A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in pregnancy

Abstract

Emerging evidence suggests that omega (n)-3 PUFA and their metabolites improve maternal and neonatal health outcomes by modifying gestation length, and reducing the recurrence of pre-term delivery. N-3 PUFA has been associated with prolonged gestation and increased birth dimensions such as birth weight and head circumference. However, mothers giving birth to larger babies are at an increased risk of having dysfunctional labour, genital tract laceration, and delivery via caesarean section. Likewise, high infant weight at birth has been linked to several metabolic and cardiovascular disorders in the offspring. Prolonged gestation also leads to reduced placental function which has been implicated in fetal distress, and perinatal death. Till date, the mechanism through which high n-3 PUFA intake during pregnancy increases gestation length and birth weight is vaguely understood. Early and later stages of pregnancy is characterised by increased production of pro-inflammatory cytokines which are required for pregnancy establishment and labour regulation respectively. Conversely, mid-stage of pregnancy requires anti-inflammatory cytokines necessary for uterine quiescence, pregnancy maintenance and optimal fetal growth. Apparently, changes in the profiles of local cytokines in the uterus during different stages of pregnancy have a profound effect on pregnancy progression. This review focuses on the intake of n-3 and n-6 PUFA during pregnancy and the impact it has on gestation length and infant weight at birth, with a particular emphasis on the expression of inflammatory cytokines required for timely pregnancy establishment (embryo reception and implantation) and labour induction. It is concluded that an appropriate dose of n-3 and n-6 PUFA needs to be established during different stages of pregnancy.

Full text

A balance of omega-3 and omega-6 polyunsaturated fatty acids is
important in pregnancy
Olatunji Anthony Akerele, Sukhinder Kaur Cheema
*
Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X9, Canada
article info
Article history:
Received 15 December 2015
Accepted 28 April 2016
Available online xxx
Keywords:
Cytokines
Pregnancy
Implantation
Labour
Polyunsaturated fatty acids
Birth outcomes
abstract
Emerging evidence suggests that omega (n)-3 PUFA and their metabolites improve maternal and
neonatal health outcomes by modifying gestation length, and reducing the recurrence of pre-term de-
livery. N-3 PUFA has been associated with prolonged gestation and increased birth dimensions such as
birth weight and head circumference. However, mothers giving birth to larger babies are at an increased
risk of having dysfunctional labour, genital tract laceration, and delivery via caesarean section. Likewise,
high infant weight at birth has been linked to several metabolic and cardiovascular disorders in the
offspring. Prolonged gestation also leads to reduced placental function which has been implicated in fetal
distress, and perinatal death. Till date, the mechanism through which high n-3 PUFA intake during
pregnancy increases gestation length and birth weight is vaguely understood. Early and later stages of
pregnancy is characterised by increased production of pro-inflammatory cytokines which are required
for pregnancy establishment and labour regulation respectively. Conversely, mid-stage of pregnancy
requires anti-inflammatory cytokines necessary for uterine quiescence, pregnancy maintenance and
optimal fetal growth. Apparently, changes in the profiles of local cytokines in the uterus during different
stages of pregnancy have a profound effect on pregnancy progression. This review focuses on the intake
of n-3 and n-6 PUFA during pregnancy and the impact it has on gestation length and infant weight at
birth, with a particular emphasis on the expression of inflammatory cytokines required for timely
pregnancy establishment (embryo reception and implantation) and labour induction. It is concluded that
an appropriate dose of n-3 and n-6 PUFA needs to be established during different stages of pregnancy.
©2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents
1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................. 00
2. Metabolism and transport of essential PUFA during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... 00
3. Omega-3 PUFA intake and pregnancy outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................... 00
3.1. Effect of omega-3 PUFA intake on the risk of pre-term birth (PTB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 00
3.2. Effects of n-3 PUFA on gestation length and infant size at birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 00
4. Role of cytokines during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................. ........................... 00
5. Omega-3 PUFA and cytokine regulation during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... ........................... 00
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................... ........................... 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 00
1. Background
Maternal diet is critical for a successful pregnancy establish-
ment, as well as fetal health outcomes [1,2]. Nutrition during
pregnancy programs set points for metabolic and physiological
*Corresponding author.
E-mail address: skaur@mun.ca (S.K. Cheema).
Contents lists available at ScienceDirect
Journal of Nutrition &Intermediary Metabolism
journal homepage: http://www.jnimonline.com/
http://dx.doi.org/10.1016/j.jnim.2016.04.008
2352-3859/©2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e11
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

responses in the offspring which manifest at either childhood or at
adult life [3e5]. The hypothesis that early life dietary insults in utero
increases the vulnerability of the offspring to developing several
pathological conditions is now unequivocally accepted [3,6].
Several studies have now established that the quantity and quality
of dietary fats consumed during pregnancy have profound health
implication during and after pregnancy [7,8]. Omega (n)-6 and n-3
polyunsaturated fatty acids (PUFA), the essential fatty acids [9], play
critical roles during fetal growth and development [8,10e12].
However, the mean n-3 PUFA intake of about 90% of Canadian
women is only 82 mg per day, which is far below the recommen-
dation of the International Society for the Study of Fatty Acids and
Lipids for North Americans (300 mg/day) [13]. Dietary shift over the
years to Western diet has caused a drastic change in the ratio of n-6
to n-3 fatty acids from about 1e2:1 in the Paleolithic diet (hunter
gatherer's diet) to about 20e30:1 [14]. This transition has been
found to promote the pathogenesis of several diseases [15]. Meta-
bolism of n-3 PUFA such as docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA) produce anti-inflammatory lipids
mediators which have been shown to reduce the risks of specific
clinical endpoints [16,17], while n-6 PUFA are generally considered
inflammatory in nature [18].
DHA is important in the overall fetal growth, as well as the
development of vital organs such as the brain and eyes [11,12].As
such, an inadequate intake of DHA during pregnancy has been
associated with impaired cognitive functions and visual acuity in
the offspring [19]. Besides, other spectrum of evidence has shown
that n-3 PUFA supplementation during pregnancy reduces the risk
of pre-term birth (PTB), especially in high risk pregnancies [20e23].
Women consuming diets high in n-3 PUFA during pregnancy were
observed to have longer gestational length, and consequently, high
birth dimensions such as birth length, birth weight and head
circumference [22e33]. To identify appropriate studies on the ef-
fect of n-3 PUFA on pregnancy establishments and outcomes,
MEDLINE (PubMed) and Web of Science databases were searched
thoroughly using the following keywords; pregnancy, implanta-
tion, labour, cytokines, polyunsaturated fatty acids, and birth out-
comes. Adequately controlled studies (Randomized controlled
clinical trials), as well as prospective cohort studies assessing the
effect of n-3 PUFA intake during pregnancy on pregnancy duration
and outcomes in women of reproductive age were considered for
this review. Studies limited by subject number (<50 subjects) were
excluded, while studies published in English language, between
1985 and 2015 were included.
Women supplemented with high n-3 PUFA had their gestation
length extended by 6 days [34] and 8.3 days longer in high risk
pregnancies [35]. Prolonged gestation and high birth weight,
however, has been associated with several maternal, fetal and
neonatal health risks. Mothers giving birth to larger babies are at an
increased risk of having prolong labour, excessive bleeding, and
genital tract laceration due to baby having head or shoulder too big
to pass through the mother's pelvis, thereby resulting in
instrument-assisted delivery, or caesarean delivery [36]. High birth
weight has also been associated with childhood obesity [37], dia-
betes [38], and metabolic syndrome [39]. Equally, prolonged
pregnancy (post-term) increases emotional stress in mothers [40].
Prolonged pregnancy also result in reduced placental function, and
this increases the risk of fetal distress and ultimately perinatal
death due to low supply of nutrients and oxygen to the developing
fetus [41]. These observations emphasize on the possible negative
impact of consuming high n-3 PUFA diet during pregnancy due to
gestational length modification, however, the dosage and mecha-
nism/s through which n-3 PUFA increases gestation length and
birth weight is yet to be clearly elucidated. Pregnancy was initially
thought to be a single event characterised by either pro-
inflammatory or anti-inflammatory molecules [42]. However,
subsequent studies disapproved the pro- or anti-inflammatory
molecules dichotomy during pregnancy.
Pregnancy is made up of three (3) distinct biological phases with
each phase having different classes of predominating pro- or anti-
inflammatory mediators [43]. Early and later stages of pregnancy
are characterised by an increased production of pro-inflammatory
cytokines which are required for timely pregnancy establishment
[44,45] and labour stimulation respectively [43,46]. In contrast, the
mid-stage requires anti-inflammatory cytokines necessary for
uterine quiescence, and optimum fetal growth [43]. This review
explores the properties of n-3 PUFA on the regulation of uterine
expression of cytokines required for timely and successful preg-
nancy establishment and labour stimulation. The focus will be on
the plausible consequences of altering pro-inflammatory cytokines
signalling on gestation length and infant weight at birth.
2. Metabolism and transport of essential PUFA during
pregnancy
Humans lack the enzyme required for the insertion of a cis
double bond at 3rd and 6th carbon of n-3 and n-6 PUFA respec-
tively, thus making these fatty acids essential [47]. The simplest
form of n-3 (alpha-linolenic acid; ALA) and n-6 PUFA (linoleic acid;
LA) must therefore be obtained from the diet. Once consumed,
longer chain PUFA, such as arachidonic acid (AA), can be synthe-
sized endogenously from LA, while EPA and DHA are produced from
ALA through series of desaturation and elongation processes [48]
(Fig. 1). Studies using stable radiolabelled fatty acids have shown
that the rate of metabolism of essential PUFA is sex specific; sex
hormones may influence the enzymatic synthesis of longer chain
fatty acids as the metabolism of ALA to DHA was observed to be
higher and faster in women than men [49,50]. In men, the con-
version rate of ALA to EPA is about 8%, while ALA to DHA is between
0 and 4%. On the other hand, about 21% and 9% ALA is converted to
EPA and DHA respectively in women [49].
DHA is very important for healthy brain and eyes (retina)
development, as well as overall fetal growth during pregnancy
[11,12]. Brain has the largest amount of lipids (60% dry weight),
compared to other organs in the body [51]. DHA constitute about
10e15% of total fatty acids in the brain, and this represents more
than 97% of total n-3 PUFA [52,53]. It has been shown that there is
acceleration of fetal brain growth during the second trimester [8];
perhaps, this is the most critical stage for DHA supplementation.
However, it has been shown that the accumulation of DHA in the
brain is most rapid during the third trimester of pregnancy and the
first year after birth [54,55]. Fetus accrues up to 70 mg DHA per day
during the last trimester, specifically in the brain, and white adi-
pose tissues [56], demonstrating the significance of maternal DHA
status on fetal health. Interestingly, studies have shown that
maternal DHA level is usually low during the last trimester, which
explains a higher rate of transfer of DHA to the fetus [57]. At the
same time, low maternal n-3 PUFA levels at the last trimester could
be an in-built regulatory mechanism to enhance the synthesis of
the pro-inflammatory molecules required for labour induction.
Nonetheless, a deficit of n-3 PUFA during pregnancy results in
impaired cognitive and physiological functions in rats [58], which
has been suggested to be irreversible by postnatal supplementation
[59].
Evidence suggests that the pathway for the synthesis of longer
chain PUFA becomes upregulated and highly efficient during
pregnancy so as to meet both maternal and fetal requirement [60].
The ALA to DHA conversion pathway is complimented by increased
mobilization of accumulated DHA reserves in the maternal tissues
prior to conception [50], and also by supplementing maternal diet
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e112
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

with DHA during pregnancy. A recent study conducted in women
undergoing frozen embryo transfer reported an increase in the
mobilization of maternal DHA at early stage of pregnancy prior to
neural tube closure [61], and the concentration of DHA in maternal
plasma doubles in twin pregnancies compared to singleton preg-
nancies. These studies emphasize the importance of maternal
metabolic response during pregnancy on fetal development,
especially in the closure of neural tube. As such, DHA intake of
women before and during pregnancy may have a great impact on
the amount of DHA available for fetal use. In addition to the
increased maternal metabolic capacity for DHA synthesis during
pregnancy, the rate of transfer across the placenta also plays a
critical role in regulating the amount of DHA in fetal tissues [62].
Pre-formed longer chain PUFA such as DHA and AA from maternal
circulation are selectively and preferentially transferred across the
placenta to the fetus during pregnancy [57,62]. Fetal accumulation
of n-3 PUFA in utero is predominantly regulated by maternal n-3
PUFA status and the placental function [62].
Development of the placenta is a remarkably coordinated
physiological adaptation required for materno-fetal interaction
during pregnancy. The placental functions are precisely regulated
to ensure efficient and timely exchange of nutrient, oxygen, and
waste between maternal circulation and the growing fetus.
Nutrients and oxygen transfer during pregnancy is further
enhanced by increased blood flow to the placenta via dilated blood
vessels [63]. In addition, the functional characteristics of the
placenta changes in order to accommodate the metabolic require-
ment of the developing fetus, and this include preferential transfer
of essential fatty acids during the last trimester of pregnancy
[62,63]. Translocation of essential fatty acids across the placenta
occur via passive diffusion or through membrane protein-mediated
mechanism [62,64] (Fig. 2). Physiologically, the protein-mediated
transportation of fatty acids has been shown to be quantitatively
more important than passive diffusion [62]. Several membrane
located proteins have been identified to be involved in the trans-
port of longer chain n-3 PUFA across the placenta, and these include
the highly glycosylated fatty acid translocase (FAT), also referred to
as cluster of differentiation-36 (CD36); placental membrane fatty
acid binding protein (p-FABPpm); and the fatty acid transport
proteins (FATP) [62]. Furthermore, transfer of long chain PUFA to
the fetus is amplified by the activity of placental lipoprotein lipase
(LPL), phospholipase A2 (PLA2), intracellular lipases, and tri-
acylglycerol hydroxylase [65,66]. LPL and PLA2 hydrolyse maternal
plasma lipoproteins and phospholipids, resulting in the liberation
of PUFA, which are subsequently transported to the fetus. Lipolytic
activity increases dramatically during the third trimester [67], and
Fig. 1. Elongation and desaturation of essential polyunsaturated fatty acids. AA: Arachidonic acid; ALA: Alpha linolenic acid; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic
acid; LA: Linoleic acid; PUFA: Polyunsaturated fatty acid.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e11 3
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

this is perhaps necessary to promote healthy fetal growth through
adequate delivery of essential longer chain PUFA via the placenta. A
deficit in essential longer chain PUFA supply due to placental
dysfunction or inadequate perinatal consumption has been attrib-
uted to specific adverse pregnancy outcomes [68].
3. Omega-3 PUFA intake and pregnancy outcomes
3.1. Effect of omega-3 PUFA intake on the risk of pre-term birth
(PTB)
PTB is a major recurrent problem in obstetrics which accounted
for about 35% of all infant deaths in the United States in 2010 [69].
PTB is currently the leading cause of developmental disabilities
[70], as well as neonatal morbidity and mortality in Canada and
worldwide [71]. Data from World Health Organization (WHO, 2015)
[72] revealed that an estimated 15 million babies are born prema-
ture every year across the globe. PTB constitutes an economic
burden of about $587.1 million per year in Canada [71]. The path-
ophysiology of PTB is yet to be completely understood, however,
several studies have reported a significant positive association be-
tween maternal n-3 PUFA intake and PTB. Earliest population-wide
study reported that women in Faroe Island consuming high
amounts of marine foods (rich source of n-3 PUFA) had a very low
risk of birth before 37th week of pregnancy [73]. Subsequent
studies further confirmed the positive effect of consuming n-3
PUFA on PTB (Table 1).
A prospective cohort study conducted in Denmark revealed that
a low intake of n-3 PUFA is a risk factor for PTB; the incidence of PTB
was higher in women who never ate fish compared to those who
consumed fish at least once per week [21]. Furthermore, data from
a 50-year-old controlled fish supplementation trial conducted in
London showed a 20.4% reduction in PTB [75]. More recent inter-
vention studies show that the hazard risk of spontaneous PTB
reduced by about 39% in women who consume moderate amount
of fish [76,77]. Fish oil intake was also observed to reduce the
recurrence of PTB from about 33% to 21% in women who received
fish oil supplementation (2.7 g/d of EPA and DHA) at 20 weeks
gestation, or 6.1 g/d of EPA and DHA at about 33 weeks gestation
[27]. The beneficial effects of consuming n-3 PUFA, relating to
reduction in the risk of PTB during pregnancy, has been attributed
to its involvement in gestation length modulation [78].
3.2. Effects of n-3 PUFA on gestation length and infant size at birth
Studies have suggested that the intake of longer chain n-3 PUFA
can improve pregnancy outcomes [20,22,24,28,31]. Data from
intervention trials and observational studies have suggested a
positive association between intake of n-3 PUFA during pregnancy
and the gestation length, and consequently the weight of infants at
birth [73,75,78]. Of interest is the observation that about 1% relative
increase in cord serum phospholipid DHA in Faroe Island women
was associated with approximately 1.5 days increase in gestation
length [79]. Likewise, high intake of marine fat slightly reduced the
Fig. 2. Transport of essential PUFA during fetal development (Adapted from Duttaroy, 2009) [62]. AA: Arachidonic acid; DHA: Docosahexaenoic acid; FAT: Fatty acid translocase;
FABP: Fatty acid binding proteins; FATP: Fatty acid transport protein; LDL: Low density lipoprotein; LPL: Lipoprotein lipase; PLA2: Phospholipase A2; p-FABPpm: Placental plasma-
membrane fatty acid binding protein; VLDL: Very low density lipoprotein.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e114
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

incidence of low weight infants among Faroese women when
compared with Danish women [73,78]. A randomized controlled
trial suggested that fish oil supplementation may alter pregnancy
duration by inhibiting the production of prostaglandins which play
key roles in labour induction at term, thereby increasing the
gestation period [26].
Randomized controlled clinical trials on the effects of n-3 PUFA
on pregnancy duration and birth weight have produced consistent
results over years (Table 2). These intervention studies showed that
marine oil supplementation increases the risk of prolonged preg-
nancy and high birth dimensions such as head circumference, birth
length and birth weight. Women supplemented with longer chain
n-3 PUFA from fish oil had a significantly longer gestation period;
average of 4 days for most pregnancy and higher in high risk
pregnancies [22,25,26,28e30]. Danish women who received fish oil
supplements during third trimester of pregnancy (1.13 g DHA/day
and 1.57 g EPA/day) had higher birth weight and increased gesta-
tion period (about 4 days) compared to the control group [25].
Similar outcomes have also been observed in epidemiological and
cohort studies where mothers consumed n-3 PUFA before preg-
nancy establishment and throughout the gestation period
[24,32,73]. A randomized, double-blind, controlled study has also
revealed that dietary supplementation with DHA-enriched eggs
(about 133 mg/egg/day) during the last trimester increases gesta-
tion length by approximately 6 days [34]; This was a population-
based study (n ¼350), in which 83% of subjects completed the
study. Also, pregnant women who received fish oil (about 323 mg/
day containing approx. 100 mg DHA) or sunflower oil, from 15
weeks gestation until delivery, showed a slightly increased gesta-
tion length in infants with higher umbilical cord plasma DHA in the
DHA-supplemented group compared to the placebo group; how-
ever, this observation did not reach statistical significance [81].It
appears that fish oil containing 2.7 g omega-3 fatty acids
(EPA þDHA)/day from 30
th
week of pregnancy until parturition
produced the most significant increase in infant weight at birth by
107 g, while consuming DHA (33 or 133 mg) from eggs at 24th and
28th week of pregnancy until parturition increased gestation
length the most by 6.0 ±2.3 days (P ¼0.009) in the higher DHA
group. The observed variations in the gestation length, as well as
the weight of the infants at birth can clearly be attributed to varying
doses of n-3 PUFA during intervention, timing of the intervention,
as well as the duration of the treatment. However, the findings
published to date do not provide evidence towards an appropriate
dose of n-3 PUFA and/or the time of intervention to cause an in-
crease in gestation time period or birth weight.
Of keen interest in the intervention studies is the observation
that n-3 PUFA treatment were generally administered after the
pregnancy had been established (Table 2). Data from observational
studies, where mothers consumed high amount of n-3 PUFA prior
to conception, revealed a significantly higher infant weight at birth.
Corrected average birth weight among Faroese woman was
3610 ±603 g, and the frequency of having new born infants heavier
than 4.5 kg was 3 (three) times higher than Denmark where n-3
PUFA consumption was very low [73]. It can therefore be argued
that n-3 PUFA supplementation at the early stage of pregnancy may
have a significant influence on gestation length and other preg-
nancy outcomes; perhaps by regulating pregnancy establishment
activities, leading to gestation length prolongation and conse-
quently high infant weight at birth. On the other hand, a fewstudies
have shown that n-3 PUFA has neither beneficial nor harmful ef-
fects on gestation length, infant weight at birth and other preg-
nancy outcomes [82,83]. In general, it appears that a diet high in n-
3 PUFA may influence various activities involved in successful and
timely pregnancy establishment, and requires a more robust and
mechanistic investigation. The mechanism through which n-3
PUFA influences gestation length is perhaps associated with their
effect on regulating the balance of pro- and anti-inflammatory
cytokines.
Table 1
Omega-3 polyunsaturated fatty acids and pre-term delivery.
Intervention Outcome(s) in the treatment group Reference(s)
Fish oil 2.7 g and 6.1 g EPA þDHA (20 weeks gestation until delivery until delivery) Fish oil reduced recurrence risk of pre-term delivery from 33% to
21%.
[27]
Fish and fish oil intake (at least once per week) Reduced incidence of preterm delivery from 7.1% to 1.9% [21]
DHA capsules, 600 mg/day (<20 weeks until delivery) Lower risk of PTB [30]
DHA supplementation; up to 600 mg/day (16e20 weeks of gestation) Reduced the rate of early PTB significantly [74]
Fish oil consumption (week 20 until delivery) 20.4% reduction in risk of early delivery [75]
Fish oil capsule containing 2.7 g n-3 PUFA at week 20 or 6.3 g n-3 PUFA at week 33 until
delivery
44% reduction in the hazard rate of spontaneous delivery [76]
DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acis; PUFA: Polyunsaturated fatty acid; PTB: Pre-term birth.
Table 2
Effects of omega-3 polyunsaturated fatty acids on gestation length and birth weight.
Intervention Outcome(s) in the treatment group Reference(s)
Fish oil containing 2.7 g n-3 fatty acids (EPA þDHA)/day (30 weeks
gestation until delivery)
Prolonged gestation by about an average of 4 days.
Increased birthweight by 107 g
[25,26]
DHA-enriched eggs, 133 mg per day (24e28 weeks gestation until
delivery)
Prolonged gestation by 6 days.
Birth weight also increased but did not reach statistical significance (P ¼0.06)
[34]
Seafood intake during pregnancy Increase in gestational length of 0.02 week (95%CI: 0.002 to 0.035).
No association was observed with birthweight.
[80]
Maternal DHA intake (<16 weeks until delivery) Higher birth weight and head circumference
Gestation length was not determined
[31]
323 mg fish oil containing about 100 mg DHA per day from 15 weeks
gestation until delivery
Increased gestation length in infants with higher umbilical cord plasma DHA
No significant effect on birth weight, length and head circumference
[81]
Maternal fatty fish consumption (about 3.8 g day) Reduction in the risk of having babies with low birth weight [32]
DHA supplementation; up to 600 mg per day (16e20 weeks of
gestation)
1.6 days increase in gestational length. No significant effects on birth weight, birth
length, or head circumference.
[74]
DHA: Docosahexaenoic acid; EPA: Eicosapantaenoic acid; PTB: Pre-term birth.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e11 5
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

4. Role of cytokines during pregnancy
Pregnancy has been clearly divided into three (3) distinct stages
(trimesters), and each of these stages is characterized by different
proportions of pro- and anti-inflammatory molecules [43]. It has
been shown that the first trimester of pregnancy is primarily
characterised by increased production of pro-inflammatory bio-
molecules such as the cytokines as they are required for embryo
reception, successful implantation, and co-ordination of fetal-
maternal cross-talk [43,44,84]. Likewise, activities involving cervi-
cal ripening and uterine contraction regulation at term are medi-
ated by local pro-inflammatory signals in the maternal uterine
tissues [43,85]. In contrast, the second stage of pregnancy requires
high levels of anti-inflammatory molecules necessary for uterine
quiescence and optimum fetal development. Implantation is a
critical stage in pregnancy establishment involving complex
sequence of signalling cascades required for a harmonized dialogue
between a functional blastocyst and the endometrium, and it is
largely mediated by pro-inflammatory cytokines [43,86].
Embryonic implantation occurs about 9 days after fertilization
in human and this process involves several cytokines such as in-
terleukins (IL), leukemia inhibitory factor (LIF), interferon (IFN)-
g
,
tumor necrosis factor (TNF)-
a
, and migration inhibitory factor
(MIF). TNF
a
regulates the synthesis and activity of matrix metal-
loproteinase (MMP-2 and MMP-9) which is associated with the
invasive phase of blastocysts implantation [87,88]. IFN
g
is involved
in the initiation of endometrial vasculature remodelling, mainte-
nance of implantation sites, and the decidua (maternal component
of the placenta) [89]. Prior to embryo implantation, activities
involving endometrial function and embryo reception regulation
has been shown to be mediated by cytokines such as TNF-
a
[87,88],
IL-1 [43,44,90,91], IL-6 [43,44,92], IL-15 [90,93,94], IL-18 [94,95],
LIF [44,96,97], IFN-
g
and MIF [97e100] (Table 3).
LIF was the first cytokine shown to be very critical for implan-
tation in mice as it was found to be very abundant at the implan-
tation site [101]. Hence, blastocyst implantation was suggested to
be strictly dependent on maternal expression of LIF. However,
several other studies argued that MIF plays a major role as a pro-
inflammatory cytokine mediator during pregnancy establishment
as it can either directly or indirectly regulate the synthesis of
several other pro-inflammatory cytokines including TNF-
a
, IL-10
and IL-12 [102]. MIF has been found to be highly expressed in the
oviduct, ovaries and uterus of mouse at early pregnancy [100].
Protein and mRNA expression of MIF was reported to be higher at
early stages of gestation in the placenta, amniotic fluid and
maternal serum [103,104]. The concentration of MIF declines as the
pregnancy progresses, with most significant changes in the late
first trimester [105]. This evidence further supports the roles of MIF
in important cellular functions leading to endometrial receptivity,
successful embryonic implantation and timely placental formation.
As expected, mice treated with MIF were shown to have enhanced
embryo implantation compared to the untreated mice [98]. Like-
wise, intraperitoneal injection of IL-1 receptor antagonist into
pregnant mice few days before implantation was observed to
interfere with embryonic interaction with the endometrial tissue,
thereby causing implantation failure [106]. IL-1 has also been
shown to be involved in the stimulation of several other cytokines
such as TNF-
a
, LIF, IL-6, and IL-8 [90]. IL-1 has been found in human
trophoblast, fallopian tube, and endometrium [107,108], and the
presence of its bioactive ligands (IL-1
a
and IL-1
b
) in human embryo
culture medium has been shown to correlate with the implantation
rates of patients undergoing in vitro fertilization-embryo transfer
[109]. Other molecular mediators involved in the embryo implan-
tation and pregnancy establishment are growth factors, adhesion
molecules, prostaglandins, hormones and lipids [43e45,86].
As pregnancy progresses towards the second trimester, the
profile of cytokines shifts towards less inflammatory/anti-
inflammatory cytokines [43]. Studies have shown that the expres-
sion of anti-inflammatory cytokines such as IL-4 and IL-10 plays an
important role in the resolution of inflammation during pregnancy,
especially at the second trimester [43,110]. Optimally functioning
inflammation resolution system during pregnancy is essentially
required to regulate series of complex processes that could
degenerate into persistent inflammation and hence, complications
during pregnancy. PTB has been associated with the induction of
prostaglandin synthesis before term via excessive production of
pro-inflammatory cytokines like TNF-
a
, IL-6, and IL-1
b
which
triggers pre-term labour [111]. Also, infusion of IL-6 and TNF-
a
has
been shown to produce symptoms of pre-eclampsia in rat [112,113].
However, other studies have associated IL-10 deficiency with the
onset of hypoxia-induced pre-eclampsia features such as protein-
uria, hypertension and renal pathology in mice [114]. As such,
administration of recombinant IL-10 was observed to reverse fea-
tures of pre-eclampsia in IL-10 knock out pregnant mice [114]. IL-10
has been shown to peak on gestation day 12 in mice, which
represent second trimester [115]. Inhibition of IL-10 during preg-
nancy has been shown to result in neonatal growth retardation
[116], while administration of exogenous IL-10 has been shown to
Table 3
Roles of pro-inflammatory cytokines in pregnancy establishment.
Cytokines Production site Roles in implantation Reference(s)
TNF
a
Peri-implantation endometrium Regulates the synthesis and activity of matrix metalloproteinase (MMP-2 and MMP-9) [87 eHuman endometrial
cells, in vitro]
IFN
g
Uterus NK cells and trophoblasts Initiates endometrial vasculature remodelling, angiogenesis at implantation sites, maintenance
of the decidua
[89 eMice]
LIF Stroma cells and endometrial
epithelium
Regulate the adhesion and invasion of uterus by embryo [96 eHuman endometrial
cells, in vitro]
IL-1 Endometrium and blastocyst Stimulate the secretion of other cytokines (IL-6, LIF, and TNF
a
), regulates uterine receptivity,
play important role in embryo implantation and decidualization
[43,44,90,91 eHuman
endometrial cells, in vitro]
IL-6 Embryo and uterus (stroma cells
and endometrial epithelium)
Regulates endometrial function and synthesis of MMP-2 and MMP-6, involved in viability of
implantation sites and decidua formation
[43,44,92 eMice]
IL-15 Decidua and endometrium Involved in implantation and decidualization, regulates the growth of NK cells in the uterus [90,93,94 eMice]
IL-18 Stroma cells and endometrial
epithelium
Regulate the growth of NK cells in the uterus, and stimulate the production of IFN
g
and IL-1
b
[94,95 eHuman
endometrial cells]
MIF Endometrial tissues and decidua Induces the expression of other cytokines (TNF
a
, IFN
g
, IL-1 and IL-6), regulates the synthesis
and activity of MMPs, and reduces the cytolytic activity of purified uNK cells in a dose-
dependent manner
[98,100 eMice]
[99 eHuman decidual
tissue]
IFN
g
: Interferon gamma; IL: Interleukine; MIF: Macrophage Migration Inhibitory Factor; MMP: Matrix metalloproteinase; TNF
a
: Tumor necrosis factor alpha; uNK cells:
Uterine natural killer cells.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e116
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

prevent fetal resorption in pregnant CBA/J DBA/2 mice [117].
Although IL-4 and IL-10 has been suggested not to be involved in
fetal or neonatal survival in mice [118], the roles of anti-
inflammatory cytokines in inflammation resolution during preg-
nancy cannot be overemphasized.
At near term, cytokine profile has been characterized to align
towards increased production of pro-inflammatory cytokines [43].
Pro-inflammatory cytokines have been suggested to play vital roles
in the coordination of several processes leading to labour; these
include cervical ripening, and uterine contraction [43]. The exact
mechanism through which labour is regulated by pro-
inflammatory cytokines is vaguely understood. An increased pro-
duction of major pro-inflammatory cytokines such as TNF
a
, IL-1
b
,
and IL-6 in the uterus has been implicated in the stimulation of
phospholipid metabolism pathways, release of arachidonic acid, as
well as serving as precursors for the production of prostaglandins
which play key role in cervical dilation and myometrial contraction
during labour [119]. Furthermore, IL-1
b
and IL-8 have been found at
increased levels in the myometrium and choriodecidua at last
trimester of pregnancy [120]. Clearly, cytokine balance during
pregnancy is very important for successful pregnancy establish-
ment, and maintenance. As such, dysregulation in pro- and anti-
inflammatory cytokines could result in detrimental pregnancy
outcomes. Plethora of evidence have shown that longer chain n-3
PUFA could alter the production, as well as the activities of pro- and
anti-inflammatory cytokines [121], which may have a profound
effect on pregnancy establishment and outcomes.
5. Omega-3 PUFA and cytokine regulation during pregnancy
Metabolism of n-3 PUFA gives rise to anti-inflammatory mole-
cules [122]. Interestingly, the same group of enzymes are required
for the metabolism of n-3 and n-6 PUFA (Fig. 1), and as such, the
anti-inflammatory properties of n-3 PUFA is partly mediated by
suppressing or inhibiting the downstream production of pro-
inflammatory molecules from n-6 PUFA metabolism [123].An
established mechanism for the anti-inflammatory effect of n-3
PUFA is by inhibiting the production of nuclear factor-kappaB (NF-
k
B), which is a transcription factor for a number of pro-
inflammatory cytokines such as TNF-
a
, and IL [122]. Likewise, it
has been shown that n-3 PUFA could directly reduce the gene
expression of IL-6, and IL-1
b
[124]. Studies have shown that sup-
plementing maternal diet with n-3 PUFA (2 g EPA þDHA per day)
results in significant reduction in the production of IL-1, IL-6, and
TNF-
a
by mononuclear cells [125]. Also, fish oil feeding reduces
ex vivo production of IL-1
b
, IL-6, and TNF-
a
by macrophages in
rodents [126]. Similar results were also obtained in cell culture
studies as EPA and DHA was observed to supress the production of
pro-inflammatory cytokines by macrophages and endothelial cells
[127,128]. However, DHA has been shown to be more effective than
EPA in reducing plasma TNF-
a
concentrations, 35% and 20% for DHA
and EPA respectively [129].
As explained earlier, the complexity of pregnancy establish-
ment, maintenance and labour is exemplified by a number of cy-
tokines and other factors playing specific roles in this process as the
pregnancy progresses [43,84]. As such, n-3 PUFA as a potent pre-
cursor for inflammation resolving biomolecules may be influencing
gestation length by disturbing the normal expression and activities
of pro-inflammatory cytokines that are required at different stages
of pregnancy as depicted in Fig. 3. However, there are no studies to
date to show the effect of n-3 PUFA at each stage of pregnancy on
the outcome of pregnancy establishment and outcome. Consuming
high amounts of n-3 PUFA prior to embryo implantation may
downregulate the expression, and the activities of key pro-
inflammatory cytokines [130], such as IL-1, IL-6, MIF, LIF, and
TNF-
a
that play key regulatory roles in the receptivity of the
endometrium, as well as the apposition, adhesion and invasion of
the uterine wall by the blastocyst. This may result in the elongation
of time required for pregnancy establishment. Thus, understanding
the effect of n-3 PUFA at this stage of pregnancy may provide
additional plausible insight into the mechanism/s through which n-
3 PUFA elongates gestation length.
Available data only suggest that n-3 PUFA prolongs pregnancy
duration by suppressing the synthesis of prostaglandins required
for the induction of labour. The effects of prolonged gestation on
both maternal and fetal health has been well documented
[131e133]. From a paediatric perspective, increased gestational
period and birth weight could be viewed as a positive outcome.
However, prolonged gestation is a predisposing factor for a number
of obstetrical complications [132]. Maternal peri-partum compli-
cations has been shown to increase as pregnancy progresses
beyond 40 weeks of gestation [133]. The risk of perinatal death also
increases from 39th week of pregnancy with a more dramatic in-
crease after week 40 of pregnancy [131]. Major reason for increased
risk of perinatal death in post-term pregnancy has been attributed
to reduced placental function [41]. Thus, prolonged pregnancy is a
major challenge in obstetrics as it is difficult to know when to
induce labour [134]. It is also challenging to distinguish between
those that will respond to labour induction and those that require
caesarean section [134]. More so, high infant weight at birth as a
consequence of prolonged gestation has been linked to childhood
obesity, as well as several metabolic and cardiovascular disorders in
the offspring. Higher birth weight was associated with higher risk
of child obesity (a risk of cardivascular diseases) in Australia in boys
and girls before and after adjusting for several socio-demographic
factors [37]. Likewise, it has been shown that metabolic syn-
drome was more prevalent in children born with larger birth
weight, thereby suggesting that hypertension and hyper-
triglyceridemia as better components for diagonising metabolic
syndrome in obese children [135]. As such, it is highly pertinent to
determine the dose of n-3 PUFA at different stages of pregnancy to
prevent detrimental pregnancy outcomes.
6. Conclusions
Supplementation of maternal diet with n-3 PUFA has been
shown to have a positive effect on fetal brain development and
reduction in the recurrence of PTB, especially in women with his-
tory of pre-term or low baseline n-3 PUFA intake (high risk popu-
lation). However, supplementation of maternal diet with high n-3
PUFA has been linked to prolonged gestation length and conse-
quently, high infant birth weight. The variation in gestation length
and birth weight of infants in mothers supplemented with n-3
PUFA during pregnancy can be attributed to dosage of the n-3
enriched diet as well as the timing and duration of intervention
during pregnancy. Plethora of adverse pregnancy outcomes
relating to maternal and perinatal health have been associated with
prolonged gestation. Increased birth weights also have prognostic
potential for development of diseases at adult life. Most n-3 PUFA
intervention studies started at the second trimester of pregnancy,
thus the available data can only suggest that n-3 PUFA prolong
pregnancy by influencing the production of prostaglandins
involved in labour induction. There is paucity of evidence on the
effects of different dosage of n-3 and n-6 PUFA on the profiles of
local cytokines in the uterus at embryo reception, and pregnancy
establishment. Although a recent prospective, observational study
of human pregnancy by Meyer et al. [61] highlights the effect of
metabolic response in women undergoing frozen embryo transfer
at early pregnancy, more evidence is required to establish the
precise function of n-3 and n-6 PUFA at different stages of
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e11 7
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

pregnancy with respect to pregnancy duration and birth di-
mensions. This review concludes that investigating the effect of
feeding different amount of n-3 and n-6 PUFA diet in animal model
on the local profiles (gene and protein expression) of inflammatory
cytokines in the uterine milieu at different stages of pregnancy may
provide a better insight unto the mechanism/s through which n-3
PUFA modifies gestation length and consequently, the weight of
infants at birth.
References
[1] Handbook of Diet and Nutrition in the Menstrual Cycle. Periconception and
Fertility. Wageningen Academic Publishers; 2014.
[2] Grieger JA, Clifton VL. A review of the impact of dietary intakes in human
pregnancy on infant birthweight. Nutrients 2015;7:153e78. http://
dx.doi.org/10.3390/nu7010153.
[3] Laker RC, Wlodek ME, Connelly JJ, Yan Z. Epigenetic origins of metabolic
disease: The impact of the maternal condition to the offspring epigenome
and later health consequences. Food Sci. Hum. Wellness 2013;2:1e11. http://
dx.doi.org/10.1016/j.fshw.2013.03.002.
[4] Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy
and death from ischaemic heart disease. Lancet 1989;2:577e80. http://
dx.doi.org/10.1016/S0140-6736(89)91939-9.
[5] Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA. Relation
of size at birth to non-insulin dependent diabetes and insulin concentrations
in men aged 50-60 years. BMJ 1996;312:406e10.
[6] Perera F, Herbstman J. Prenatal environmental exposures, epigenetics, and
disease. Reprod. Toxicol. 2011;31:363e73. http://dx.doi.org/10.1016/
j.reprotox.2010.12.055.
[7] Schwab U, Lauritzen L, Tholstrup T, Haldorssoni T, Riserus U, Uusitupa M,
et al. Effect of the amount and type of dietary fat on cardiometabolic risk
factors and risk of developing type 2 diabetes, cardiovascular diseases, and
cancer: a systematic review. Food Nutr. Res. 2014;58. http://dx.doi.org/
10.3402/fnr.v58.25145.
[8] Coletta JM, Bell SJ, Roman AS. Omega-3 fatty acids and pregnancy. Rev.
Obstet. Gynecol. 2010;3:163e71. http://dx.doi.org/10.3909/riog0137.
[9] Abedi E, Sahari MA. Long-chain polyunsaturated fatty acid sources and
evaluation of their nutritional and functional properties. Food Sci. Nutr.
2014;2:443e63. http://dx.doi.org/10.1002/fsn3.121.
[10] Birch EE, Garfield S, Casta~
neda Y, Hughbanks-Wheaton D, Uauy R,
Hoffman D. Visual acuity and cognitive outcomes at 4 years of age in a
double-blind, randomized trial of long-chain polyunsaturated fatty acid-
supplemented infant formula. Early Hum. Dev. 2007;83:279e84. http://
dx.doi.org/10.1016/j.earlhumdev.2006.11.003.
[11] Singh M. Essential fatty acids, DHA and human brain. Indian J. Pediatr.
2005;72:239e42.
[12] Uauy R, Birch E, Birch D, Peirano P. Visual and brain function measurements
in studies of n-3 fatty acid requirements of infants. J. Pediatr. 1992;120:
S168e80.
[13] Denomme J, Stark KD, Holub BJ. Directly quantitated dietary (n-3) fatty acid
intakes of pregnant Canadian women are lower than current dietary rec-
ommendations. J. Nutr. 2005;135:206e11.
[14] G
omez Candela C, Bermejo L
opez LM, Loria Kohen V. Importance of a
balanced omega 6/omega 3 ratio for the maintenance of health. Nutritional
recommendations. Nutr. Hosp. 2011;26:323e9. http://dx.doi.org/10.3305/
nh.2011.26.2.5117.
[15] Simopoulos AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and
genetic variation: nutritional implications for chronic diseases. Biomed.
Pharmacother. 2006;60:502e7. http://dx.doi.org/10.1016/
j.biopha.2006.07.080.
[16] Mozaffarian D, Wu JHY. Omega-3 fatty acids and cardiovascular disease:
effects on risk factors, molecular pathways, and clinical events. J. Am. Coll.
Cardiol. 2011;58:2047e67. http://dx.doi.org/10.1016/j.jacc.2011.06.063.
[17] Mori TA. Dietary n-3 PUFA and CVD: a review of the evidence. Proc. Nutr.
Soc. 2014;73:57e64. http://dx.doi.org/10.1017/S0029665113003583.
[18] Calder PC. Polyunsaturated fatty acids and inflammatory processes: new
twists in an old tale. Biochimie 2009;91:791e5. http://dx.doi.org/10.1016/
j.biochi.2009.01.008.
[19] Cheatham CL, Colombo J, Carlson SE. n-3 Fatty acids and cognitive and visual
acuity development: methodologic and conceptual considerations. Am. J.
Clin. Nutr. 2006;83:S1458e66.
Fig. 3. Possible effects of omega-3 PUFA on pregnancy establishment and outcomes. DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; IFN-
g
: Interferon gamma; IL:
Interleukin; LIF: Leukaemia inhibition factor; PUFA: Polyunsaturated fatty acids; TNF-
a
: Tumor necrosis factor alpha.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e118
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

[20] Horvath A, Koletzko B, Szajewska H. Effect of supplementation of women in
high-risk pregnancies with long-chain polyunsaturated fatty acids on preg-
nancy outcomes and growth measures at birth: a meta-analysis of ran-
domized controlled trials. Br. J. Nutr. 2007;98:253e9. http://dx.doi.org/
10.1017/S0007114507709078.
[21] Olsen SF, Secher NJ. Low consumption of seafood in early pregnancy as a risk
factor for preterm delivery: prospective cohort study. BMJ 2002;324:447.
[22] Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin precursor,
supplementation for pregnancy uncomplicated by pre-eclampsia or intra-
uterine growth restriction. Cochrane Database Syst. Rev. 2006:CD003402.
http://dx.doi.org/10.1002/14651858.CD003402.pub2.
[23] De Giuseppe R, Roggi C, Cena H. n-3 LC-PUFA supplementation: effects on
infant and maternal outcomes. Eur. J. Nutr. 2014;53:1147e54. http://
dx.doi.org/10.1007/s00394-014-0660-9.
[24] Olsen SF, Hansen HS, Sørensen TI, Jensen B, Secher NJ, Sommer S, et al. Intake
of marine fat, rich in (n-3)-polyunsaturated fatty acids, may increase birth-
weight by prolonging gestation. Lancet Lond. Engl. 1986;2:367e9.
[25] Olsen SF, Sørensen JD, Secher NJ, Hedegaard M, Henriksen TB, Hansen HS,
et al. Randomised controlled trial of effect of fish-oil supplementation on
pregnancy duration. Lancet Lond. Engl. 1992;339:1003e7.
[26] Olsen SF, Søorensen JD, Secher NJ, Hedegaard M, Henriksen TB, Hansen HS,
et al. Fish oil supplementation and duration of pregnancy. A randomized
controlled trial. Ugeskr. Laeger 1994;156:1302e7.
[27] Olsen SF, Secher NJ, Tabor A, Weber T, Walker JJ, Gluud C. Randomised
clinical trials of fish oil supplementation in high risk pregnancies. Fish oil
trials in pregnancy (FOTIP) team. BJOG 2000;107:382e95.
[28] Szajewska H, Horvath A, Koletzko B. Effect of n-3 long-chain polyunsaturated
fatty acid supplementation of women with low-risk pregnancies on preg-
nancy outcomes and growth measures at birth: a meta-analysis of ran-
domized controlled trials. Am. J. Clin. Nutr. 2006;83:1337e44.
[29] Jacobson JL, Jacobson SW, Muckle G, Kaplan-Estrin M, Ayotte P, Dewailly E.
Beneficial effects of a polyunsaturated fatty acid on infant development:
evidence from the inuit of arctic Quebec. J. Pediatr. 2008;152:356e64. http://
dx.doi.org/10.1016/j.jpeds.2007.07.008.
[30] Carlson SE, Colombo J, Gajewski BJ, Gustafson KM, Mundy D, Yeast J, et al.
DHA supplementation and pregnancy outcomes. Am. J. Clin. Nutr. 2013;97:
808e15. http://dx.doi.org/10.3945/ajcn.112.050021.
[31] Dirix CEH, Kester AD, Hornstra G. Associations between neonatal birth di-
mensions and maternal essential and trans fatty acid contents during
pregnancy and at delivery. Br. J. Nutr. 2009;101:399e407. http://dx.doi.org/
10.1017/S0007114508006740.
[32] Muthayya S, Dwarkanath P, Thomas T, Ramprakash S, Mehra R, Mhaskar A,
et al. The effect of fish and omega-3 LCPUFA intake on low birth weight in
Indian pregnant women. Eur. J. Clin. Nutr. 2009;63:340e6. http://dx.doi.org/
10.1038/sj.ejcn.1602933.
[33] Ramakrishnan U, Stein AD, Parra-Cabrera S, Wang M, Imhoff-Kunsch B,
Ju
arez-M
arquez S, et al. Effects of docosahexaenoic acid supplementation
during pregnancy on gestational age and size at birth: randomized, double-
blind, placebo-controlled trial in Mexico. Food Nutr. Bull. 2010;31:S108e16.
[34] Smuts CM, Huang M, Mundy D, Plasse T, Major S, Carlson SE. A randomized
trial of docosahexaenoic acid supplementation during the third trimester of
pregnancy. Obstet. Gynecol. 2003;101:469e79. http://dx.doi.org/10.1016/
S0029-7844(02)02585-1.
[35] Imhoff-Kunsch B. WHOjMarine Oil Supplementation in Pregnancy and
Maternal and Neonatal Health Outcomes. 2011. http://www.who.int/elena/
titles/commentary/fish_oil_pregnancy/en/.
[36] Fuchs F, Bouyer J, Rozenberg P, Senat M-V. Adverse maternal outcomes
associated with fetal macrosomia: what are the risk factors beyond birth-
weight? BMC Pregnancy Childbirth 2013;13:90. http://dx.doi.org/10.1186/
1471-2393-13-90.
[37] Oldroyd J, Renzaho A, Skouteris H. Low and high birth weight as risk factors
for obesity among 4 to 5-year-old Australian children: does gender matter?
Eur. J. Pediatr. 2011;170:899e906. http://dx.doi.org/10.1007/s00431-010-
1375-4.
[38] Wei J-N, Sung F-C, Li C-Y, Chang C-H, Lin R-S, Lin C-C, et al. Low birth weight
and high birth weight infants are both at an increased risk to have type 2
diabetes among schoolchildren in taiwan. Diabetes Care 2003;26:343e8.
[39] Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood:
association with birth weight, maternal obesity, and gestational diabetes
mellitus. Pediatrics 2005;115:e290e6. http://dx.doi.org/10.1542/peds.2004-
1808.
[40] ACOG. ACOG practice patterns. Management of postterm pregnancy. Num-
ber 6, October 1997. American College of Obstetricians and Gynecologists.
Int. J. Gynaecol. Obstet. 1998;60:86e91.
[41] Vorherr H. Placental insufficiency in relation to postterm pregnancy and fetal
postmaturity. Evaluation of fetoplacental function; management of the
postterm gravida. Am. J. Obstet. Gynecol. 1975;123:67e103.
[42] Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine in-
teractions in the maternal-fetal relationship: is successful pregnancy a TH2
phenomenon? Immunol. Today 1993;14:353e6. http://dx.doi.org/10.1016/
0167-5699(93)90235-D.
[43] Paulesu L, Bhattacharjee J, Bechi N, Romagnoli R, Jantra S, Ietta F. Pro-in-
flammatory cytokines in animal and human gestation. Curr. Pharm. Des.
2010;16:3601e15.
[44] Dimitriadis E, White CA, Jones RL, Salamonsen LA. Cytokines, chemokines
and growth factors in endometrium related to implantation. Hum. Reprod.
Update 2005;11:613e30. http://dx.doi.org/10.1093/humupd/dmi023.
[45] Singh M, Chaudhry P, Asselin E. Bridging endometrial receptivity and im-
plantation: network of hormones, cytokines, and growth factors.
J. Endocrinol. 2011;210:5e14. http://dx.doi.org/10.1530/JOE-10-0461.
[46] Mendelson CR. Minireview: fetal-maternal hormonal signaling in pregnancy
and labor. Mol. Endocrinol. 2009;23:947e54. http://dx.doi.org/10.1210/
me.2009-0016.
[47] Bell SJ, Bradley D, Forse RA, Bistrian BR. The new dietary fats in health and
disease. J. Am. Diet. Assoc. 1997;97. http://dx.doi.org/10.1016/S0002-
8223(97)00072-2. 280e6; quiz 287e8.
[48] Leonard AE, Pereira SL, Sprecher H, Huang Y-S. Elongation of long-chain fatty
acids. Prog. Lipid Res. 2004;43:36e54.
[49] Burdge GC, Wootton SA. Conversion of alpha-linolenic acid to eicosa-
pentaenoic, docosapentaenoic and docosahexaenoic acids in young women.
Br. J. Nutr. 2002;88:411e20. http://dx.doi.org/10.1079/BJN2002689.
[50] Burdge GC, Calder PC. Conversion of alpha-linolenic acid to longer-chain
polyunsaturated fatty acids in human adults. Reprod. Nutr. Dev. 2005;45:
581e97. http://dx.doi.org/10.1051/rnd:2005047.
[51] Chang C-Y, Ke D-S, Chen J-Y. Essential fatty acids and human brain. Acta
Neurol. Taiwan 2009;18:231e41.
[52] O'Brien JS, Fillerup DL, Mead JF. Quantification and fatty acid and fatty
aldehyde composition of ethanolamine, choline, and serine glycer-
ophosphatides in human cerebral grey and white matter. J. Lipid Res. 1964;5:
329e38.
[53] Makrides M, Neumann MA, Byard RW, Simmer K, Gibson RA. Fatty acid
composition of brain, retina, and erythrocytes in breast- and formula-fed
infants. Am. J. Clin. Nutr. 1994;60:189e94.
[54] Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Intra-
uterine fatty acid accretion rates in human brain: implications for fatty acid
requirements. Early Hum. Dev. 1980;4:121e9.
[55] Martínez M, Mougan I. Fatty acid composition of human brain phospholipids
during normal development. J. Neurochem. 1998;71:2528e33.
[56] Innis SM. Essential fatty acid transfer and fetal development. Placenta
2005;26(Suppl. A):S70e5. http://dx.doi.org/10.1016/j.placenta.2005.01.005.
[57] Montgomery C, Speake BK, Cameron A, Sattar N, Weaver LT. Maternal do-
cosahexaenoic acid supplementation and fetal accretion. Br. J. Nutr. 2003;90:
135e45.
[58] Catalan J, Moriguchi T, Slotnick B, Murthy M, Greiner RS, Salem N. Cognitive
deficits in docosahexaenoic acid-deficient rats. Behav. Neurosci. 2002;116:
1022e31.
[59] Nesheim MC, Yaktine AL. Seafood Choices: Balancing Benefits and Risks. Natl
Acad Press; 2007. p. 1e736.
[60] Chambaz J, Ravel D, Manier MC, Pepin D, Mulliez N, Bereziat G. Essential fatty
acids interconversion in the human fetal liver. Biol. Neonate 1985;47:
136e40.
[61] Meyer BJ, Onyiaodike CC, Brown EA, Jordan F, Murray H, Nibbs RJB, et al.
Maternal plasma DHA levels increase prior to 29 days post-LH surge in
women undergoing frozen embryo transfer: a prospective, observational
study of human pregnancy. J. Clin. Endocrinol. Metab. 2016;101:1745e53.
http://dx.doi.org/10.1210/jc.2015-3089.
[62] Duttaroy AK. Transport of fatty acids across the human placenta: a review.
Prog. Lipid Res. 2009;48:52e61. http://dx.doi.org/10.1016/
j.plipres.2008.11.001.
[63] Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the
normal human placenta. Thromb. Res. 2004;114:397e407. http://dx.doi.org/
10.1016/j.thromres.2004.06.038.
[64] Xu Y, Cook TJ, Knipp GT. Methods for investigating placental fatty acid
transport. Methods Mol. Med. 2006;122:265e84.
[65] Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus
and newborn. Endocrine 2002;19:43e55. http://dx.doi.org/10.1385/ENDO:
19:1:43.
[66] Waterman IJ, Emmison N, Dutta-Roy AK. Characterisation of triacylglycerol
hydrolase activities in human placenta. Biochim. Biophys. Acta 1998;1394:
169e76.
[67] Elliott J a. The effect of pregnancy on the control of lipolysis in fat cells
isolated from human adipose tissue. Eur. J. Clin. Investig. 1975;5:159e63.
[68] Morgan TK. Placental insufficiency is a leading cause of preterm labor.
Neoreviews 2014;15:e518e25. http://dx.doi.org/10.1542/neo.15-12-e518.
[69] Callaghan WM, MacDorman MF, Rasmussen SA, Qin C, Lackritz EM. The
contribution of preterm birth to infant mortality rates in the United States.
Pediatrics 2006;118:1566e73. http://dx.doi.org/10.1542/peds.2006-0860.
[70] Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and
developmental disability after extremely preterm birth. EPICure study group.
N. Engl. J. Med. 2000;343:378e84. http://dx.doi.org/10.1056/
NEJM200008103430601.
[71] Johnston KM, Gooch K, Korol E, Vo P, Eyawo O, Bradt P, et al. The economic
burden of prematurity in Canada. BMC Pediatr. 2014;14:93. http://
dx.doi.org/10.1186/1471-2431-14-93.
[72] WHOjPreterm birth. http://www.who.int/mediacentre/factsheets/fs363/en/
n.d.
[73] Olsen SF, Joensen HD. High liveborn birth weights in the Faroes: a com-
parison between birth weights in the Faroes and in Denmark. J. Epidemiol.
Community Health 1985;39:27e32.
[74] Harris MA, Reece MS, McGregor JA, Wilson JW, Burke SM, Wheeler M, et al.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e11 9
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

The effect of omega-3 docosahexaenoic acid supplementation on gestational
length: randomized trial of supplementation compared to nutrition educa-
tion for increasing n-3 intake from foods. Biomed. Res. Int. 2015. http://
dx.doi.org/10.1155/2015/123078.
[75] Olsen SF, Secher NJ. A possible preventive effect of low-dose fish oil on early
delivery and pre-eclampsia: indications from a 50-year-old controlled trial.
Br. J. Nutr. 1990;64:599e609. http://dx.doi.org/10.1079/BJN19900063.
[76] Olsen SF, Østerdal ML, Salvig JD, Weber T, Tabor A, Secher NJ. Duration of
pregnancy in relation to fish oil supplementation and habitual fish intake: a
randomised clinical trial with fish oil. Eur. J. Clin. Nutr. 2007;61:976e85.
http://dx.doi.org/10.1038/sj.ejcn.1602609.
[77] Swanson D, Block R, Mousa SA. Omega-3 fatty acids EPA and DHA: health
benefits throughout life. Adv. Nutr. Int. Rev. J. 2012;3:1e7. http://dx.doi.org/
10.3945/an.111.000893.
[78] Olsen SF, Hansen HS, Sommer S, Jensen B, Sørensen TI, Secher NJ, et al.
Gestational age in relation to marine n-3 fatty acids in maternal erythro-
cytes: a study of women in the Faroe Islands and Denmark. Am. J. Obstet.
Gynecol. 1991;164:1203e9.
[79] Grandjean P, Bjerve KS, Weihe P, Steuerwald U. Birthweight in a fishing
community: significance of essential fatty acids and marine food contami-
nants. Int. J. Epidemiol. 2001;30:1272e8. http://dx.doi.org/10.1093/ije/
30.6.1272.
[80] Guldner L, Monfort C, Rouget F, Garlantezec R, Cordier S. Maternal fish and
shellfish intake and pregnancy outcomes: a prospective cohort study in
Brittany, France. Environ. Health 2007;6:33. http://dx.doi.org/10.1186/1476-
069X-6-33.
[81] Malcolm CA, McCulloch DL, Montgomery C, Shepherd A, Weaver LT.
Maternal docosahexaenoic acid supplementation during pregnancy and vi-
sual evoked potential development in term infants: a double blind, pro-
spective, randomised trial. Arch. Dis. Child. Fetal Neonatal Ed. 2003;88:
F383e90.
[82] Onwude JL, Lilford RJ, Hjartardottir H, Staines A, Tuffnell D. A randomised
double blind placebo controlled trial of fish oil in high risk pregnancy. Br. J.
Obstet. Gynaecol. 1995;102:95e100.
[83] Helland IB, Saugstad OD, Smith L, Saarem K, Solvoll K, Ganes T, et al. Similar
effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and
lactating women. Pediatrics 2001;108:E82. http://dx.doi.org/10.1542/
peds.108.5.e82.
[84] Jones ML, Mark PJ, Waddell BJ. Maternal dietary omega-3 fatty acids and
placental function. Reproduction 2014;147:R143e52. http://dx.doi.org/
10.1530/REP-13-0376.
[85] Kelly RW. Inflammatory mediators and cervical ripening. J. Reprod. Immunol.
2002;57:217e24.
[86] Sim
on C, Martín JC, Pellicer A. Paracrine regulators of implantation. Bailliere's
Best. Pract. Res. Clin. Obstet. Gynaecol. 2000;14:815e26. http://dx.doi.org/
10.1053/beog.2000.0121.
[87] Meisser A, Chardonnens D, Campana A, Bischof P. Effects of tumour necrosis
factor-alpha, interleukin-1 alpha, macrophage colony stimulating factor and
transforming growth factor beta on trophoblastic matrix metalloproteinases.
Mol. Hum. Reprod. 1999;5:252e60.
[88] Cohen M, Meisser A, Haenggeli L, Bischof P. Involvement of MAPK pathway
in TNF-alpha-induced MMP-9 expression in human trophoblastic cells. Mol.
Hum. Reprod. 2006;12:225e32. http://dx.doi.org/10.1093/molehr/gal023.
[89] Ashkar AA, Di Santo JP, Croy BA. Interferon gamma contributes to initiation
of uterine vascular modification, decidual integrity, and uterine natural killer
cell maturation during normal murine pregnancy. J. Exp. Med. 2000;192:
259e70.
[90] Minas V, Loutradis D, Makrigiannakis A. Factors controlling blastocyst im-
plantation. Reprod. Biomed. Online 2005;10:205e16. http://dx.doi.org/
10.1016/S1472-6483(10)60942-X.
[91] Gonzalez RR, Rueda BR, Ramos MP, Littell RD, Glasser S, Leavis PC. Leptin-
induced increase in leukemia inhibitory factor and its receptor by human
endometrium is partially mediated by interleukin 1 receptor signaling.
Endocrinology 2004;145:3850e7. http://dx.doi.org/10.1210/en.2004-0383.
[92] Robertson SA, Christiaens I, Dorian CL, Zaragoza DB, Care AS, Banks AM, et al.
Interleukin-6 is an essential determinant of on-time parturition in the
mouse. Endocrinology 2010;151:3996e4006. http://dx.doi.org/10.1210/
en.2010-0063.
[93] Zourbas S, Dubanchet S, Martal J, Chaouat G. Localization of pro-
inflammatory (IL-12, IL-15) and anti-inflammatory (IL-11, IL-13) cytokines
at the foetomaternal interface during murine pregnancy. Clin. Exp. Immunol.
2001;126:519e28. http://dx.doi.org/10.1046/j.1365-2249.2001.01607.x.
[94] Laskarin G, Strbo N, Bogovic Crncic T, Juretic K, Ledee Bataille N, Chaouat G,
et al. Physiological role of IL-15 and IL-18 at the maternal-fetal interface.
Chem. Immunol. Allergy 2005;89:10e25. http://dx.doi.org/10.1159/
000087906.
[95] L
ed
ee N, Dubanchet S, Lombroso R, Ville Y, Chaouat G. Downregulation of
human endometrial IL-18 by exogenous ovarian steroids. Am. J. Reprod.
Immunol. 2006;56:119e23. http://dx.doi.org/10.1111/j.1600-
0897.2006.00401.x.
[96] Nakajima S, Tanaka T, Umesaki N, Ishiko O. Leukemia inhibitory factor reg-
ulates cell survival of normal human endometrial stromal cells. Int. J. Mol.
Med. 2003;11:353e6.
[97] Murphy SP, Tayade C, Ashkar AA, Hatta K, Zhang J, Croy BA. Interferon
gamma in successful pregnancies. Biol. Reprod. 2009;80:848e59. http://
dx.doi.org/10.1095/biolreprod.108.073353.
[98] Bondza PK, Metz CN, Akoum A. Postgestational effects of macrophage
migration inhibitory factor on embryonic implantation in mice. Fertil. Steril.
2008;90:1433e43. http://dx.doi.org/10.1016/j.fertnstert.2007.08.046.
[99] Arcuri F, Cintorino M, Carducci A, Papa S, Riparbelli MG, Mangioni S, et al.
Human decidual natural killer cells as a source and target of macrophage
migration inhibitory factor. Reproduction 2006;131:175e82. http://
dx.doi.org/10.1530/rep.1.00857.
[100] Suzuki H, Kanagawa H, Nishihira J. Evidence for the presence of macrophage
migration inhibitory factor in murine reproductive organs and early em-
bryos. Immunol. Lett. 1996;51:141e7.
[101] Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, K€
ontgen F, et al. Blastocyst
implantation depends on maternal expression of leukaemia inhibitory factor.
Nature 1992;359:76e9. http://dx.doi.org/10.1038/359076a0.
[102] Stavitsky A.B, Xianli J. In vitro and in vivo regulation by macrophage
migration inhibitory factor (MIF) of expression of MHC-II, costimulatory,
adhesion, receptor, and cytokine molecules. Cell Immunol. 217:95e104.
[103] Zeng FY, Weiser WY, Kratzin H, Stahl B, Karas M, Gabius HJ. The major
binding protein of the interferon antagonist sarcolectin in human placenta is
a macrophage migration inhibitory factor. Arch. Biochem. Biophys.
1993;303:74e80. http://dx.doi.org/10.1006/abbi.1993.1257.
[104] Ietta F, Todros T, Ticconi C, Piccoli E, Zicari A, Piccione E, et al. Macrophage
migration inhibitory factor in human pregnancy and labor. Am. J. Reprod.
Immunol. 2002;48:404e9.
[105] Ietta F, Wu Y, Romagnoli R, Soleymanlou N, Orsini B, Zamudio S, et al. Ox-
ygen regulation of macrophage migration inhibitory factor in human
placenta. Am. J. Physiol. Endocrinol. Metab. 2007;292:E272e80. http://
dx.doi.org/10.1152/ajpendo.00086.2006.
[106] Sim
on C, Valbuena D, Krüssel J, Bernal A, Murphy CR, Shaw T, et al. Inter-
leukin-1 receptor antagonist prevents embryonic implantation by a direct
effect on the endometrial epithelium. Fertil. Steril. 1998;70:896e906.
[107] Tabibzadeh S, Sun XZ. Cytokine expression in human endometrium
throughout the menstrual cycle. Hum. Reprod. 1992;7:1214e21.
[108] Krüssel JS, Sim
on C, Rubio MC, Pape AR, Wen Y, Huang HY, et al. Expression
of interleukin-1 system mRNA in single blastomeres from human preim-
plantation embryos. Hum. Reprod. 1998;13:2206e11.
[109] Karagouni EE, Chryssikopoulos A, Mantzavinos T, Kanakas N, Dotsika EN.
Interleukin-1beta and interleukin-1alpha may affect the implantation rate of
patients undergoing in vitro fertilization-embryo transfer. Fertil. Steril.
1998;70:553e9.
[110] Chatterjee P, Chiasson VL, Bounds KR, Mitchell BM. Regulation of the anti-
inflammatory cytokines interleukin-4 and interleukin-10 during preg-
nancy. Front. Immunol. 2014;5:253. http://dx.doi.org/10.3389/
fimmu.2014.00253.
[111] Keelan JA, Blumenstein M, Helliwell RJA, Sato TA, Marvin KW, Mitchell MD.
Cytokines, prostaglandins and parturition ea review. Placenta 2003;24:2e6.
http://dx.doi.org/10.1053/plac.2002.0948.
[112] Lamarca B, Speed J, Ray LF, Cockrell K, Wallukat G, Dechend R, et al. Hy-
pertension in response to IL-6 during pregnancy: role of AT1-receptor acti-
vation. Int. J. Infereron Cytokine Mediat. Res. 2011;2011:65e70. http://
dx.doi.org/10.2147/IJICMR.S22329.
[113] LaMarca BBD, Bennett WA, Alexander BT, Cockrell K, Granger JP. Hyperten-
sion produced by reductions in uterine perfusion in the pregnant rat: role of
tumor necrosis factor-alpha. Hypertension 2005;46:1022e5. http://
dx.doi.org/10.1161/01.HYP.0000175476.26719.36.
[114] Lai Z, Kalkunte S, Sharma S. A critical role of interleukin-10 in modulating
hypoxia-induced preeclampsia-like disease in mice. Hypertension 2011;57:
505e14. http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.163329.
[115] Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG. Synthesis of T
helper 2-type cytokines at the maternal-fetal interface. J. Immunol.
1993;151:4562e73.
[116] Rijhsinghani AG, Thompson K, Tygrette L, Bhatia SK. Inhibition of
interleukin-10 during pregnancy results in neonatal growth retardation. Am.
J. Reprod. Immunol. 1997;37:232e5.
[117] Chaouat G, Assal Meliani A, Martal J, Raghupathy R, Elliott JF, Elliot J, et al. IL-
10 prevents naturally occurring fetal loss in the CBA x DBA/2 mating com-
bination, and local defect in IL-10 production in this abortion-prone com-
bination is corrected by in vivo injection of IFN-tau. J. Immunol. 1995;154:
4261e8.
[118] Svensson L, Arvola M, S€
allstr€
om MA, Holmdahl R, Mattsson R. The Th2 cy-
tokines IL-4 and IL-10 are not crucial for the completion of allogeneic
pregnancy in mice. J. Reprod. Immunol. 2001;51:3e7.
[119] Moln
ar M, Romero R, Hertelendy F. Interleukin-1 and tumor necrosis factor
stimulate arachidonic acid release and phospholipid metabolism in human
myometrial cells. Am. J. Obstet. Gynecol. 1993;169:825e9.
[120] Elliott CL, Loudon JA, Brown N, Slater DM, Bennett PR, Sullivan MH. IL-1beta
and IL-8 in human fetal membranes: changes with gestational age, labor, and
culture conditions. Am. J. Reprod. Immunol. 2001;46:260e7.
[121] Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune dis-
eases. J. Am. Coll. Nutr. 2002;21:495e505.
[122] Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory pro-
cesses: nutrition or pharmacology? Br. J. Clin. Pharmacol. 2013;75:645e62.
http://dx.doi.org/10.1111/j.1365-2125.2012.04374.x.
[123] Schmitz G, Ecker J. The opposing effects of n-3 and n-6 fatty acids. Prog. Lipid
Res. 2008;47:147e55. http://dx.doi.org/10.1016/j.plipres.2007.12.004.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e1110
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008

[124] Yamashita A, Kawana K, Tomio K, Taguchi A, Isobe Y, Iwamoto R, et al.
Increased tissue levels of omega-3 polyunsaturated fatty acids prevents
pathological preterm birth. Sci. Rep. 2013;3:3113. http://dx.doi.org/10.1038/
srep03113.
[125] Trebble T, Arden NK, Stroud MA, Wootton SA, Burdge GC, Miles EA, et al.
Inhibition of tumour necrosis factor-alpha and interleukin 6 production by
mononuclear cells following dietary fish-oil supplementation in healthy men
and response to antioxidant co-supplementation. Br. J. Nutr. 2003;90:
405e12.
[126] Renier G, Skamene E, DeSanctis J, Radzioch D. Dietary n-3 polyunsaturated
fatty acids prevent the development of atherosclerotic lesions in mice.
Modulation of macrophage secretory activities. Arterioscler. Thromb.
1993;13:1515e24.
[127] Lo CJ, Chiu KC, Fu M, Lo R, Helton S. Fish oil decreases macrophage tumor
necrosis factor gene transcription by altering the NF kappa B activity. J. Surg.
Res. 1999;82:216e21. http://dx.doi.org/10.1006/jsre.1998.5524.
[128] Khalfoun B, Thibault F, Watier H, Bardos P, Lebranchu Y. Docosahexaenoic
and eicosapentaenoic acids inhibit in vitro human endothelial cell produc-
tion of interleukin-6. Adv. Exp. Med. Biol. 1997;400B:589e97.
[129] Mori TA, Woodman RJ, Burke V, Puddey IB, Croft KD, Beilin LJ. Effect of
eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and
inflammatory markers in treated-hypertensive type 2 diabetic subjects. Free
Radic. Biol. Med. 2003;35:772e81.
[130] Zhan ZP, Huang FR, Luo J, Dai JJ, Yan XH, Peng J. Duration of feeding linseed
diet influences expression of inflammation-related genes and growth per-
formance of growing-finishing barrows. J. Anim. Sci. 2009;87:603e11.
http://dx.doi.org/10.2527/jas.2007-0177.
[131] Hilder L, Costeloe K, Thilaganathan B. Prolonged pregnancy: evaluating
gestation-specific risks of fetal and infant mortality. Br. J. Obstet. Gynaecol.
1998;105:169e73. http://dx.doi.org/10.1111/j.1471-0528.1998.tb10047.x.
[132] Olesen AW, Westergaard JG, Olsen J. Perinatal and maternal complications
related to postterm delivery: A national register-based study, 1978-1993.
Am. J. Obstet. Gynecol. 2003;189:222e7. http://dx.doi.org/10.1067/
mob.2003.446.
[133] Caughey AB, Stotland NE, Washington a E, Escobar GJ. Maternal and obstetric
complications of pregnancy are associated with increasing gestational age at
term. Am. J. Obstet. Gynecol. 2007;196. http://dx.doi.org/10.1016/
j.ajog.2006.08.040. 155.e1e6.
[134] Galal M, Symonds I, Murray H, Petraglia F, Smith R. Postterm pregnancy.
Facts Views Vis. Obgyn 2012;4:175e87.
[135] Wang X, Liang L, Junfen FU, Lizhong DU. Metabolic syndrome in obese
children born large for gestational age. Indian J. Pediatr. 2007;74:561e5.
O.A. Akerele, S.K. Cheema / Journal of Nutrition &Intermediary Metabolism xxx (2016) 1e11 11
Please cite this article in press as: O.A. Akerele, S.K. Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, Journal of Nutrition &Intermediary Metabolism (2016), http://dx.doi.org/10.1016/j.jnim.2016.04.008