Omega-3 long-chain polyunsaturated fatty acids for extremely preterm infants: a systematic review.

Omega-3 Long-Chain Polyunsaturated Fatty Acids for Extremely Preterm Infants: A Systematic Review Peiyin Zhang, Pascal M. Lavoie, Thierry Lacaze-Masmonteil, Marc Rhainds and Isabelle Marc Pediatrics 2014;134;120; originally published online June 9, 2014; DOI: 10.1542/peds.2014-0459

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/134/1/120.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Omega-3 Long-Chain Polyunsaturated Fatty Acids for Extremely Preterm Infants: A Systematic Review abstract BACKGROUND AND OBJECTIVE: Omega-3 long chain polyunsaturated fatty acid (LCPUFA) exposure can be associated with reduced neonatal morbidities. We systematically review the evidence for the benefits of omega-3 LCPUFAs for reducing neonatal morbidities in extremely preterm infants. METHODS: Data sources were PubMed, Embase, Center for Reviews and Dissemination, and the Cochrane Register of Controlled Trials. Original studies were selected that included infants born at ,29 weeks’ gestation, those published until May 2013, and those that evaluated the relationship between omega-3 LCPUFA supplementation and major adverse neonatal outcomes. Data were extracted on study design and outcome. Effect estimates were pooled. RESULTS: Of the 1876 studies identified, 18 randomized controlled trials (RCTs) and 6 observational studies met the defined criteria. No RCT specifically targeted a population of extremely preterm infants. Based on RCTs, omega-3 LCPUFA was not associated with a decreased risk of bronchopulmonary dysplasia in infants overall (pooled risk ratio [RR] 0.97, 95% confidence interval [CI] 0.82–1.13], 12 studies, n = 2809 infants); however, when considering RCTs that include only infants born at #32 weeks’ gestation, a trend toward a reduction in the risk of bronchopulmonary dysplasia (pooled RR 0.88, 95% CI 0.74–1.05, 7 studies, n = 1156 infants) and a reduction in the risk of necrotizing enterocolitis (pooled RR 0.50, 95% CI 0.23–1.10, 5 studies, n = 900 infants) was observed with LCPUFA. CONCLUSIONS: Large-scale interventional studies are required to determine the clinical benefits of omega-3 LCPUFA, specifically in extremely preterm infants, during the neonatal period. Pediatrics 2014;134:120–134

AUTHORS: Peiyin Zhang, MS-2,a Pascal M. Lavoie, MD, PhD,b Thierry Lacaze-Masmonteil, MD, PhD,c Marc Rhainds, MD, PhD,d and Isabelle Marc, MD, PhDa aDepartment of Pediatrics, Centre Mère-Enfant, and dHealth Technology Assessment Unit, CHU de Quebec, Laval University, Quebec, Canada; bDepartment of Pediatrics, Children’s and Women’s Health Centre, University of British Columbia, Vancouver, Canada; and cDepartment of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa University, Ottawa, Canada

KEY WORDS omega-3, fatty acids, systematic review, preterm, infants, neonatal ABBREVIATIONS ALA—a-linolenic acid BPD—bronchopulmonary dysplasia CI—confidence interval DHA—docosahexaenoic acid DINO—Docosahexaenoic acid for the Improvement in Neurodevelopmental Outcome GA—gestational age IVH—intraventricular hemorrhage LCPUFA—long-chain polyunsaturated fatty acid NEC—necrotizing enterocolitis PMA—postmenstrual age RCT—randomized controlled trial ROP—retinopathy of prematurity RR—risk ratio Dr Marc conceptualized and designed the protocol, screened the titles and abstracts, and retrieved articles for inclusion and quality, performed the analyses, drafted the initial manuscript, and approved the final manuscript as submitted; Ms Zhang critically reviewed the protocol, screened the titles and abstracts and retrieved articles for inclusion and quality, drafted the tables and figures, and reviewed the final manuscript as submitted; Dr Lavoie screened the articles for quality, revised the manuscript, participated in the redaction of the final manuscript, and reviewed the final manuscript as submitted; Dr Rhainds designed and conducted the systematic database search, reviewed the manuscript, and approved the final manuscript as submitted; and Dr Lacaze-Masmonteil reviewed the manuscript and approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2014-0459 doi:10.1542/peds.2014-0459 Accepted for publication Apr 22, 2014 Address correspondence to Isabelle Marc, MD, PhD, Département de Pédiatrie, Université Laval, Centre Mère Enfant du CHUQ, 2705 bd Laurier, Québec G1V 4G2, Canada. E-mail: isabelle. [email protected] (Continued on last page)

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Despitemajorimprovementsinperinatal and neonatal care over the past few decades, extremely preterm infants continue to face high morbidity and mortality. In North America, 1 of 8 of these infants do not survive and ∼15% of survivors suffer major long-term neurodevelopmental disabilities. In these vulnerable infants, the neonatal period is a critical time that can set the stage for lifelong morbidities, such as respiratory diseases and cognitive, motor, and behavioral impairments. During this time, preventive measures can have great and lasting impact.1–4 Bronchopulmonary dysplasia (BPD) is one of the most common and most serious complications occurring in extremely preterm infants.5 BPD occurs in ∼45% of infants born at ,29 weeks of gestation and clinically presents with persistent need for supplemental oxygen or respiratory support beyond the neonatal period.1 The disease is characterized by impaired pulmonary vascular and alveolar development. A dysregulation of inflammation has been proposed to play a central role in the etiology of lung injury characteristic of this disease. Inflammatory responses are well known to be modulated by longchain polyunsaturated fatty acids (LCPUFAs), including omega-3 fatty acids, such as docosahexaenoic acid (DHA). It also has been proven that extremely preterm infants are deficient in LCPUFAs, particularly in DHA.6,7 Therefore, it is possible that supplementing the diet of extremely preterm infants with DHA could reduce inflammation that predisposes to BPD and other major neonatal diseases.8–10 Establishing a causal link between exposure to omega-3 lipids and neonatal outcomes in high-risk preterm infants has important clinical implications in neonatal care. Recent studies have investigated associations between re-

duced nutritional omega-3 during the perinatal or neonatal period and adverse neonatal outcomes, with the hope that supplementation may improve those outcomes.11–13 However, whether supplementing in omega-3 improves neonatal health in extremely preterm infants is unknown. The objective of this study was to conduct a systematic review of observational studies and randomized controlled trials and, where possible, a meta-analysis, to examine whether omega-3 LCPUFA exposure or its supplementation (compared with no exposure or a placebo group) reduces the incidence of BPD and other major adverse neonatal outcomes in extremely preterm infants.

METHODS The protocol of this review has been registered in PROSPERO (#CRD42013004794 http://www.crd.york.ac.uk/NIHR_PROSPERO/) with the participation of a multidisciplinary team, including neonatologists, epidemiologists, and research methodologists. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement for reporting the review.14

Search Strategy and Study Selection: We searched PubMed, Embase up to May 2013, and specialized sites (eg, Center for Reviews and Dissemination, Cochrane Register of Controlled Trials) by using MeSH terms and text words, adapting the search strategy if needed for each database. The search strategy on PubMed was as follows: #1 “Infant, Premature”[Mesh] OR “Infant, Very Low Birth Weight”[Mesh] OR ((preterm OR premature) AND (infant* OR newborn* OR neonat*)) #2: “Fish Oils”[Mesh] OR “fish oil” OR n-3 OR “omega-3” OR omega-3 OR PUFA OR “polyunsaturated

fatty acid*” OR “marine oil” OR “algal oil” OR “Docosahexaenoic Acids”[Mesh] OR “docosahexaenoic acid*” OR DHA #3: inclusion of strategy #1 AND #2. In Embase, the strategy search used the terms #1: ’prematurity’/exp OR ’very low birth weight’/exp OR (preterm OR premature AND (infant* OR newborn* OR neonat*)) #2: ’fish oil’/exp OR ’polyunsaturated fatty acid’/exp OR ’omega-3 fatty acid’/ exp OR ’docosahexaenoic acid’/exp OR ’fish oil’ OR pufa OR ’polyunsaturated fatty acid’ OR ’n-39 OR ’omega-39 OR ’marine oil’ OR ’algal oil’ #3: #1 AND #2. We developed search strategies with terms related to the exposure/ intervention (omega-3) and the target population (preterm) and did not use any filter for randomized controlled trials (RCTs) or cohort studies to maximize the sensitivity of the search strategies. There was no language restriction. Finally, we looked at reference lists and citations of relevant articles (previous reviews and included studies) to identify any additional eligible studies. All citations were then combined and duplicates were excluded. Studies were excluded if they were conference abstracts, reviews, or case reports. The bibliographies of review articles were manually searched for potentially relevant citations that were not detected by the electronic search. Eligibility Criteria We considered all observational studies (case-control, cohort, cross-sectional) or randomized controlled trials assessing the effects of omega-3 LCPUFA on mortality or adverse neonatal outcomes in infant populations including exclusively or in part extremely preterm infants. Extremely preterm infants were defined as infants with a gestational age (GA) of ,29 weeks of gestation. For the purpose of this study, studies were included that reported any omega-3 LCPUFA exposure in the infant (eg,

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measured on blood concentration) or any omega-3 LCPUFA supplementation directly to the infant in the neonatal period or through the mother during pregnancy or lactation. The intervention or exposure was compared with other standard interventions, placebo, or any other control levels of omega-3 LCPUFA exposure. The primary outcome of interest in this study was BPD-free survival at 36 weeks postmenstrual age (PMA), with BPD defined as the need for oxygen and/or ventilation at 36 weeks PMA. Nevertheless, studies reporting BPD with any definition were considered in the review. Studies also were included even if they did not include data on our primary outcome as long as they included other relevant secondary neonatal outcomes listed in the next sentence. Secondary outcomes (as defined in the original publications) comprised death; duration of ventilation or oxygen support; length of hospitalization; or occurrence of intraventricular hemorrhage (IVH), periventricular leukomalacia, necrotizing enterocolitis (NEC), infections, retinopathy of prematurity (ROP), or hemodynamically significant patent ductus arteriosus. Mortality was defined as death from any cause. Because these specific outcomes of interest might not have been reported in the title or the abstract, we did not narrow our initial search to include them. Instead, we did filter out databases to include any of these outcomes when reviewing articles at the stage of thorough reading. Data Extraction Process Two reviewers (P.Z., I.M.) independently screened the titles for potential relevance. Only titles that were mutually agreed as being not relevant were excluded. The 2 reviewers then screened abstractsand,finally, full-text articles for inclusion/exclusion criteria. To reach consensus, reviewers resolved disagreement between themselves by fur122

ther discussion. Once the articles were selected for the purpose of full-text review, the 2 investigators independently reviewed the articles and extracted the following information by using a specific form: year and country of the study; study population; study design; type of the interventions or exposure (source of omega-3, dose, mode of administration, timing, association with another LCPUFA); comparison groups, such as a placebo or another nutrient or another dosage or mode of administration; number of exposed/unexposed or cases/controls; definitions and criteria used for BPD and each of the neonatal outcomes; and dichotomous variables or continuous data. The risk of bias was assessed by examining the sample selected, recruitment method, completeness of follow-up, andblinding according to the guidelines for assessing non-RCTs proposed by the Ohio Department of Mental Health and adapted in French by us (available at www.chuq.qc.ca/fr/ evaluation/uetmis). RCTs were assessed by the checklist proposed by COMPUS Adapted SIGN 50 (www.sign.ac.uk/ methodology/checklists.html), To indicate the summary judgment of quality of each study, we used the summary ratings of unsatisfactory, satisfactory, or very satisfactory. Definitions of Neonatal Outcomes Neonatal outcomes were defined by the presence or absence of the diagnosis based on standard criteria or the criteria as reported in the studies. When .1 category was available for a given neonatal outcome (eg, none, mild, moderate, severe) and when these categories were mutually exclusive, we combined numbers to provide an effect estimate for “any definition” of the neonatal outcome. Otherwise, we extracted data matching with the more severe category of the outcome. If there were .2 comparison groups (eg, different sources of LCPUFA versus a placebo), we combined

the data of the experimental groups if they involved similar intervention; furthermore, these data were compared with the data of the reference group (eg, placebo). Finally, in cases in which outcome data were available for subgroups of preterm infants as part of the larger studied group, only the data from the subgroup that was the closest to our population of interest (ie, preterm infants of ,29 weeks’ gestation) were included in the combined analyses for this outcome. For example, results for the outcome BPD in the subgroup of infants with a birth weight ,1250 g available from Manley et al 201111 were included in the meta-analysis instead of the results for the preterm infants of ,33 weeks as reported in Makrides et al 2009.15 Synthesis of Results We classified studies according to their design and also by neonatal outcomes. For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CIs). Continuous data were not pooled, because they were measured only in a minority of studies. We used fixed-effect metaanalysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect (ie, where the trials’ population interventions and methods were judged sufficiently similar). If there was a clinical heterogeneity or if we detected substantial statistical heterogeneity, we used random-effects meta-analysis to produce an overall summary. Heterogeneity of the effect estimates was assessed by calculating the I2 statistic,12 and significant heterogeneity was defined per protocol as I2 $50%. Prespecified subgroup analyses were performed where possible for the infant GA (studies including preterm infants of ,37 weeks versus studies targeting preterm infants of #32 weeks of gestation), the DHA dose,

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timing and duration of exposure, the definition or severity of the outcomes, the mode of administration, and for the comparison between omega-3 provided alone or in association with another LCPUFA (ie, omega-6 LCPUFA).

RESULTS Overview of Included Studies Using our search strategy, we identified and screened 1876 citations. Fig 1 describes the process of selection for the final 24 studies included in the qualitative analysis. Characteristics of the 24 studies are summarized in Table 1. Eighteen of these studies were RCTs.11–13,15–29 Among nonrandomized studies, 4 were interventional studies with a control group30–33 and the remaining 2 studies8,34 did not test an intervention because they examined the association of BPD with LCPUFA concentrations in blood or in tracheal aspirates. Fifteen RCTs presented dichotomous outcomes. Finally, 13 studies (7 RCTs) assessed outcomes in a population of preterm infants of #32 weeks of gestation. No RCT or study subanalyses were performed exclusively in extremely preterm infants (,29 weeks of gestation). Characteristics of Exposure and Outcomes In randomized and nonrandomized interventional studies, there was heterogeneity between studies regarding the sources of omega-3 (fish, alga, egg), their mode of administration (intravenous or enteral), the vehicle used for supplementation (formula or breast milk), the timing of exposure (started within 10 days after birth or later, but usually provided at least up to 36 weeks of PMA), the DHA percentage in formula or breast milk (usually ,0.40% of total fatty acids [with high dose defined as DHA concentration of ∼1% of total fatty acids in the experimental group prod-

FIGURE 1 Flowchart of studies through the review process.

uct]), or the cointerventions (exposure to omega-3 LCPUFA alone, generally DHA, or in association with other nutrients, usually in combination with arachidonic acid) (Table 1). Except for 1 study,30 the DHA intakes (dosage in mg/kg/d) based on the daily amount of feeds in the first weeks of life and the percentage of DHA in formula or breast milk were not reported. No RCTs reported survival free of BPD as an outcome. None of the studies reported BPD as a primary outcome. Most of the studies (n = 15, including 12 RCTs) defined BPD according to an oxygen requirement up to 28 days of postnatal age, or at 36 weeks PMA, but none of these studies used a physiologic definition35 (Table 2). Of all the observational studies or RCTs reporting neonatal outcomes as dichotomous variables, the association between omega-3 LCPUFA and any definition of BPD was examined in 18 studies (combined in 12 RCTs), with 1 RCT23 reporting

a composite outcome including BPD. Similarly, NEC was reported in 14 studies (combined in 11 RCTs), IVH in 12 studies (combined in 7 RCTs), infections in 15 studies (combined in 10 RCTs), ROP in 10 studies (combined in 6 RCTs), and death in 8 studies (combined in 6 RCTs). Several studies examined .1 neonatal outcome at a time (Table 1). Only a few studies reported other relevant neonatal outcomes, such as number of days of ventilation, or the use or duration of supplementation oxygen,13,20,22,27,28 patent ductus arteriosus,12,20,23,30–32 cholestasis,31,32 or number of days of hospital admission.8,11,13,18,31,32 Effect Estimates for Dichotomous Neonatal Outcomes For each neonatal outcome of interest, combined effect estimates were calculated where possible and are outlined in Figs 2, 3, 4, and 5. Heterogeneity of effect estimates was reported.



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195 preterms

Clandinin 2005, Canada19

195 preterms GA , 37 wk BW ,1750 g

238 preterms GA ,35 wk BW #2000 g

43 preterms GA ,37 wk BW ,1800 g

60 preterms GA ,33 wk BW 750–1800 g

Fewtrell 2002, United Kingdom20

Fewtrell 2004, United Kingdom21

Foreman-van Drongelen 1996, Netherlands22

Groh-Wargo 2005, United States23

GA , 35 wk

120 preterms GA #32 wk BW 725–1375 g

GA,30 wk

94 preterms


Participants

Carlson 1998, United States18

Carlson 1996, United States17

RCTs Carlson 1992, United States16

Studies

Standard formula (no LCPUFA)








Control Group

Formula enriched with marine oil DHA 0.20% EPA 0.30% ARA Not reported Formula enriched with marine oil DHA 0.20% EPA 0.06% ARA Not reported Formula enriched with egg phospholipids DHA 0.13% EPA 0.00% ARA 0.41% Formula enriched with either fish and fungal oil DHA 0.33% EPA 0.1% ARA 0.67% or Algal oil DHA 0.33% EPA 0.00% ARA 0.67% Formula enriched with egg phospholipids DHA 0.17% EPA 0.04% ARA 0.31% Formula enriched with borage and fish oil: DHA 0.50% EPA 0.10% ARA 0.04% Formula enriched with algal and fungal oils DHA 0.30% EPA 0.00% ARA 0.61% Formula enriched with either fish and fungal oil DHA 0.27%

Treatment Group

—

$day 14 of enteral intake (mean ∼day30) to hospital discharge

√

√

—

—

1st days of life (mean ∼day 14) to 9 mo after term

,day 10 to 3 mo

Within 72 h of first enteral feeding, by day 28 to 1 y CA

√

√

√

√

√

√

√

BPD

√ Day 10 to discharge neonatal unit

√

—

#day 5 to discharge

∼day 5 to discharge

—

Death

√

—

√

√

√

√

—

—

NEC

—

√

√

√

√

—

—

—

IVH

—

—

—

√

√

√

—

—

ROP

—

√

√

√

√

√

—

—

Infections

Dichotomous Outcomes (Any Definition) or Equivalent Continuous Outcomes

From enteral feeding .110 kcal/k g/j (day 9 to day 40) to discharge

Timing

TABLE 1 Characteristics of the Studies Including Extremely Premature Infants and Reporting the Effects of Omega 3 LCPUFA (Alone or in Association With ARA) on Adverse Neonatal Outcomes

852 pregnant women with a history of previous preterm birth

141 preterms GA,31 wk BW ,1500 g

194 preterms ,32 wk BW 845–1560 g

27 preterms GA ,37 wk BW #1850 g

2399 pregnant women ,21 wk of gestation

657 preterms GA ,33 wk Subgroup of 294 preterms ,1200 g

Henriksen 2008, Norway13

Innis 2002, Canada24

Koletzko 1995, Germany25

Makrides 2010, Australia15

Manley 2011 substudy of Makrides 2009, Australia11

Participants

Harper 2010, United States12

Studies

TABLE 1 Continued

DHA 0.26% 6 0.09 EPA 0.08% 6 0.02 ARA 0.45% 6 0.09 following mother daily supplementation with six 500-mg soy oil capsules

Breast milk

Daily supplementation with vegetable oil

Formula without LCPUFA

Daily infant supplementation with 0.5 mL control oil (no DHA, no ARA) /100 mL human milk (mother or donor) Standard formula (no LCPUFA)

Placebo mineral oil (no LCPUFA)

Control Group

DHA 1.07% 6 0.46% EPA 0.16% 6 0.06% ARA 0.43% 6 0.11% following mother daily supplementation with six 500-mg DHA-rich tuna oil (43%) capsules

EPA 0.10% ARA 0.43% or fish oil and egg triglycerides DHA 0.24% EPA 0.00% ARA 0.41% Mother daily omega-3 fish oil supplementation (1200 mg EPA and 800 mg DHA) Daily infant supplementation with 0.5 mL study oil (DHA 32 mg, ARA 31 mg) /100 mL of human milk (mother or donor) Formula enriched with either alga oil (DHA alone) DHA 0.34% EPA not reported ARA 0.00% or alga oil (DHA+ARA) DHA 0.34% EPA not reported ARA 0.60% Formula enriched with egg-TG and evening primrose oil DHA 0.30% EPA 0.03% ARA 0.50% Daily supplementation with omega-3 fish oil (100 mg EPA and 800 mg DHA) Breast milk

Treatment Group

Within 5 d of any enteral feeding to expected date of delivery

From full enteral feeding ($130 mL milk/kg/d) for at least 21 d During pregnancy from 21 wk of gestation until birth

From enteral feeding 50 kcal/kg/d for at least 28 d

During pregnancy within 16–22 wk to 36 wk of gestation or delivery From enteral feeding .100 mL /kg/d to ∼day 63 post delivery

Timing

—

√

√

√

—

—

—

√

√

—

√

BPD

—

Death

√

—

√

√

√

√

NEC

√

—

—

—

√

√

IVH

√

—

—

—

√

√

ROP

√

—

—

√

—

√

Infections


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60 preterms GA #34 wk BW 1000–2500 g

288 preterms

Tomsits 2010, Hungary28

Vanderhoof 1999, United States29

Pawlik 2011, Poland31

Martin 2011, United States8

88 preterms GA ,30 wk 337 preterms GA ,32 wk

Observational studies and interventional clinical trials Marc 2011, Canada30 36 preterms GA #29 wk

BW 750–2000 g


BW ,1800 g

470 preterms GA ,30 wk

Participants

Skouroliakou 2010, Greece27

O’Connor 2001, United States26

Studies

TABLE 1 Continued

Intravenous lipid emulsion containing soybean and olive oil emulsion (20% Clinoleic)

None

Breast milk DHA 0.10% 6 0.20% EPA 0.00% 6 0.10% ARA 0.30% 6 0.30%


Intravenous lipid emulsion containing conventional soybean lipid (Intralipid 20%)

Intravenous lipid emulsion containing conventional soybean lipid (Intralipid)


Control Group

Intravenous lipid emulsion containing 50% of soybean and olive oil emulsion (20% Clinoleic)

Breast milk DHA 1.20% 6 0.60% EPA 0.00% 6 0.10% AA 0.40% 6 0.20% Following supplementation of mother with DHA-rich algal oil (DHA 1.2 g/d) Fatty acids profiles

Formula enriched with either fish and fungal oil DHA 0.26% EPA 0.08% ARA 0.42% or egg-TG and fish oil DHA 0.24% EPA 0.00% ARA 0.41% Intravenous lipid emulsion SMOFlipid, containing lipids from soya bean oil (30%), olive oil (25%) and fish oil (15%) and medium-chain TG (30%) Intravenous lipid emulsion SMOFlipid, containing lipids from soya bean oil (30%), olive oil (25%) and fish oil (15%) and medium-chain TG (30%) Formula enriched with fish oil DHA 0.35% EPA not reported ARA 0.50%

Treatment Group

First day of birth to 1 mo postnatal Day 1 after birth to relay with enteral nutrition

From day 3–7 post birth to 36 wk PMA

Approximately up to 3–4 wk before full enteral feeding until 48 wk postconceptional age

From day 3–7 postbirth to day 14

From day 1–2 postbirth to at least day 14

Within 72 h of the first enteral feeding to term

Timing

√ √

— —

√

—

√

√

—

√

√

√

—

—

BPD

Death

—

√

√

√

—

—

√

NEC

√

√

√

—

—

—

—

IVH

√

√

—

—

—

—

—

ROP

√

√

√

√

√

—

√

Infections


— √ √ √

√

√

—

√

—

Although most of the nonrandomized interventional studies were in favor of the intervention, they were not pooled because of the clinical and statistical heterogeneity between the studies with regard to design, DHA exposure, and methodology (Table 1).

None

Parenteral lipid emulsions of soybean- lipid (Intralipid)

25 preterms GA ,32 wk

282 preterms GA 23–36 wk BW ,2500 g Subgroups: 129 very low BW BW ,1500 g 153 low BW BW 1500–2500 g

Rudiger 2000, Germany34

Skouroliakou 2012, Greece33

√ reported outcomes; ARA, arachidonic acid; BW, birth weight; CA, corrected age; EPA, eicosapentaenoic acid; PUFA, polyunsaturated fatty acid; TG, Triglycerids.

Intravenous lipid emulsion soybean and olive oil emulsion (Clinoleic 20%) 84 preterms GA ,32 wk BW ,1250 g

Parenteral lipid emulsions of medium-chain TG and omega-3–PUFA (SMOFlipid,)

Day 1 after birth and in the following 4 d First or second day after birth for at least 7 d

—

—

—

√ √ √ Day 1 after birth to relay with enteral nutrition

—

—

√

Infections ROP IVH Death

BPD

NEC

and 50% of fish-oil emulsion (10% Omegaven) Intravenous lipid with emulsion 50% fish oil emulsion (Omegaven 10%) 50% soybean and olive oil emulsion (Clinoleic 20%) Tracheal and pharyngeal amount of PUFA Pawlik 2011, Poland32

Studies

TABLE 1 Continued

Participants

Control Group

Treatment Group

Timing


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Among RCTs reporting the association between omega-3 LCPUFA and BPD (n = 12), the between-study variance accounted for 1% of the total variance (Fig 2A). The overall effect of omega-3 total fatty acids was not significant (pooled RR 0.97, 95% CI 0.82–1.13). None of the 12 RCTs reported an increased risk of BPD in the experimental group. Four-point estimates yielded RRs ,1, 3 of which had CIs that extended above 1. As part of a large study including preterm infants of ,33 weeks’ gestation,15 a subgroup analysis in the low birth weight preterm infants (birth weight ,1200 g, n = 294) found that a high dose of DHA was protective for the development of BPD (adjusted RR 0.75, 95% CI 0.57–0.98).11 In this study, DHA was delivered early after birth to the preterm infants through breast milk from their mothers, who had been supplemented with DHA during their lactation period. According to these data, a nearly significant lower risk for BPD was found in subgroup analyses of RCTs targeting only the preterm infants born at #32 weeks of gestation (n = 7 RCTs; Fig 2A) or reporting an intervention delivering omega-3 LCPUFA alone (n = 5 RCTs; Fig 2B). In RCTs assessing the effect of LCPUFA on death during the neonatal period (RR 0.76, 95% CI 0.42–1.38), the betweenstudy variance for effect estimates was 44% of the total variance (Fig 3). With the exception of 2 studies with RRs .1, all other studies had RRs of ,1 but with several studies reporting large 95% CI. The RR of NEC (Fig 4A), after combining the 5 RCTs reporting the effects of omega-3 LCPUFA in preterm infants



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TABLE 2 The Reporting of BPD Studies Carlson 199216 Carlson 199617 Carlson 199818 Clandinin 200519 Fewtrell 200220 Fewtrell 200421 Foreman-Van Drongelen 199622 Groh-Wargo 200523 Harper 201012 Henriksen 200813 Manley 201111 O’Connor26 2001 Skouroliakou 201027 Tomsits 201028 Vanderhoof 199929 Marc I 201130 Martin 20118 Pawlik 201131 Pawlik 201132 Rudiger 200034 Skouroliakou 201233

Quality Analysis Definition

No definition for BPD Supplemented oxygen for .28 d and/or pulmonary changes on radiologic examination Supplemental oxygen on day 28 of age with radiographic changes Supplemental oxygen at 36 wk PMA with severe or chronic radiologic changes on chest x-ray Oxygen requirement .30% for .28 d Respiratory assistance (ventilation, CPAP, or supplemental oxygen) at 36 wk No definition for BPD Composite outcomes (Need for supplemental oxygen beyond 1 mo postnatal or 36 wk corrected age (CA) OR patent ductus arteriosus OR IVH) Requirement for supplemental oxygen at 36 wk CA for neonates born before 34 wk Need for respiratory support (no mention of timing); days with oxygen Oxygen required at 36 wk PMA Supplemental oxygen beyond 1-mo postnatal age or at 36 wk PMA Days of ventilation (no dichotomous variable was reported) Days of supplemental oxygen (no dichotomous variable was reported) No definition for BPD Supplemental oxygen required at 36 wk PMA Supplemental oxygen required at 36 wk PMA Oxygen requirement and/ or respiratory support at 36 wk CA Oxygen requirement and/or respiratory support at 36 wk CA Need for mechanical ventilation or oxygen therapy at day 28 of age with radiologic signs of BPD Need for supplementary oxygen at day 28 of age and classified as mild, moderate, and severe according to the need for supplemental oxygen at 36 wk PMA or at 56 d postnatally

CA, corrected age; CPAP, continuous positive airway pressure.

born at #32 weeks of gestation, was in favor of the intervention, although this relative risk was not statistically significant (RR 0.50, 95% CI 0.23–1.10; I2 = 0%). Nevertheless, the effect of administering omega-3 to these preterm infants was significantly different and more beneficial where the intervention focused on this population rather than on the older neonate population. There was no clear trend in risk of ROP (n = 6 RCTs, RR 1.10, 95% CI 0.91–1.33; I2 = 0%), infections (n = 10 RCTs, RR 1.10, 95% CI 0.91–1.33; I2 = 0%), and IVH of any grade (n = 7 RCTs, RR 0.96, 95% CI 0.76–1.21; I2 = 0%) between the preterm infants receiving a placebo or omega-3 LCPUFA-supplemented nutrition overall, or among subgroups according to GA analyses (Fig 4A and Fig 5). When taking into consideration the severity of IVH (grade 3–4; n = 5 studies; RR 1.37, 95% CI 0.67–2.81; I2 = 128

Heterogeneity in study quality, design, and reporting made quality evaluation difficult, especially for some RCTs. The inclusion/exclusion criteria often excluded more at-risk populations. Randomization process was poorly reported in 5 RCTs. Depending on the report of randomization, percentage of follow-up loss for the main outcome, and blinding, the study quality was judged as unsatisfactory, satisfactory, or very satisfactory for 5, 7, and 6, respectively, of the 18 RCTs. Definition of the various neonatal outcomes and timing of measures according to the beginning of the intervention varied substantially across studies. Analyses were often not reported to be performed in intentionto-treat. The number of dropouts and the reasons for subjects lost to followup were not clearly reported. The 6 observational studies were classified as satisfactory.

DISCUSSION 0%) or the severity of the ROP (grade 3–4 or need for treatment; n = 3 studies; RR 0.86, 95% CI 0.47–1.58; I2 = 0%), results did not change significantly. Reporting of Continuous and Other Dichotomous Outcomes Five studies individually reported no differences in the numbers of days of hospital admission (Table 1). A few studies reported either continuous or dichotomous outcomes relating to the neonatal outcomes of interest. The data available were for (1) BPD severity (1 observational study), (2) days of ventilation or with oxygen, (3) occurrence of periventricular leukomalacia (3 studies), and (4) type of infections (systemic, confirmed). The study results did not reach statistical significance. Pooling was not performed because of the small numbers of studies for these outcomes.

The main finding of this study is the potential protective effect of omega-3 LCPUFA supplementation on BPD and NEC when examining RCTs exclusively targeting preterm infants born at #32 weeks of gestation. This finding is of major clinical relevance mainly because infants born at the extreme lower end of prematurity are at particularly high risk for a nutritional deficit in omega-3 lipids, potentially predisposing to adverse neonatal outcomes. These results also are in accordance with observational studies, indicating an association between DHA levels and adverse neonatal outcomes in very preterm infants.8,30,33 Preterm infants are nutritionally deficient in DHA. Daily nutritional DHA requirements of extremely preterm infants are estimated at the range of 40 to 60 mg/kg.36 An essential nutrient, the a-linolenic acid (ALA) is the major n-3 fatty acid. In the body, ALA is metabolized

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FIGURE 2

Meta-analysis comparing the effects of LCPUFA supplementation on BPD. A, According to all RCTs and a subgroup of RCTs including preterm infants of #32 weeks of gestation. B, According to a subgroup of RCTs evaluating an intervention that exclusively supplement in omega-3 LCPUFA.

to either eicosapentaenoic acid or DHA. As an important constituent of cell membranes, DHA is highly concentrated in several tissues, including the brain

(23% of total body stores in a term infant), muscles, and stored adipose tissue.37 In extremely preterm infants, DHA stores represent ,10% of the total body

stores in lipids when compared with a full-term neonate.38,39 Preterm infants can synthesize small amounts of DHA from the omega-3 dietary precursor



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FIGURE 3 Meta-analysis comparing the effects of LCPUFA supplementation on death.

ALA, via the desaturation-elongation pathway.40 However, because of limited fat stores, considerable oxidation, and increased requirements to support rapidly growing tissues, availability of DHA is insufficient during the neonatal period.38,41–44 In extreme preterm infants, high systemic inflammatory biomarkers are measured in the earliest hours after birth and for extended periods of time during the neonatal period, particularly in infants exposed to mechanical ventilation and supplemental O2.45–49 Preterm infants also have a limited ability to counteract inflammatory and oxidative stress during the neonatal period.50 Sustained oxidative stress and inflammation are key factors contributing to the development of BPD as well as other neonatal complications. Dietary LCPUFA, particularly DHA and eicosapentaenoic acid are important modulators of inflammation. Considering the anti-inflammatory effect of DHA, and of its downstream metabolite eicosanoids,51,52 authors have argued that DHA deficits in preterm infants may have considerable, underestimated adverse effects during the neonatal period.9,10,53,54 In light of the strong association between elevated inflammation and both shortand long-term morbidities in extreme preterm infants,48,55 we postulate that a DHA supplementation or a decrease in the omega-6/omega-3 reduces the occurrence of these major adverse 130

neonatal outcomes, including BPD. Of note, when specifically examining studies in which omega-6 lipids were coadministered with DHA, we detected no additional benefit on BPD compared with studies using DHA alone (Fig 2B), indicating a selective role of DHA or the ratio omega-6/omega-3. Biological Plausibility Interventions that modulate DHA levels have been shown to reduce pulmonary inflammation in animal models, although data are lacking in humans. Indeed, intravenous omega-3 lipids improve the redox potential of glutathione and reduce lung inflammation in the neonatal guinea pig model.52 Maternal DHA supplementation reduces inflammation in the neonatal mouse hyperoxia model of BPD.56 In extremely preterm infants, reduced serum DHA during the first postnatal month was associated with increased need for supplemental oxygen at 36 weeks PMA (odds ratio 2.5, 95% CI 1.3–5.0).8 The ratio of n6-linoleic acid to n3-DHA in these infants was highly predictive of lung disease, confirming the importance of balanced ratios of LCPUFA and potential selective role of DHA in protecting against BPD.8 A balanced LCPUFA ratio was also protective against late-onset infections, providing an additional protective mechanism against adverse neonatal outcomes.8

Altogether, our data strongly suggest that low DHA contributes to a dysregulation of inflammation, predisposing to major neonatal morbidities, and that restoring an adequate ratio in LCPUFA may prevent the adverse effects of an excessive inflammatory and oxidative stress exposure repeatedly associated with lung injury in extreme preterm infants. This nutritional approach has gained interest recently, since publication of the Docosahexaenoic acid for the Improvement in Neurodevelopmental Outcome (DINO) trial15 and of a secondary analysis in low birth weight infants suggesting an effect of omega-3 LCPUFA to reduce the need for oxygen at 36 weeks PMA in this population.11 The DINO trial substantially influences but does not dominate the meta-analytic findings. Therefore, since the last review in 2008,57 this review is valuable for placing the DINO trial results in a broader context, and to highlight the need for a definitive trial testing the impact of LCPUFA on neonatal morbidities. Limitations Although it is the aim of this review to estimate treatment effects with more precision, the major limitation with our systematic review and meta-analysis of RCTs is the low occurrence of reported events on the outcomes of interest. This is mainly due to the large GA range of preterm infants included in the studies, and especially to the inclusion of a large

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FIGURE 4 Meta-analysis comparing the effects of LCPUFA supplementation on (A) NEC and (B) ROPaccording to all RCTs and a subgroup of RCTs including preterm infants of #32 weeks of gestation.

proportion of older preterm infants who are relatively lower risk of neonatal complications. Furthermore, in none of the studies were neonatal outcomes stated as the primary outcomes, with

older studies mainly reporting neonatal complications as safety outcomes only. Finally, the studies varied widely in terms of methodology quality, sample size, DHA doses, source and adminis-

tration protocol, and in the populations studied. Because the daily amount of feeds administered to infants was not reported in most studies, it is impossible to extrapolate a dose-effect



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FIGURE 5 Meta-analysis comparing the effects of LCPUFA supplementation on (A) neonatal infection according to all RCTs and a subgroup of RCTs including preterm infants of #32 weeks of gestation, and (B) IVH.

of DHA (eg, in mg/kg body weight) required to achieve a therapeutic benefit.

IMPLICATIONS AND CONCLUSIONS According to results of preclinical experimental animal studies, as well as observational studies in humans, DHA supplementation is safe and likely to be beneficial in extremely preterm infants. This systematic review highlights potential benefits of DHA in the prevention of BPD or NEC when specifically targeting the youn132

ger, most immature preterm infants immature preterm infants. No detrimental effect was reported with omega-3 LCPUFA in this age group. In current clinical practice, enteral supplementation remains the best strategy for optimizing fat absorption and bioavailability in extremely preterm infants. Future studies focused on an early supplementation of DHA are required to establish more definitively the clinical benefits relative to therapeutic effects of different methods of supplementation of DHA for extremely premature infants, with

the prospect of reducing neonatal mortality and morbidities in this age group. Overall, our results support the need for definitive RCTs to examine the effectiveness of omega-3 LCPUFA versus placebo in reducing the occurrence of BPD and of other adverse neonatal complications in extremely preterm infants. Of note, a large RCT is ongoing testing the effect of a direct oral supplementation of extremely preterm infants with fish oil (N3RO: N-3 LCPUFA for improvement in Respiratory Outcomes; www.anzctr.org.au/#ACTRN, trial #12612000503820).

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REFERENCES 1. Jobe AH. The new bronchopulmonary dysplasia. Curr Opin Pediatr. 2011;23(2):167– 172 2. Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet. 2006; 367(9520):1421–1431 3. Anderson PJ, Doyle LW. Neurodevelopmental outcome of bronchopulmonary dysplasia. Semin Perinatol. 2006;30(4):227–232 4. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely lowbirth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003;289(9):1124–1129 5. Short EJ, Klein NK, Lewis BA, et al. Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics. 2003;112(5). Available at: www.pediatrics. org/cgi/content/full/112/5/e359 6. Carlson SE, Rhodes PG, Ferguson MG. Docosahexaenoic acid status of preterm infants at birth and following feeding with human milk or formula. Am J Clin Nutr. 1986;44(6):798–804 7. Koletzko B, Sauerwald U, Keicher U, et al. Fatty acid profiles, antioxidant status, and growth of preterm infants fed diets without or with long-chain polyunsaturated fatty acids. A randomized clinical trial. Eur J Nutr. 2003;42(5):243–253 8. Martin CR, Dasilva DA, Cluette-Brown JE, et al. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr. 2011;159: 743–749.e1–2 9. Valentine CJ. Maternal dietary DHA supplementation to improve inflammatory outcomes in the preterm infant. Adv Nutr. 2012;3(3):370–376 10. Clandinin MT, Larsen BM. Docosahexaenoic acid is essential to development of critical functions in infants. J Pediatr. 2010;157(6): 875–876 11. Manley BJ, Makrides M, Collins CT, et al; DINO Steering Committee. High-dose docosahexaenoic acid supplementation of preterm infants: respiratory and allergy outcomes. Pediatrics. 2011;128(1). Available at: www. pediatrics.org/cgi/content/full/128/1/e71 12. Harper M, Thom E, Klebanoff MA, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Omega-3 fatty acid supplementation to prevent recurrent preterm birth: a randomized controlled trial. Obstet Gynecol. 2010;115(2 pt 1):234–242 Henriksen C, Haugholt K, Lindgren M, et al. Improved cognitive development among preterm infants attributable to early supplementation of human milk with docosahexaenoic acid and arachidonic acid. Pediatrics. 2008;121(6):1137–1145 Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65–W94 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):175–182 Carlson SE, Cooke RJ, Werkman SH, Tolley EA. First year growth of preterm infants fed standard compared to marine oil n-3 supplemented formula. Lipids. 1992;27(11): 901–907 Carlson SE, Werkman SH, Tolley EA. Effect of long-chain n-3 fatty acid supplementation on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia. Am J Clin Nutr. 1996;63(5): 687–697 Carlson SE, Montalto MB, Ponder DL, Werkman SH, Korones SB. Lower incidence of necrotizing enterocolitis in infants fed a preterm formula with egg phospholipids. Pediatr Res. 1998;44(4):491–498 Clandinin MT, Van Aerde JE, Merkel KL, et al. Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid. J Pediatr. 2005;146(4):461–468 Fewtrell MS, Morley R, Abbott RA, et al. Double-blind, randomized trial of longchain polyunsaturated fatty acid supplementation in formula fed to preterm infants. Pediatrics. 2002;110(1 pt 1):73–82 Fewtrell MS, Abbott RA, Kennedy K, et al. Randomized, double-blind trial of longchain polyunsaturated fatty acid supplementation with fish oil and borage oil in preterm infants. J Pediatr. 2004;144(4):471– 479 Foreman-van Drongelen MM, van Houwelingen AC, Kester AD, Blanco CE, Hasaart TH, Hornstra G. Influence of feeding artificial-formula milks containing docosahexaenoic and arachidonic acids on the postnatal longchain polyunsaturated fatty acid status of

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

healthy preterm infants. Br J Nutr. 1996;76 (5):649–667 Groh-Wargo S, Jacobs J, Auestad N, O’Connor DL, Moore JJ, Lerner E. Body composition in preterm infants who are fed long-chain polyunsaturated fatty acids: a prospective, randomized, controlled trial. Pediatr Res. 2005;57(5 pt 1):712–718 Innis SM, Adamkin DH, Hall RT, et al. Docosahexaenoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula. J Pediatr. 2002; 140(5):547–554 Koletzko B, Edenhofer S, Lipowsky G, Reinhardt D. Effects of a low birthweight infant formula containing human milk levels of docosahexaenoic and arachidonic acids. J Pediatr Gastroenterol Nutr. 1995;21 (2):200–208 O’Connor DL, Hall R, Adamkin D, et al; Ross Preterm Lipid Study. Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial. Pediatrics. 2001; 108(2):359–371 Skouroliakou M, Konstantinou D, Koutri K, et al. A double-blind, randomized clinical trial of the effect of omega-3 fatty acids on the oxidative stress of preterm neonates fed through parenteral nutrition. Eur J Clin Nutr. 2010;64(9):940–947 Tomsits E, Pataki M, Tölgyesi A, Fekete G, Rischak K, Szollár L. Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil: a randomised, doubleblind clinical trial in premature infants requiring parenteral nutrition. J Pediatr Gastroenterol Nutr. 2010;51(4):514–521 Vanderhoof J, Gross S, Hegyi T, et al. Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age. J Pediatr Gastroenterol Nutr. 1999;29 (3):318–326 Marc I, Plourde M, Lucas M, et al. Early docosahexaenoic acid supplementation of mothers during lactation leads to high plasma concentrations in very preterm infants. J Nutr. 2011;141(2):231–236 Pawlik D, Lauterbach R, Hurka1a J. The efficacy of fish-oil based fat emulsion administered from the first day of life in very low birth weight newborns. Med Wieku Rozwoj. 2011;15(3):306–311 Pawlik D, Lauterbach R, Turyk E. Fish-oil fat emulsion supplementation may reduce the



133

33.

34.

35.

36.

37.

38.

39.

40.

risk of severe retinopathy in VLBW infants. Pediatrics. 2011;127(2):223–228 Skouroliakou M, Konstantinou D, Agakidis C, et al. Cholestasis, bronchopulmonary dysplasia, and lipid profile in preterm infants receiving MCT/v-3-PUFA-containing or soybean-based lipid emulsions. Nutr Clin Pract. 2012;27(6):817–824 Rüdiger M, von Baehr A, Haupt R, Wauer RR, Rüstow B. Preterm infants with high polyunsaturated fatty acid and plasmalogen content in tracheal aspirates develop bronchopulmonary dysplasia less often. Crit Care Med. 2000;28(5):1572–1577 Finer NN, Carlo WA, Walsh MC, et al; SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010;362(21): 1970–1979 Lapillonne A, Jensen CL. Reevaluation of the DHA requirement for the premature infant. Prostaglandins Leukot Essent Fatty Acids. 2009;81(2-3):143–150 Kuipers RS, Luxwolda MF, Offringa PJ, Boersma ER, Dijck-Brouwer DA, Muskiet FA. Fetal intrauterine whole body linoleic, arachidonic and docosahexaenoic acid contents and accretion rates. Prostaglandins Leukot Essent Fatty Acids. 2012;86 (1-2):13–20 Cunnane SC, Francescutti V, Brenna JT, Crawford MA. Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate. Lipids. 2000;35(1):105–111 Foreman-van Drongelen MM, van Houwelingen AC, Kester AD, Hasaart TH, Blanco CE, Hornstra G. Long-chain polyunsaturated fatty acids in preterm infants: status at birth and its influence on postnatal levels. J Pediatr. 1995; 126(4):611–618 Carnielli VP, Wattimena DJ, Luijendijk IH, Boerlage A, Degenhart HJ, Sauer PJ. The very low birth weight premature infant is capable of synthesizing arachidonic and

41.

42.

43.

44.

45.

46.

47.

48.

docosahexaenoic acids from linoleic and linolenic acids. Pediatr Res. 1996;40(1):169– 174 Carnielli VP, Simonato M, Verlato G, et al. Synthesis of long-chain polyunsaturated fatty acids in preterm newborns fed formula with long-chain polyunsaturated fatty acids. Am J Clin Nutr. 2007;86(5):1323– 1330 Cunnane SC, Crawford MA. Survival of the fattest: fat babies were the key to evolution of the large human brain. Comp Biochem Physiol A Mol Integr Physiol. 2003;136(1): 17–26 Plourde M, Cunnane SC. Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements. Appl Physiol Nutr Metab. 2007;32(4):619–634 Sarkadi-Nagy E, Wijendran V, Diau GY, et al. The influence of prematurity and long chain polyunsaturate supplementation in 4week adjusted age baboon neonate brain and related tissues. Pediatr Res. 2003;54 (2):244–252 Chang BA, Huang Q, Quan J, et al. Early inflammation in the absence of overt infection in preterm neonates exposed to intensive care. Cytokine. 2011;56(3):621–626 Lavoie PM, Lavoie JC, Watson C, Rouleau T, Chang BA, Chessex P. Inflammatory response in preterm infants is induced early in life by oxygen and modulated by total parenteral nutrition. Pediatr Res. 2010;68 (3):248–251 Lista G, Castoldi F, Bianchi S, Battaglioli M, Cavigioli F, Bosoni MA. Volume guarantee versus high-frequency ventilation: lung inflammation in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2008;93(4):F252– F256 Paananen R, Husa AK, Vuolteenaho R, Herva R, Kaukola T, Hallman M. Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia. J Pediatr. 2009;154:39–43.e3

49. Vento M, Moro M, Escrig R, et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics. 2009;124(3). Available at: www.pediatrics.org/cgi/content/full/124/ 3/e439 50. Sharma AA, Jen R, Butler A, Lavoie PM. The developing human preterm neonatal immune system: a case for more research in this area. Clin Immunol. 2012;145(1):61–68 51. Chapkin RS, Kim W, Lupton JR, McMurray DN. Dietary docosahexaenoic and eicosapentaenoic acid: emerging mediators of inflammation. Prostaglandins Leukot Essent Fatty Acids. 2009;81(2-3):187–191 52. Miloudi K, Comte B, Rouleau T, Montoudis A, Levy E, Lavoie JC. The mode of administration of total parenteral nutrition and nature of lipid content influence the generation of peroxides and aldehydes. Clin Nutr. 2012;31(4):526–534 53. Crawford MA, Costeloe K, Ghebremeskel K, Phylactos A, Skirvin L, Stacey F. Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies? Am J Clin Nutr. 1997;66(suppl 4):1032S–1041S 54. Crawford MA, Golfetto I, Ghebremeskel K, et al. The potential role for arachidonic and docosahexaenoic acids in protection against some central nervous system injuries in preterm infants. Lipids. 2003;38(4):303–315 55. Chau V, Poskitt KJ, McFadden DE, et al. Effect of chorioamnionitis on brain development and injury in premature newborns. Ann Neurol. 2009;66(2):155–164 56. Rogers LK, Valentine CJ, Pennell M, et al. Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice. J Nutr. 2011;141(2):214–222 57. Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials. Am J Clin Nutr. 2008;87(4):912–920

(Continued from first page) PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Ms Zhang was supported by a summer bursary from the Fondation des Étoiles. Dr Marc was supported by a clinician research award from the Fonds de Recherche Québec–Santé, Canada. Dr Lavoie is funded by a Michael Smith Foundation Career Investigator Award and a Child and Family Research Institute Clinician-Scientist Award. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Omega-3 Long-Chain Polyunsaturated Fatty Acids for Extremely Preterm Infants: A Systematic Review Peiyin Zhang, Pascal M. Lavoie, Thierry Lacaze-Masmonteil, Marc Rhainds and Isabelle Marc Pediatrics 2014;134;120; originally published online June 9, 2014; DOI: 10.1542/peds.2014-0459 Updated Information & Services

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.


Long-chain polyunsaturated fatty acids supplementation in preterm infants.

Oxygen saturation target range for extremely preterm infants: a systematic review and meta-analysis.

Omega-3 long chain polyunsaturated fatty acids to prevent preterm birth: a systematic review and meta-analysis.

Polyunsaturated fatty acids and thrombosis.

Polyunsaturated fatty acids in preeclampsia.

Addition of long-chain polyunsaturated fatty acids to formula for very low birth weight infants.

Cranial sonography in extremely preterm infants.

SENSORY PROCESSING DURING CHILDHOOD IN PRETERM INFANTS: A SYSTEMATIC REVIEW.

Protein Intake and Growth in Preterm Infants: A Systematic Review.

Hormone profiles in extremely preterm infants.

Neurodevelopmental outcomes of extremely preterm infants.

Factors affecting long-chain polyunsaturated fatty acid composition of plasma choline phosphoglycerides in preterm infants.

Increased tissue levels of omega-3 polyunsaturated fatty acids prevents pathological preterm birth.

Short- and Long-Term Outcomes for Extremely Preterm Infants.

Intravenous lipids for preterm infants: a review.

Polyunsaturated fatty acids in multiple sclerosis.

Anorexia nervosa, seasonality, and polyunsaturated fatty acids.

Serum Polyunsaturated Fatty Acids and Endometriosis.

Polyunsaturated fatty acids and the brain.

Polyunsaturated fatty acids in multiple sclerosis.

Polyunsaturated fatty acids and fetal brain development.

Telomere length and polyunsaturated fatty acids.

Digestion and absorption of polyunsaturated fatty acids.

Targeted lipidomic strategies for oxygenated metabolites of polyunsaturated fatty acids.