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)
120
ZHANG et al
REVIEW ARTICLE
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 rePEDIATRICS Volume 134, Number 1, July 2014
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,
121
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
ZHANG et al
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,
REVIEW ARTICLE
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 prodPEDIATRICS Volume 134, Number 1, July 2014
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.
123
124
ZHANG et al
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
65 preterms
GA ,32 wk
BW ,1400 g
Participants
Carlson 1998, United States18
Carlson 1996, United States17
RCTs
Carlson 1992, United States16
Studies
Standard formula
(no LCPUFA)
Standard formula
(no LCPUFA)
Standard formula
(no LCPUFA)
Standard formula
(no LCPUFA)
Standard formula
(no LCPUFA)
Standard formula
(no LCPUFA)
Standard formula
(no LCPUFA)
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
Participants
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
Studies
Harper 2010, United States12
Henriksen 2008, Norway13
Innis 2002, Canada24
Koletzko 1995, Germany25
Makrides 2010, Australia15
Manley 2011 substudy
of Makrides 2009, Australia11
TABLE 1 Continued
PEDIATRICS Volume 134, Number 1, July 2014
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
Dichotomous Outcomes (Any Definition) or
Equivalent Continuous Outcomes
REVIEW ARTICLE
125
126
ZHANG et al
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
38 preterms
GA ,32 wk
BW ,1500 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%
Standard formula
(no LCPUFA)
Intravenous lipid emulsion
containing conventional
soybean lipid
(Intralipid 20%)
Intravenous lipid emulsion
containing conventional
soybean lipid (Intralipid)
Standard formula
(no LCPUFA)
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
Dichotomous Outcomes (Any Definition) or
Equivalent Continuous Outcomes
—
√
√
√
√
√
—
√
—
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
PEDIATRICS Volume 134, Number 1, July 2014
√ 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
Dichotomous Outcomes (Any Definition) or
Equivalent Continuous Outcomes
REVIEW ARTICLE
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
127
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
ZHANG et al
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
REVIEW ARTICLE
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
PEDIATRICS Volume 134, Number 1, July 2014
(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
129
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
ZHANG et al
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
REVIEW ARTICLE
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
PEDIATRICS Volume 134, Number 1, July 2014
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
131
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
ZHANG et al
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).
REVIEW ARTICLE
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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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