REVIEW

n-3 LC-PUFA supplementation: effects on infant and maternaloutcomes

Rachele De Giuseppe • Carla Roggi •

Hellas Cena

Received: 22 May 2013 / Accepted: 15 January 2014

� Springer-Verlag Berlin Heidelberg 2014

Abstract

Background Long-chain polyunsaturated fatty acids (LC-

PUFA), particularly docosahexaenoic acid (DHA) and

arachidonic acid, are, respectively, n-3 and n-6 family

members and play an important role in fetal and infant

growth and development. Pregnancy and lactation impose

special nutritional needs for the mother-fetus situation.

Since the LC-PUFA required by the fetus is supplied by

preferential placental transfer of preformed LC-PUFA

rather than their precursor, it has been hypothesized that

additional maternal supply of LC-PUFA, especially DHA,

during pregnancy may improve maternal and infant

outcomes.

Aim To summarize evidences of the effect of n-3 LC-

PUFA intake during pregnancy and lactation on maternal

and infant outcomes in order to offer a comprehensive view

of this issue that should be useful for clinical practice.

Results Maternal n-3 LC-PUFA supplementation may

reduce risk for early preterm birth [34 weeks and seems

very promising for primary allergy prevention during

childhood. On the contrary, there are not sufficient data

proving that the consumption of oils rich in n-3 LC-PUFA

during pregnancy optimizes child’s visual and neurode-

velopment and reduces the risk for preeclampsia and

perinatal depression; the implications of these findings

remain to be elucidated.

Conclusion The implications of n-3 LC-PUFA supple-

mentation on fetal development, maternal outcomes and

later infant growth is worth being elucidated and is

promising in its potential for a positive impact on fetal and

maternal outcomes.

Keywords Pregnancy � Docosahexaenoic acid �a-Linolenic acid � Long-chain polyunsaturated fatty acids

Introduction

Long-chain polyunsaturated fatty acids (LC-PUFA), par-

ticularly Docosahexaenoic Acid (DHA, 22:6n-3) and Ara-

chidonic Acid (AA, 20:4n-6), are important constituents of

the phospholipids of all cell membranes, where they play

roles assuring the correct environment for membrane protein

function, maintaining membrane fluidity, regulating cell

signaling, gene expression and cellular function, and serving

as substrates for the synthesis of lipid mediators [1].

DHA may be obtained directly from dietary fish oils or

from the precursor a-linolenic acid (ALA, 18:3n-3); the

usual precursor of AA is dietary linoleic acid (LA, 18:2n-6)

from plant sources.

Because humans don’t possess desaturase enzymes

capable of inserting either the n-3 or the n-6 double

bounds, AA and LA are considered essential and can be

derived only from the diet [2].

Over the past decades, evidences from observational

studies and randomised trials have suggested that the intake

of LC-PUFA throughout pregnancy, particularly DHA,

plays potential benefits on maternal and fetal/neonatal

health [3].

R. De Giuseppe (&)

Dipartimento di Scienze Biomediche Chirurgiche e

Odontoiatriche, U.O. Ematologia e CTMO, Fondazione IRCCS

Ca’ Granda Ospedale Maggiore Policlinico, Universita degli

Studi di Milano, Via F. Sforza 35, 20122 Milan, Italy

e-mail: rachele.degiuseppe@unimi.it

C. Roggi � H. Cena

Unit of Human Nutrition and Dietetics, Department of Public

Health, Experimental and Forensic Medicine, University of

Pavia, Via Bassi 21, 27100 Pavia, Italy

123

Eur J Nutr

DOI 10.1007/s00394-014-0660-9

Since the ability of the fetus and the human placenta to

desaturate and elongate fatty acids is limited, a preferential

materno-fetal transfer of LCPUFA via specific fatty acid

transport system, including multiple placental transport

proteins (FATP) [4], has been suggested.

Numerous studies have reported that LC-PUFA per-

centages in the lipids of cord plasma are higher than in

maternal plasma at birth time [5].

In vitro and in vivo experiments show that the placenta

is capable of transporting LC-PUFA preferably to the fetal

site, with the following preference order: DHA [ AA [ALA [ LA [6].

Therefore, since preferential placental transfer of pre-

formed LC-PUFA rather than the precursor ALA and LA

supplies the LC-PUFA required by the fetus, it has been

hypothesized that additional maternal supply of DHA

during pregnancy may improve maternal and infant

outcomes.

The aim of this article was to summarize evidence of n-3

LC-PUFA intake during pregnancy on children’s cognitive

and visual development, gestational length, preeclampsia,

postpartum depression and childhood’s allergic diseases.

Visual and cognitive development

About 60 % of the dry weight of brain tissue is fat; DHA

and AA are the most abundant LC-PUFA in the brain and

are critical for proper brain, nervous system and eye

development [7]. Because considerable amounts of fatty

acids accumulate in the fetal renal cortex tissue and retinal

membrane synapses during the third trimester of pregnancy

and during the first postpartum month [8, 9], data from

large cohort studies as well as from randomized controlled

trials (RCTs) indicated that an adequate amount of n-3 LC-

PUFA is important for the neonate to support long-term

cognitive and visual development [10].

However, even if results from in vivo studies [11] and

from many observational ones in humans suggested a

benefit of n-3 LC-PUFA supplementation, data from RCTs

of LC-PUFA administration in pregnancy and lactation are

not consistent in showing a benefit in infant retinal and

neurocognitive development [8].

We reported the two most recently systematic review

and meta-analysis of RCTs which evaluated the poten-

tial effects of n-3 LC-PUFA supplementation on infant

neurobehavioral and visual development during preg-

nancy [12] as well as during both pregnancy and lac-

tation [9].

Lo and colleagues [12] identified 9 RCTs of n-3 LC-

PUFA supplementation (DHA and EPA supplied, varied

among trials) focused on retinal development and neuro-

development with a starting point of intervention which

ranged from the 15th to the 25th week gestational age.

Data presented in this systematic review were conflict-

ing. In fact, as for visual acuity, the authors identified only

a small longitudinal, double-blinded RCT of 30 non-

smoking women supplemented with either DHA-fortified

cereal bars (n = 16) or placebo bars (n = 14), in which

there was a significant improvement in visual acuity

(assessed by Teller Acuity Cards Procedures) in DHA-

supplemented group at 4 months, but not at 6 month

postnatal [13]. Another randomized double-blind and pla-

cebo-controlled study, included in this systematic review,

reported that although DHA maternal supplementation

didn’t correlate with DHA infant status and had no effect

on retinal development, infants in the highest quartile for

cord blood DHA had significantly higher retinal sensitivity

when compared with infants in the lowest quartile [14].

Because the small number of trials, short-term follow-up

and assessments used, further research is needed to clarify

the effect of n-3 LC-PUFA supplementation on visual

development.

With regard to the neurodevelopment, the neurocogni-

tive studies included in this systematic review [12] reported

variable results in terms of whether LC-PUFA supple-

mentation during pregnancy could lead to benefits or not in

neurocognitive outcomes. Among 6 RCTs on the effect of

maternal LC-PUFA supplementation on neurocognitive

development in infants, 3 studies on mothers supplemented

daily with 10 mL cod liver oil or 10 mL corn oil placebo,

from 18 gestational weeks until 3 months after delivery,

have been reported [15–17]. In these trials, the neurode-

velopment measurement was assessed at ages day 2, at 3, 6,

9 months [15], as well as at 4 [16] and 7 years [17] of age;

differences were found only at 4 years old when children

of cod-oil-supplemented mothers had a higher score on the

mental processing composite of Kaufman Assessment

battery for Children, compared to children of placebo

group mothers [16].

Another RCT reported that significantly higher problem-

solving scores (i.e., better performance), assessed by the

infant planning test (IPT), were found in children of

mothers supplemented with DHA-rich cereal bars when

compared to placebo bars group [18].

A further double-blind and placebo-controlled study

described that a supplementation of fish oil (3.7 n-3 LC-

PUFA g/day) during pregnancy from 20 weeks till delivery

improved significantly the scores on the eye and hand

coordination of the Griffiths Mental Development Scales in

infants at age 2.5–3 years old [19].

Despite favorable effect of some studies reported in this

systematic review, considering the results of these 6 studies

on neurocognitive development, there is no evidence which

describes a correlation between the LC-PUFA supple-

mentation during pregnancy and the improvement in child

neurodevelopment. The authors reported that a possible

Eur J Nutr

123

explanation for these conflicting results may be due to the

presence of several other confounding factors (such as

nutrients, drugs, social stimulation and diseases) or to the

use of sufficiently sensitive or not standardized (such as

IPT) cognitive tests [12].

The 9 RCTs included in the systematic review by Lo

and colleagues [12] were also reported in the most recent

and first comprehensive systematic review and meta-ana-

lysis of RCTs published by Gould et al. [9] which sum-

marized 23 published and unpublished double-blind

randomized trials of n-3 PUFA supplementation during

pregnancy as well as during both pregnancy and lactation

on neurologic and visual development of the offspring.

The authors evaluated the development standard score

(DSS) in infants, toddlers and preschoolers and the intel-

ligence quotient (IQ) in children; secondly, they evaluated

other aspects of neurodevelopment (such as language,

behavior and motor development) and visual development.

Authors reported that differences between the treatment

and control groups for cognition were observed only in

preschool children 2–5 years who had a 3.92 point increase

in DSS when compared to the control group. Also sec-

ondary neurodevelopment aspects, such as motor and lan-

guage, didn’t differ between treated and placebo group

after supplementation during pregnancy as well as during

both pregnancy and lactation [9].

Because visual outcomes were evaluated with a variety

of assessment at different ages, they were not combined in

a meta-analysis; no difference was found between infants

in the treatment group when compared to the placebo group

on retinal sensitivity at 1 week and visual acuity at any

ages.

In summary, despite the encouraging data from in vivo

and observational studies, results reported by Lo et al. [12]

and by Gould et al. [9] do not support or refute the

hypothesis that n-3 LC-PUFA supplementation in preg-

nancy or in pregnancy and lactation improve child visual

and cognitive outcomes.

Many of the trials reviewed had methodological prob-

lems such as small sample sizes, inadequate blinded par-

ticipants and assessors, inadequate follow-up, inadequate

random sequence generation and inadequate compliance.

Therefore, in order to improve the basis of evidence-based

guidelines for pregnant women, future high-quality RCTs

will need large samples and appropriately specialized

assessments.

Gestational length

Preterm infants are recognized as being at risk of LC-

PUFA dietary insufficiency because they are born before

the last trimester is completed, prematurely ending the

supply of LC-PUFA across the placenta [20].

The maternal n-3 LC-PUFA intake during pregnancy

has been proposed as a mechanism to delay the onset of

spontaneous labor because DHA seems to be in part

responsible for the E2 and F2 prostaglandins inhibition

involved in the ripening of the cervix. DHA also appears to

relax uterine smooth muscles via increased production

PGI2 and PGI3 levels, thereby slowing contractions in the

last weeks of pregnancy [21].

Some observational studies, mainly in women living in

communities with high fish consumption, have suggested

that greater marine n-3 LC-PUFA intake during pregnancy

promotes longer gestation and higher birth weight [22, 23].

Several systematic reviews and meta-analysis of RCTs

reported that n-3 LC-PUFAs’ treatment was associated

with significantly longer gestational period, as compared to

no treated control group.

For example, Szajewska et al. [2] reported that n-3

supplementation LC-PUFA during pregnancy may increase

the duration of gestational period by an average of 1.6 day.

A Cochrane review (6 RCTs and 2,783 women) [24]

revising such findings revealed a mean 2.6 days longer

gestation in the marine-oil-supplemented group compared

with the no supplemented group.

Salvig and Lamont [25] reported that the mean gesta-

tional age at delivery was significantly higher by 4.5 days

in the supplemented n-3 LC-PUFA group when compared

to placebo.

The effect of n-3 LC-PUFA on the rate of preterm birth

is controversial and is still debated.

Szajewska et al. [2] didn’t find significant difference

between supplemented and non-supplemented women at

low-risk pregnancies in the percentage of preterm deliv-

eries (\37 week gestation) as not even Makrides et al. [24]

in a Cochrane review in the relative risk of birth before 37

completed weeks (5 RCTs, involving 1,916 women);

however, women allocated to marine oil supplementation

showed a lower risk of giving birth before 34 completed

weeks’ gestation compared with placebo (2 RCTs,

involving 860 women).

Similar findings were reported in a subsequent meta-

analysis about the effects of LC-PUFA supplementation on

women in high-risk pregnancies [26] demonstrating no

association of maternal fatty acid intake with risk of pre-

term birth \37 weeks of gestation (3 RCTs involving 523

participants); however, when the effects of supplementa-

tion were examined on the rate of early preterm birth

(\34 weeks of gestation), the relative risk was found to be

reduced in the supplemented group (2 RCTs involving 291

participants).

Finally, a recent meta-analysis [25] that, for the outcome

of preterm birth evaluated 4 RCTs involving 927 women,

demonstrated that fish oil or DHA-enriched eggs supple-

mentation significantly reduced preterm deliveries

Eur J Nutr

123

\37 weeks; data on delivery before 34 completed weeks

showed the same trend.

With regard to the influence of n-3 LC-PUFA supple-

mentation during pregnancy on growth measure at birth,

results are conflicting.

Szajewska et al. [2] reported that only head circumfer-

ence was significantly higher in the n-3 LC-PUFA sup-

plemented group.

Salvig and Lamont [25] described a mean birth weight

in women who received n-3 PUFA during pregnancy

higher by 71 g than that of women who did not receive the

treatment.

On the contrary, a Cochrane review [27] covering 15

RCTs and involving 1,889 term infants reported that none

of the studies considered showed beneficial effects of LC-

PUFA supplementation on weight, length and head cir-

cumference until 3 years of age. The results were the same

regardless of the type, concentration and duration of LC-

PUFA supplementation.

As described in a systematic review by Larque et al.

[10], the higher birth weight after n-3 LC-PUFA sup-

plementation during pregnancy could be probably due to

a greater length of these pregnancies; moreover, the

authors cited a study in which the difference in birth

weight disappeared when using the gestational age as

covariable.

The evidences so far produced do not support the routine

use of marine oil, or other PG precursor, supplements

during pregnancy to reduce the risk of preterm birth and

low birth weight, even if it has been reported an association

of maternal fatty acid intake with risk of preterm birth

\34 weeks of gestation. No advice can be given to their

rational use to avoid preterm deliveries in low- or high-risk

pregnancies; further research is required to establish this

therapeutic effect.

Allergic diseases

The biological activities of n-3 LC-PUFA have led inves-

tigators to hypothesize that maternal supplementation with

n-3 LC-PUFA during pregnancy and lactation may mod-

ulate immune response and allergy in neonates and

children.

The predisposition to allergic diseases may result from

insufficiently balanced T helper cell type 1 and 2 (Th1 and

Th2) pathways during fetal life. A possible mechanism

whereby n-3 LC-PUFA may alter the T helper cell balance

is through suppression of interleukin-13 (IL-13) production

which may be related to allergic diseases through its role in

inducing immunoglobulin E (IgE) synthesis in B cells and

Th2-type differentiation in T cells [28].

DHA and EPA also competitively inhibit the metabo-

lism of AA, resulting in reduced production of the ‘‘pro-

allergic four-series leukotrienes’’ and the two-series pros-

taglandins [28].

There are so far a number of studies investigating the

role of n-3 LC-PUFA supplementation in the development

and progression of atopy, childhood asthma and other

allergic diseases [29, 30].

Anandan et al. [29] conducted a systematic review and

meta-analysis of 6 RCTs evaluating the effectiveness of

LC-PUFA oil supplementation for the primary prevention

of sensitization, eczema/atopic dermatitis, allergic rhinitis,

asthma and other allergic disorders. Four of these RCTs

involved n-3 LC-PUFA supplementation and the others

involved n-6 LC-PUFA supplementation; both studies of

n-3 supplementation and n-6 supplementation were com-

bined. The results from well-conducted experimental

studies suggested that supplementation with n-3 and/or n-6

LC-PUFA oils was unlikely to be associated with a marked

reduction in risk of developing sensitization or allergic

disease.

On the contrary, a subsequent systematic review and

meta-analysis of 5 RCTs (949 participants) by Klemens

et al. [30] investigated the role of pregnancy and/or preg-

nancy and lactation n-3 LC-PUFA supplementation in

infant and childhood allergy, asthma, atopy and inflam-

matory markers (IL-13 and interferon-gamma). Authors

described a significant reduction in the incidence of asthma

(2 RCTs, involving 482 participants) and response to skin

prick tests (2 RCTs, involving 187 participants) in children

of mothers who received n-3 LC-PUFA supplementation

when compared to children of mothers receiving placebo.

A further significant difference was found in IL-13 levels

in cord blood.

Supplementation during lactation only did not signifi-

cantly affect these and other atopic outcome.

One of the sections of the most recent systematic review

by Kremmida et al. [31] evaluated five epidemiological

studies that investigated the association between maternal

fish intake in pregnancy and perinatal life (4 RCTs) and

during lactation (one study) and atopic outcomes in the

offspring of these mothers. In each of these observational

studies, maternal fish consumption had a protective effect

between 25 and 95 %; only the study investigating the

effects of maternal fish intake during lactation did not

report any significant association [32].

Another section of this systematic review [31] reported

five RCTs investigating the effects of fish oil supplemen-

tation during pregnancy or lactation on immune or atopic

outcomes in the offspring during infancy or childhood.

These studies reported that fish oil supplementation during

pregnancy and/or lactation is associated with immunologic

changes in cord blood and could impact on allergic sensi-

tization and on the development of atopic disease. How-

ever, authors prospect that these findings need to be

Eur J Nutr

123

confirmed by future and adequately powered trials in order

to examine clinical outcomes in the offspring later or in life

to inform recommendations [31].

Summarizing, the effects of n-3 LC-PUFA supplemen-

tation on reducing allergic disease in children seems very

promising, but more trials are recommended to clarify

when and how supplementation should be administered in

order to optimize the benefits.

Preeclampsia

Supplementation with n-3 LC-PUFA has been proposed as

a potential strategy to prevent preeclampsia, a pregnancy

complication associated with vasoconstriction and endo-

thelial damage, because of the effects of n-3 LC-PUFA on

modulating inflammatory and vascular function [33].

However, to date, there is uncertainty regarding the

efficacy of increasing n-3 LC-PUFA intake during preg-

nancy in reducing the risk of preeclampsia.

In the meta-analysis of 6 RCTs by Szajewska et al. [2],

no significant difference in the rate of preeclampsia or

eclampsia was found between n-3 LC-PUFA supplemented

group and non-supplemented group.

Similar findings were reported by a Cochrane review

[24] in which there were no clear differences in the relative

risk of high blood pressure (5 trials, 1,831 women) or the

incidence of preeclampsia (four trials, 1,683 women)

between marine-oil-treated and control groups.

A subsequent meta-analysis of 4 RCTs focused on the

effect of LC-PUFA supplementation during high-risk

pregnancy [26] demonstrated that no difference in the rate

of preeclampsia was found (one RCT involving 321

woman).

Despite observational literature supported an association

between lowered maternal n-3 LC-PUFA levels and pre-

eclampsia, RCTs have not demonstrated any benefit for

supplementation. Therefore, this clinical uncertainty is a

prerequisite for more large-scale RCTs to evaluate the

influence and the available treatment options of such

interventions.

Postpartum depression

Because a mother actively transfers DHA to her fetus and

nursing infant [4], a deficiency may result if dietary intake

is not adequate. Observational studies suggest an associa-

tion between a low maternal DHA status after pregnancy

and the occurrence of postpartum depression (PPD) [34,

35].

There has been conflicting evidence of efficacy from the

available clinical trials because the effect of n-3 LC-PUFA

supplementation during pregnancy on maternal depression

has been addressed in very few and not very well-con-

ducted studies.

In a recent systematic review of 7 placebo-controlled

trials of n-3 LC-PUFA for prevention or treatment of

perinatal depression, which involved 612 women who were

supplemented during pregnancy and/or post partum, Jans

et al. [36] did not find significant change in depressive

symptoms.

Interestingly, the authors reported that only one study

randomized double-blind placebo-controlled reported a

beneficial effect of n-3 LC-PUFA supplementation (2.2 g

EPA ? 1.2 g DHA) on perinatal depression in Taiwanese

women [37]; therefore, Jans et al. advocated the impor-

tance of replicating this finding using a larger and multi-

ethnic study population [36].

Authors also reported that the results of this meta-ana-

lysis were not in agreement with two previous meta-anal-

yses on the efficacy of n-3 LC-PUFA for unipolar major

depression in which n-3 LC-PUFA treatment showed

benefits when compared to placebo group; these discrep-

ancies were probably due by the significant heterogeneity

of the two previous meta-analyses [36].

Even if the available evidence seems to suggest that

EPA and/or DHA supplementation is more likely to be

beneficial in treating existing symptoms of perinatal

depression than in preventing perinatal depression, to date,

literature doesn’t support n-3 LC-PUFA supplementation

in order to prevent or treat perinatal depression.

Conclusions

Maternal n-3 LC-PUFA status during pregnancy may

influence a number of maternal and infant outcomes.

Actually, as shown in Table 1, there are some evidences

from meta-analyses and review articles that maternal n-3

LC-PUFA supplementation may reduce risk for early pre-

term birth \34 weeks and seems very promising for pri-

mary allergy prevention during childhood.

On the contrary, there are not sufficient data proving that

the consumption of oils rich in n-3 LC-PUFA during

pregnancy optimizes child’s visual and neurodevelopment

and reduce the risk for preeclampsia and perinatal

depression; the implications of these findings remain to be

elucidated.

Maternal lifestyle and nutrition have long been recog-

nized as important factors for both perinatal health and for

the long-term health of the infant; particular attention

should be paid to population groups at risk such as smokers

and vegans and non-fish-eating vegetarians.

The relationship between n-3 LC-PUFA and smoking

status is a controversial topic [38, 39].

Eur J Nutr

123

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Mothers’ smoking habits are associated with reduced

pools of LC-PUFA in their infants at birth. As previously

described by Agostoni et al. [40], the product/precursor

ratios, markers of LC-PUFA synthesis, are progressively

reduced in infants born to smoking mothers according to

smoking duration during pregnancy because maternal

smoking could, at least partly, interfere with the biosyn-

thesis and consequently the incorporation of LC-PUFA,

particularly DHA, in infants’ tissues [40]. In addition, the

pro-oxidative state characteristic of smokers might be

expected to accelerate the destruction of LC-PUFA like

EPA and DHA [39].

Although conversion from ALA to EPA and DHA

occurs, this is limited, and diets that do not include fish and

eggs (e.g., vegans and non-fish-eating vegetarians) gener-

ally guarantee a low EPA and DHA dietary intake.

Therefore, vegetarian and vegan diets, which are generally

rich in n-6 LC-PUFA, may be marginal in n-3 LC-PUFA

[41, 42], and vegetarians, particularly vegans, tend to have

lower blood levels of EPA and DHA than nonvegetarians

[43].

The implications of n-3 LC-PUFA supplementation on

fetal development, maternal outcomes and later infant

growth is worth being elucidated and is promising in its

potential for a positive impact on fetal and maternal

outcomes.

Conflict of interest The authors declare that they have no conflict

of interest.

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