Effects of fish oil-containing lipid emulsions on retinopathy of prematurity in very low birth weight infants

Journal Pre-proof Effects of Fish Oil-Containing Lipid Emulsions on Retinopathy of Prematurity in Very Low Birth Weight Infants Chiung-Fang Tu, Cheng-Han Lee, Hsiao-Neng Chen, Lon-Yen Tsao, Jia-Yuh Chen, Chien-Chou Hsiao PII:

S1875-9572(19)30550-9

DOI:

https://doi.org/10.1016/j.pedneo.2019.11.010

Reference:

PEDN 988

To appear in:

Pediatrics & Neonatology

Received Date: 5 June 2019 Revised Date:

3 October 2019

Accepted Date: 8 November 2019

Please cite this article as: Tu C-F, Lee C-H, Chen H-N, Tsao L-Y, Chen J-Y, Hsiao C-C, Effects of Fish Oil-Containing Lipid Emulsions on Retinopathy of Prematurity in Very Low Birth Weight Infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.11.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.

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PEDN_2019_348_After Eng edited_final

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Original Article

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Effects of Fish Oil-Containing Lipid Emulsions on Retinopathy of Prematurity in Very Low Birth

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Weight Infants

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Chiung-Fang Tu1 , Cheng-Han Lee1 , Hsiao-Neng Chen1 , Lon-Yen Tsao1 , Jia-Yuh Chen1,2 ,

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Chien-Chou Hsiao1,2,3

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1.Department of Neonatology, Changhua Christian Children’s Hospital, Changhua, Taiwan

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2. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.

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3. School of Medicine, Kaohsiung Medical University, Taiwan

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Conflicts of Interest Statement

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Declarations of Interest: None

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Acknowledgements

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The authors thank the staff at the Epidemiology and Biostatistics Center, Department of

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Changhua Christian Hospital for statistical assistance. The authors are grateful to the infants

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and their parents, as well as all the staff in NICU of the Changhua Christian Children's

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Hospital for their assistance.

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1

Corresponding author: Dr. Chien-Chou Hsiao, Department of Pediatrics, Changhua Christian

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Children Hospital, Changhua, Taiwan.

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Address: #135 Nanshiao Street, Changhua City 500, Taiwan

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E-mail: [email protected]

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TEL: +886-4-7238595

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Fax: +886-4-7238847

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Short title:

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Fish oil-based lipids reduced retinopathy of prematurity

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1

Abbreviations:

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ARA: Arachidonic acid

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ALT: Alanine amino transferase

4

ALP: Alkaline phosphatase

5

BPD: Bronchopulmonary dysplasia

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CI: Confidence interval

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DHA: Docosahexaenoic acid

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GA: Gestational age

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IVH: Intraventricular hemorrhage

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IQR: Interquartile range

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LCPUFA: Long-chain polyunsaturated fatty acids

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MCT: Medium-chain triglycerides

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NEC: Necrotizing enterocolitis

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NICU: Neonatal intensive care unit

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PUFA: Polyunsaturated fatty acid

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RNV: Retinal neovascularization

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ROP: Retinopathy of prematurity

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SD: Standard deviation

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TPN: Total parenteral nutrition

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1

VLBW: Very low birth weight

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Abstract

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Background:

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The aim of the study was to assess the impact of different types of parenteral emulsions on

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retinopathy of prematurity (ROP) in very low birth weight (VLBW, birth body weight < 1500 g)

7

infants by comparing fish oil-containing and soy-based parenteral emulsions.

8 9

Methods:

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Data of preterm infants with body weights below 1500 gm at birth and receiving total

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parenteral nutrition (TPN) for a minimum of 7 days during the period between January 2009

12

and November 2017 were analyzed in this retrospective study. We compared clinical

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outcomes in two epochs using different lipid emulsions: epoch 1 (soybean-based lipid

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emulsions, January 2009–February 2014) versus epoch 2 (fish oil-containing lipid emulsions,

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January 2015–November 2017). The primary outcomes measured were the incidence of ROP

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and the number of ROP cases requiring bevacizumab therapy.

17 18

Results:

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A total of 396 infants were enrolled in this study (203 in epoch 1 and 193 in epoch 2). A lower

5

1

incidence of any stage ROP (24.1 vs. 11.4%, p < 0.001) and lower requirement of

2

bevacizumab therapy (12.8 vs. 5.2%, p = 0.001) were observed in epoch 2. Gestational age,

3

glutamic-pyruvic transaminase, total bilirubin, and alkaline phosphatase levels, and type of

4

lipid emulsion in TPN were associated with higher ROP incidence. Multivariate logistic

5

regression analysis revealed that parenteral nutrition in the form of lipid emulsions

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containing fish oil was associated with a lower risk of development of ROP [Odds Ratio: 0.178,

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95% confidence interval (CI): 0.095–0.330, p < 0.001].

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Conclusions:

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Compared with soybean-based lipid solutions, the use of fish oil-containing lipid solutions

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may be associated with a lower incidence of ROP and decreased need for bevacizumab

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treatment in preterm infants.

13 14

Key words

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fish oil; docosahexaenoic acids; n-3 polyunsaturated fatty acid; premature infants;

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retinopathy of prematurity

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1

Introduction

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Retinopathy of prematurity (ROP) is the leading cause of childhood blindness in high-income

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countries currently. It is a disorder of abnormal vascularization of the retina and affects

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premature infants. With improvements in neonatal care in recent times, the survival rate of

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premature infants has improved, and thus the incidence of ROP is increasing worldwide.1

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ROP is thought to be induced by a combination of various factors that lead to reduced retinal

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vessel growth and microvascular degeneration, followed by pathologic retinal

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neovascularization (RNV). Manipulation of oxygen administration is used for preventing this

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multifactorial disease; however, the condition still presents with significant morbidity in the

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preterm infant.2 Many therapeutic strategies for treating ROP are targeted toward

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suppressing RNV, which might cause the vulnerable retina injury and impair visual function

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later.3-8 Therefore, there is an urgent need to find a solution for preventing ROP in order to

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maximize visual development and acuity in these preterm infants.

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Preterm infants lack third trimester lipid stores because of loss of placental and maternal

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growth factors at birth. They also have a poor ability to synthesize docosahexaenoic acid

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(DHA).9 DHA is an omega-3 long-chain polyunsaturated fatty acid (PUFA), and it is the main

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structural lipid in the retinal photoreceptor outer segment disc membrane.10 There is

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evidence that omega-3 long-chain PUFAs play a role in visual development and

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anti-inflammatory processes.11

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1

Previous studies in humans and animal models of ROP suggest that supplementation with

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omega-3 long-chain PUFAs improves retinal angiogenesis and visual acuity.12–14

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Most preterm infants require a few weeks to achieve complete enteral feeding, and they are

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dependent on parenteral nutrition in the early stages. Therefore, preventive measures in the

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form of omega-3 long-chain PUFA supplementation with lipid emulsions containing fish oil

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may be beneficial in preterm infants. The aim of the present study was to assess the impact

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of different types of parenteral emulsions (fish oil-containing and soy-based) on ROP in very

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low birth weight (VLBW, birth body weight < 1500 g) infants.

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1

Methods

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Ethics

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The study protocol was approved by the Ethics Review Board at Changhua Christian Hospital.

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Patients and enrollment criteria

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This retrospective study included patients admitted to the neonatal intensive care unit (NICU)

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of our hospital. The parenteral nutrition protocol in our NICU was changed from

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soybean-based lipid emulsion (Lipovenoes medium-chain triglycerides [MCT] 20%; Fresenius

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Kabi, Bad Homburg, Germany; containing 50% soybean oil and 50% MCT) to fish

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oil-containing lipid emulsion (SMOFlipid; Fresenius Kabi, Bad Homburg, Germany; containing

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30% soybean oil, 30% MCT, 25% olive oil, and 15% fish oil) in January 2015. We were

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interested in comparing the outcomes of the two epoch groups, in which either fish

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oil-containing lipid emulsion or soybean-based lipid emulsion was used. Thus, the two groups

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analyzed in our study included epoch 1 (soybean-based lipid emulsion, January 2009–

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February 2014) and epoch 2 (fish oil-containing lipid emulsion, January 2015–November

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2017). We had conducted a randomized control trial (RCT) about fish oil-containing lipid

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emulsion versus soybean-based lipid emulsion between March 1, 2012 and February 28,

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2014 in our NICU. Totally sixty premature infants enrolled in that RCT were excluded from

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this retrospective study.

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We accessed hospital electronic databases and chart reviews of the two patient groups to

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1

retrieve clinical data (total parenteral nutrition [TPN] data, medical records, pathology, and

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imaging) such as body weight; body height; head circumference; gestational age (GA); sex;

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Apgar scores; administration of prenatal steroids; number of days of supplemental oxygen

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therapy; presence of late onset sepsis, bronchopulmonary dysplasia (BPD), necrotizing

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enterocolitis (NEC), intraventricular hemorrhage (IVH); duration of parenteral nutrition; and

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laboratory data including total bilirubin, direct bilirubin, alanine amino transferase (ALT), and

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alkaline phosphatase (ALP). The timing of biochemistry tests was routinely obtained on the

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1st day of life and checked weekly until TPN was discontinued. The peak level of these

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biochemistry tests are compared in Table 2 and 3. In both epochs, the level of oxygen

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saturation was monitored by pulse oximetry within the first minutes of life and discontinued

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after the infant was discharged. Residents, respiratory therapists and clinical nurses adjusted

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the supplemental oxygen to maintain the target level of oxygen saturation between 90 and

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95 in both epochs.

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Preterm infants with birth weight < 1500 g who received at least 7 consecutive days of a

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single parenteral lipid emulsion formula were included in the study.

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Infants with severe congenital malformations including chromosomal abnormalities, lethal

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congenital abnormalities, cyanotic congenital heart disease, or metabolic disorders were

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excluded.

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Intervention

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1

Infants requiring TPN were prescribed either fish oil-containing lipid emulsions or

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soybean-based lipid emulsion within 24 hours of birth for a duration of at least 7 consecutive

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days. Most infants were administered TPN through peripherally inserted central venous

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catheters, and the infusion rate of both lipid solutions was gradually increased to 3 g/kg body

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weight/day.

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The intravenous lipid emulsions were infused along with a standardized mixed solution

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containing amino acids, dextrose, minerals, and trace elements in a separate syringe. TPN

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and lipid emulsion were discontinued at the same day. Parenteral nutrition was continued in

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both epochs until full enteral feeding was resumed. RBC transfusion is performed according

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to the following conditions: (1) patient is symptomatic(tachycardia, tachypnea, poor feeding)

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with a hematocrit of < 20% and no compensatory reticulocytosis; (2) patient is symptomatic

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with oxygen dependency, ventilator dependency(MAP<6cm of water), poor weight gain

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despite adequate nutritional provision, and a hematocrit of < 30%; (3) patient has a

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hematocrit of < 35% but oxygen requirement is > 35% or needs ventilator-assisted

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breathing(MAP>6cm of water); and (4) phlebotomy blood loss reaches 15% of patient's total

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blood volume in the 1st week of life. Packed RBCs were transfused in a volume of 10–15

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mL/kg of body weight over 2–4 hours. Patients in the two epochs were cared for by the same

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three attending neonatologists with strict adherence to the transfusion guideline for

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premature infants. The frequency of PRBC transfusion in the two epochs is compared in Table

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1

2.

2 3

Outcomes

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The primary study outcomes measured were the incidence of any stage of ROP and the

5

number of patients with ROP requiring bevacizumab therapy. Secondary outcomes compared

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included BPD, NEC (all stages), any grade of IVH, duration of oxygen requirement, TPN

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duration, and late-onset sepsis. Serum biochemistry data were collected after cessation of

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TPN.

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Three ophthalmologists with training in the diagnosis of ROP performed ROP screening on all

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infants in both groups (screening criteria: < 32 weeks gestational age or < 1500 g). The stage

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of the ROP was defined according to The International Classification of Retinopathy of

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Prematurity. The patients were treated with intravitreal Bevacizumab therapy as determined

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by the Early Treatment for Retinopathy of Prematurity (ETROP) study, including stage 1 or 2

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ROP in zone I with plus disease or stage 3 ROP in zone I, or stage 2 or 3 ROP with plus disease

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in zone II. If the patients did not improve in retinal vessel tortuosity and neovascularization

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after intravitreal Bevacizumab therapy in 2 to 3 weeks, conventional laser treatment of ROP

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was performed. BPD was defined as a need for supplemental oxygen (O2) for > 28 days, and

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the severity was assessed by respiratory support at 36 weeks postmenstrual age according to

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the National Institute of Child Health and Human Development consensus definition. NEC

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1

was diagnosed clinically based on the modified Bell's criteria. IVH was diagnosed using

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cranial ultrasonography.

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Statistical Analyses

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All statistical analyses were conducted using the SPSS software for Windows, version 22.0

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(IBM Corp., Armonk, NY). Continuous variables were expressed as mean (standard deviation

6

[SD]), whereas categorical variables were presented as number (percentage). Student’s t test

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was performed for analysis of normally distributed data. Chi-squared test or Fisher's exact

8

test was used for analysis of categorical variables. The independent variables with a p-value

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of less than 0.50 in the univariate analysis were selected for multivariate analysis.

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Multivariate logistic regression analyses after adjusting for possible confounding factors were

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performed to ascertain the significant influences for ROP and were calculated as adjusted

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odds ratio (95%, confidence interval [CI]). The final model only retained the significant

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predictors. P-values < 0.05 were considered statistically significant.

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Results

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A total of 396 VLBW infants who had received parenteral nutrition lipid emulsions for at least

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7 days were recruited during the study period. There were 203 infants in epoch 1 who

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received soybean-based lipid emulsions (Lipovenoes MCT 20%) and 193 infants in epoch 2

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who received fish oil-containing lipid emulsions (SMOFlipid).

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Table 1 summarizes the demographic characteristics of each group. The mean birth body

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weight [1114.5 (284.4) vs. 1121.9 (295) grams; p = 0.80] and gestational age [28.8 (2.5) vs.

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28.9 (2.5) weeks; p = 0.69] did not differ between the two epoch groups. The demographic

9

characteristics were similar (Table 1) in the two epoch groups, with no statistically significant

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differences with regard to sex, 1 and 5 minute APGAR scores, or administration of antenatal

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steroids.

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Table 2 shows the clinical outcomes in the infants and laboratory data after cessation of TPN.

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A lower incidence of any stage ROP (24.1 vs. 11.4%, p < 0.001) and lower requirement of

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bevacizumab therapy (12.8 vs. 5.2%, p = 0.001) were noted in epoch 2. There was a

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significant difference in the mean (SD) TPN duration [27.6 (14.3) vs. 19.7 (9.33) days; p <

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0.05], and incidence of IVH (22.2 vs. 14.4%; p = 0.01), and BPD (36.5 vs. 26.4%; p = 0.04)

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between the epochs. The mean (SD) direct bilirubin was higher in epoch 1 than in epoch 2

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[0.9 (1.5) vs. 0.6 (1.3); p = 0.04], but there were no significant differences with regard to total

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bilirubin, glutamic-pyruvic transaminase, or ALP. Furthermore, after adjusting for the

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gestational age, gender, and 1-min Apgar score, comparison of these clinical outcomes for

2

the two epochs still had the same test results (Table 2).

3

In Table 3, we first conducted univariate analysis for the ROP variable using student’s t-test,

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chi-square test or Fisher's exact test on each demographic characteristic and clinical variable.

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Then, we used logistic regressions to predict factors associated with the ROP. The

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independent variables with a P-value of less than 0.05 in the univariate analysis were

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selected for multivariate analysis. The final model only retained the significant predictors (P <

8

0.05). Univariate analysis identified a high correlation of factors including gestational age, ALT,

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total bilirubin, ALP, and the type of lipid emulsions with the development of ROP. After

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controlling for these factors, multivariate logistic regression analysis revealed that the

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different kinds of lipid emulsions had a significant impact on the incidence of ROP (crude

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odds ratio = 0.306 [95% CI = 0.195–0.480], p < 0.001; adjusted odds ratio = 0.178 [95% CI =

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0.095–0.330], p < 0.001).

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1

Discussion

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In this study, VLBW infants receiving a fish oil-containing lipid emulsion were compared with

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those receiving soybean-based lipid emulsions in their early life; it was observed that infants

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receiving fish oil-containing lipid emulsion had a lower incidence of ROP and less need for

5

bevacizumab therapy.

6

Long-chain PUFAs (LCPUFAs), including omega-3 and omega-6 LCPUFAs, play an important

7

role in cell signaling and membrane structure.15 DHA, an omega-3 LCPUFA, is the most

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abundant fatty acid in the brain and retina, and it is involved in several physiological

9

processes, including the inflammatory process.16

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Recent evidence indicates the importance of inflammation in the pathogenesis of ROP.17

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Several cytokines and chemokines have been shown to be involved in the pathological

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process of ROP, including interleukin (IL)-6, IL-7, IL-8, tumor necrosis factor (TNF)-α,

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monocyte chemoattractant protein-1, and macrophage inflammatory protein 1

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alpha/beta.18–20

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DHA protects the retina against ischemia, hypoxia, and hyperoxia through its

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anti-inflammatory action, and it might be a promising therapeutic intervention.10, 21–23

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Omega-6 LCPUFA-derived products have been known to have an inflammatory effect; in

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contrast, omega-3 LCPUFA-derived metabolites protect against neovascularization and

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inflammation. The metabolites of omega-3 LCPUFA inhibit inflammation and angiogenesis via

16

1

two groups of enzymes, the cyclooxygenases and lipoxygenases. A study in Fat-1 transgenic

2

mice demonstrated that a high omega-3 to omega-6 LCPUFA ratio suppressed pathological

3

retinal neovascularization; expression of the Caenorhabditis elegans gene encoded an

4

enzyme, which was responsible for the conversion of omega-3 to omega-6 LCPUFA.14

5

Omega-3 PUFAs have been reported to reduce stimulation of neovascularization due to

6

hypoxia by reducing angiogenesis under hyperoxic conditions, thereby reducing the avascular

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region of the retina in oxygen-induced retinopathy. Bioactive omega-3-PUFA-derived

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mediators also effectively prevent neovascularization by inhibiting TNF-α.24 4-hydroxy-DHA, a

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5-lipooxygenase omega-3 LCPUFA metabolite, directly inhibits angiogenesis and proliferation

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of endothelial cells via peroxisome proliferator-activated receptor-g, without losing the

11

beneficial effects of dietary omega-3 PUFAs even when used together with cyclooxygenase

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inhibitors.25

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Previous studies have demonstrated that n-3 LCPUFAs exhibit cellular therapeutic and

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protective effects and thus have anti-angiogenic and neuroprotective mechanisms within the

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retina.15, 26, 27 An earlier study demonstrated that, compared to soybean-based lipid emulsion,

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fish oil-containing lipid emulsion had a reduced ratio of omega-6 LCPUFAs (arachidonic acid

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[ARA])to omega-3 LCPUFAs (DHA).28 DHA supplements delivered by enteral feeding in infants

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have shown beneficial effects on visual acuity in previous studies.29, 30 It is possible that the

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LCPUFA status in the retinal tissue is dependent upon whether the infant is on enteral or

17

1

parenteral nutritional supplementation. In preterm infants especially, with limited enteral

2

feeding in the first few weeks, most nutrition comes from parenteral nutritional support. The

3

incidence of ROP can be reduced by using lipid emulsions containing a higher ratio of

4

omega-3 to omega-6 LCPUFAs, which inhibit the metabolism of ARA and result in decreased

5

production of proinflammatory cytokines such as IL-6, IL-8, and TNF-α.31 Supplementation of

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LCPUFAs with more DHA than ARA may be a promising prevention strategy for ROP. It was

7

recently reported that low levels of omega-6 LCPUFAs were associated with ROP

8

development,32 which suggests that the relationship between omega-3 and omega-6

9

LCPUFAs is complex and optimal supplementation to create a balance between these two

10

different LCPUFAs is important to avoid adverse effects. We also found that the incidence of

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bronchopulmonary dysplasia (BPD) is lower in epoch 2, compared to epoch 1. Several studies

12

demonstrated that elevated levels of several inflammatory cytokines and chemokines in the

13

serum and lungs cytokines of preterm neonates during the 1st week of life were associated

14

with the development of BPD. Using lipid emulsions containing a higher ratio of omega-3 to

15

omega-6 LCPUFAs might lower the incidence of BPD by improving balance of pro- and

16

anti-inflammatory mechanisms. In preterm infants, early administration of fish oil-containing

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lipid emulsion significantly decreased IL-1β and IL-6 levels in serum and bronchoalveolar

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lavage fluid was associated with shorter duration of ventilator support and less

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bronchopulmonary dysplasia (BPD).33 It is reasonable to conclude that lower inflammatory

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1

cytokines and BPD may also associated with lower incidence of ROP.

2

Our study has some limitations. First, there is the possibility of selection bias, as it was not

3

possible to accurately control the lipid agent used since this was a retrospective study in a

4

single center. Another limitation of our study is that we did not check the DHA

5

concentrations in the two groups, and therefore we were unaware of how many infants had

6

DHA/eicosapentaenoic acid deficiency. The other limitation is the retrospective design,

7

meaning that extrinsic and confounding variables can influence the results. Subsequent

8

changes in neonatal care practices might affect the possible association between fish

9

oil-containing lipid emulsions and ROP. The ideal target ranges for oxygen saturation

10

remain controversial as per several large randomized controlled studies.34–36 We routinely

11

checked blood gases every 12 hours to adjust ventilator settings in order to avoid fluctuations

12

in oxygen saturation and maintain PaO2 between 50–80 mmHg. 37–39 Optimal DHA dosage,

13

optimal ratios of omega-3 and omega-6 LCPUFAs, and the timing of supplementation need to

14

be evaluated in future studies.

15

In conclusion, our study demonstrated that parenteral nutrition with fish oil-containing lipid

16

emulsions may decrease the incidence of ROP and the need for bevacizumab treatment

17

compared with soybean-based lipid emulsions in VLBW preterm infants. Nevertheless,

18

well-designed, multicenter, randomized, controlled studies are needed in the future to

19

investigate the optimal DHA to ARA ratio to prevent ROP in extremely preterm infants.

19

1

Conflicts of Interest Statement

2

The authors have no conflicts of interest to declare.

3

Acknowledgements

4

The authors thank the staff at the Epidemiology and Biostatistics Center, Department of

5

Changhua Christian Hospital for statistical assistance. The authors are grateful to the infants

6

and their parents, as well as all the staff in NICU of the Changhua Christian Children's

7

Hospital for their assistance.

20

1

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1

Table 1 Demographic characteristics. Epoch 1

Epoch 2

p-Value

(n = 203)

(n = 193)

Gestational age, mean (SD), wk

28.8 (2.5)

28.9 (2.5)

0.69

Males, n (%)

99 (48.8)

98 (50.5)

0.73

1-min Apgar score, mean (SD)

6 (1.6)

6.2 (1.8)

0.34

5-min Apgar score, mean (SD)

7.8 (1.3)

8 (1.2)

0.22

Weight, mean (SD), grams

1114.5 (284.4)

1121.9 (295)

0.80

Length, mean (SD), cm

36.4 (3.5)

36.5 (3.8)

0.75

Head circumference, mean (SD), cm

25.8 (2.5)

26.2 (2.8)

0.11

Small for gestational age, n (%)

65(32.0)

69(35.7)

0.68

Multiple birth, n (%)

62(30.5)

64(33.2)

0.45

Antenatal steroids, n (%)

158 (77.8)

162 (83.5)

0.15

Cesarean section, n (%)

138(67.9)

145(75.1)

0.34

PIH, n (%)

40(19.7)

49(25.3)

0.12

GDM, n (%)

9(4.4)

11(5.6)

0.86

PROM (> 18 h), n (%)

90(44.3)

62(32.1)

0.25

At birth

2

SD: Standard deviation

27

1

GDM: gestational diabetes mellitus; PIH: pregnancy-induced hypertension; PROM: prolonged

2

ruptured of membrane

3

28

1

Table 2 Clinical findings and laboratory data in infants after receiving total parenteral

2

nutrition. Epoch 1

Epoch 2

Adjusted

(n = 203)

(n = 193)

P-value*

ROP stage 1–3, n (%)

49 (24.1)

22 (11.4)

<0.001

ROP treated with bevacizumab therapy, n (%)

26 (12.8)

10 (5.2)

0.001

Laser treatment after bevacizumab therapy, n (%)

6(3.0)

0(0)

0.16

NEC, n (%)

15 (7.4)

10 (5.2)

0.36

IVH, n (%)

45 (22.2)

28 (14.4)

0.01

BPD, n (%)

74 (36.5)

51 (26.4)

0.04

Sepsis, n (%)

51 (25.1)

42 (21.7)

0.58

TPN duration, mean (SD), days

27.6 (14.3)

19.7 (9.33)

< 0.001

O2 therapy, mean (SD), days

48.8 (32.7)

46.2 (32)

0.43

Mechanical ventilation, mean (SD), days

29.2(25.5)

21.8(20.3)

0.35

Peak PaO2, mean (SD), mmHg

124.9(68.5)

133.3(79.8)

0.57

Patent ductus arteriosus, n (%)

105(51.7)

100(51.8)

0.98

Surfactant use, n (%)

54(26.6)

51(26.4)

0.95

Frequency of PRBC transfusion, mean (SD), times

1.2(0.68)

1.1(0.75)

0.64

Accumulation doses of lipid, mean (SD), gm

38.6(30.8)

33.2(35.4)

0.36

29

Max Glucose, mean (SD), (mg/dL)

168.6(42.7)

163.8(62.7)

0.38

Total bilirubin, mean (SD), (mg/dL)

5.1 (3.7)

5.5 (3.1)

0.17

Direct bilirubin, mean (SD), (mg/dL)

0.9 (1.5)

0.6 (1.3)

0.04

ALT, mean (SD), (mg/dL)

20.8 (38.2)

17.1 (17.4)

0.21

ALP, mean (SD), (IU/L)

468.6 (232.9)

450.2 (199.5)

0.40

After TPN

1

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; BPD: Bronchopulmonary dysplasia;

2

IVH: Intraventricular hemorrhage; NEC: Necrotizing enterocolitis; ROP: Retinopathy of

3

prematurity; SD: Standard deviation; TPN: Total parenteral nutrition

4

*: Adjusted p-value for gestational age, gender, and 1-min Apgar score.

5 6

30

1

Table 3 Risk factors for retinopathy of prematurity in logistic regression models.

Risk factor

Univariate

p-Value Multivariate

p-Value

GA

0.566 (0.501-0.639)

< 0.001

0.588 (0.507-0.682)

< 0.001

ALT

1.030 (1.015-1.045)

< 0.001

1.020 (1.005-1.035)

0.010

Bil (T)

0.840 (0.780-0.904)

< 0.001

0.904 (0.819-0.996)

0.042

ALP

1.004 (1.003-1.005)

< 0.001

1.002 (1.000-1.003)

0.016

SMOFlipid

0.306 (0.195-0.480)

< 0.001

0.178 (0.095-0.330)

< 0.001

2

Data expressed as odds ratio (95% CI)

3

ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; Bil (T): Total bilirubin; GA:

4

Gestational age