their potent bioactive products at physiolog-
Laser photocoagulation: 1 Laser photocoagulation: 1
ic levels reduce pathologic neovascularization through enhanced vessel
Cholestasis:2 Cholestasis: 2
regrowth after vascular loss and injury, and that enriching the sources of
Nosocomial infection: 2 Nosocomial infection: 3 ω−3 PUFA may be an effective approach to help prevent proliferative
Necrotising enterocolitis: 9 Necrotising enterocolitis: 9 retinopathy.
Chronic lung disease: 12 Chronic lung disease: 14 ROP is the major cause of visual impairment and blindness in
Mortality: 4 Mortality: 3 preterm neonates. Numerous factors participate in the genesis of ROP.
Because DHA is important for retinal cell development and preterm
Fig. 1. Flow diagram of randomized trial study. infants lack DHA, the visual system for many of these children may be
30 S. Beken et al. / Early Human Development 90 (2014) 27–31

Table 2
Laboratory data of the infants before and after total parenteral nutrition.

Group 1 (n = 40) Group 2 (n = 40) p

Before TPN
Hemoglobin (g/dL)a 14.2 (12.8–17.1) 14.5 (12.3–17.8) 0.43
Leucocyte (/mm3)b 14250 (6000–254000) 14500 (6500–35000) 0.97
Platelets (/mm3)b 169000 (105000–425000) 173000 (11000–500000) 0.68
Triglyceride (mg/dL)a 51.7 (31–107) 52 (24–100) 0.55
Creatinine (mg/dL)b 0.6 (0.3–1.1) 0.8 (0.4–1.3) 0.83
Total bilirubin (mg/dL)a 3.1 ± 1.3 3.5 ± 1.6 0.27
Direct bilirubin (mg/dL)b 0.2 (0.1–0.6) 0.2 (0.1–0.8) 0.29
ALT (mg/dL)a 40.6 ± 10.4 35 (20–126) 0.14
GGT (mg/dL)b 0 (0–62) 2 (0–10) 0.06

After TPN
Hemoglobin (g/dL)b 11.0 (7.8–14) 11.5 (7.5–14.4) 0.41
Leucocyte (/mm3)b 11800 (4800–124000) 12400 (4200–35000) 0.58
Platelets (/mm3)a 170750 ± 79143 157000 ± 86258 0.37
Triglyceride (mg/dL)a 83.5 (42–110) 89 (41–120) 0.56
Creatinine (mg/dL)b 0.6 (0.1–1.1) 0.8 (0.12–1.3) 0.83
Total bilirubin (mg/dL)a 5.3 ± 2.3 4.7 ± 2.2 0.31
Direct bilirubin (mg/dL)b 0.4 (0.1–1.2) 0.4 (0.0–1.2) 0.75
ALT (mg/dL)a 54.8 ± 14.5 51.7 ± 17.7 0.98
GGT (mg/dL)b 5 (0–62) 5 (0–20) 0.93

ALT: alanine aminotransferase, GGT: gamma glutamyltransferase.

a
Mean ± standard deviation.
b
Median (minimum, maximum).

adversely affected [15]. Developing fetus depends on that of its mother Recent animal studies demonstrated that ω−3 PUFA supplementation
and DHA is transferred mostly in the last trimester [2,3]. In formula reduced the development of retinal neovascularization [14,20]. Connor
fed preterm infants, it is demonstrated that inadequate dietary intake KM et al. showed that DHA supplementation may have protective effect
of DHA early in life is related to adverse visual processing outcomes against retinal neovascularization or phase II retinopathy in mouse
[16,17]. In meta-analyses it was reported that supplementation of infant model of oxygen-induced retinopathy by formation of cytoprotective
formula with DHA increased the rate of visual maturation in preterm in- and anti-inflammatory metabolites [14]. Similarly, Pawlik et al. reported
fants but ascribe no clear long-term benefits above 6 months of age that infants receiving ω−3 PUFA in lipid emulsions from the first day
[18,19]. In 2008, Koletzko et al. [16] recommended the use of an infant of life had lower risk of laser therapy for severe ROP [8]. In another
formula that provides DHA at levels between 0.2 and 0.5 wt.% of total study, the authors stated that infants receiving fish-oil lipid emulsions
fat. Our patients in the fish-oil group had received different dosages had less ROP requiring laser treatment, less cholestasis and higher plasma
of DHA, depending on the daily intravenous lipid intake. However, and erythrocyte DHA levels than those receiving a standard lipid emul-
because the concentration of DHA in breast milk was not evaluated rou- sion [21]. In our study, laser requirement did not differ between the
tinely we were not able to establish the total intake of DHA, supple- groups, however ROP development was found to be lower in infants
mented either intravenously or enterally. According to our findings, it who received fish-oil lipid emulsions.
was impossible to calculate the precise dose of DHA (mg/kg per day) The limitation of our study is that participants are mostly above
that an infant should receive to avoid ROP as stated by Pawlik et al. [8]. 1000 g. It was a single center study and DHA levels were not measured.
Although preterm infants benefit from diets supplemented with DHA In seven infants who died, only the first ophthalmological examination
very early in visual development, there are very limited data of DHA could be performed. Nevertheless, we believe that this study is valuable
enriched parenteral nutrition in the first days of life in preterm infants. as it compares two lipid emulsions in VLBW infants and showed the in-
fluence of fish-oil emulsions on the development of ROP.
In conclusion fish-oil lipid emulsions may be preventive for ROP
Table 3
development in preterm infants requiring TPN. If these infants are
Clinical variables in the study infants. minimally fed by enteral route and receive routine TPN that does not
contain DHA, this condition might have an additive effect on ROP devel-
Group 1 (n = 40) Group 2 (n = 40) p
opment. Multicenter studies are needed to assess this effect in preterm
Hyperglycemia (n, %) 1 (2.5) 3 (7.5) 0.12 infants.
Hypoglycemia (n, %) 0 (0) 3 (7.5) 0.03
RDS (n, %) 26 (68.5) 25 (62.5) 0.58
IVH (≥grade 2) (n, %) 6 (15.8) 7 (17.5) 0.83
Cholestasis (n, %) 2 (5.0) 2 (5.0) 0.78 Conflict of interest
Sepsis (n, %) 2 (5.0) 3 (7.5) 0.73
NEC (≥grade 2) (n, %) 9 (23.7) 9 (22.5) 0.90 None.
ROP (n, %) 2 (5.0) 13 (32.5) 0.001
CLD (n, %) 12 (31.6) 14 (35) 0.74
Oxygen therapy (days)a 11.5 (0–180) 12 (5–58) 0.61
Mechanical ventilation (days)a 9 (0–90) 10 (0–57) 0.83 Funding
RBC transfusion (number)a 1 (0–8) 1 (0–4) 0.58
Mortality (n, %) 4 (10.0) 3 (7.5) 0.64
None.
Duration of hospitalizationa 34 (20–64) 34 (21–53) 0.77
Duration of parenteral nutritiona 14 (10–28) 14 (10–21) 0.53

RDS: respiratory distress syndrome, IVH: intraventricular hemorrhage, NEC: necrotizing

enterocolitis, ROP: retinopathy of prematurity, CLD: Chronic lung disease, and RBC: red
Acknowledgements
blood cell.
a
Median (minimum, maximum). None.
 S. Beken et al. / Early Human Development 90 (2014) 27–31
References
[1] Carlson SJ, Fallon EM, Kalish BT, Gura KM, Puder M. The role of the ω−3 fatty acid
DHA in the human life cycle. JPEN J Parenter Enter Nutr 2013;37:15–22.
[2] Haggarty P. Fatty acid supply to the human fetus. Annu Rev Nutr 2010;30:237–55.
[3] Martinez M, Mougan I. Fatty acid composition of human brain phospholipids during
normal development. J Neurochem 1998;71:2528–33.
[4] SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated fatty
acids in health and disease of the retina. Prog Retin Eye Res 2005;24:87–138.
[5] Adolph M. Lipid emulsions in parenteral nutrition. Ann Nutr Metab 1999;43:1–13.
[6] Rayyan M, Devlieger H, Jochum F, Allegaert K. Short-term use of parenteral nutrition
with a lipid emulsion containing a mixture of soybean oil, olive oil, medium-chain
triglycerides, and fish oil: a randomized double-blind study in preterm infants.
JPEN J Parenter Enter Nutr 2012;36(1 Suppl.):81S–94S.
[7] Gura KM, Lee S, Valim C, Zhou J, Kim S, Modi BP, et al. Safety and efficacy of a fish-oil-
based fat emulsion in the treatment of parenteral nutrition-associated liver disease.
Pediatrics 2008;121:e678–86.
[8] Pawlik D, Lauterbach R, Turyk E. Fish-oil fat emulsion supplementation may reduce
the risk of severe retinopathy in VLBW infants. Pediatrics 2011;127:223–8.
[9] 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;88:1049–56.
[10] Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications
for the treatment of retinopathy of prematurity: results of the early treatment for
retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;121:1684–94.
[11] 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
31
evidence from cognitive and behavioral tests in humans and animals. Am J Clin
Nutr 2005;82:281–95.
[12] Fliesler SJ, Anderson RE. Chemistry and metabolism of lipids in the vertebrate retina.
Prog Lipid Res 1983;22:79–131.
[13] Querques G, Forte R, Souied EH. Retina and omega-3. J Nutr Metab 2011;2011:748361.
[14] Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, et al.
Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathologi-
cal retinal angiogenesis. Nat Med 2007;13:868–73.
[15] Molloy C, Doyle LW, Makrides M, Anderson PJ. Docosahexaenoic acid and visual
functioning in preterm infants: a review. Neuropsychol Rev 2012;22:425–37.
[16] Koletzko B, Lien E, Agostoni C, Böhles H, Campoy C, Cetin I, 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;36:5–14.
[17] O'Connor DL, Hall R, Adamkin D, Auestad N, Castillo M, Connor WE, et al. Growth
and development in preterm infants fed long-chain polyunsaturated fatty acids: a
prospective, randomized controlled trial. Pediatrics 2001;108:359–71.
[18] Simmer K. Long-chain polyunsaturated fatty acid supplementation in preterm
infants. Cochrane Database Syst Rev 2000;2:CD000375.
[19] Schulzke SM, Patole SK, Simmer K. Long-chain polyunsaturated fatty acid supple-
mentation in preterm infants. Cochrane Database Syst Rev 2011;2:CD000375.
[20] Stahl A, Sapieha P, Connor KM, Sangiovanni JP, Chen J, Aderman CM, et al.
Short communication: PPAR gamma mediates a direct antiangiogenic effect of
omega 3-PUFAs in proliferative retinopathy. Circ Res 2010;20(107):495–500.
[21] 21.Pawlik D, Lauterbach R, Walczak M, Hurkala J, Sherman MP. Fish-oil fat emulsion
supplementation reduces the risk of retinopathy in very low birth weight infants: a
prospective, randomized study. JPEN J Parenter Enteral Nutr [DOI: http://dx.doi.org/
10.1177/0148607113499373, Epub ahead of print].