Prostaglandins, Leukotrienes and Essential Fatty Acids 85 (2011) 149–153

Contents lists available at ScienceDirect

Prostaglandins, Leukotrienes and

Essential Fatty Acids
journal homepage: www.elsevier.com/locate/plefa

Reduced levels of placental long chain polyunsaturated fatty acids in

preterm deliveries$
Madhavi V. Dhobale a, Nisha Wadhwani a, Savita S. Mehendale b, Hemlata R. Pisal a, Sadhana R. Joshi a,n
a
Department of Nutritional Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune 411043, India
b
Dept. of Obstetrics and Gynaecology, Bharati Medical College and Hospital, Bharati Vidyapeeth University, Pune 411043, India

a r t i c l e i n f o abstract

Article history: Reports suggest that the placenta in preterm birth may provide clues to predicting the risk of
Received 1 April 2011 individuals developing chronic diseases in later life. Placental delivery of long chain polyunsaturated
Received in revised form fatty acids (LCPUFA) (constituents of the cell membrane and precursors of prostaglandins) is essential
15 June 2011
for the optimal development of the central nervous system of the fetus. The present study examines the
Accepted 24 June 2011
levels of LCPUFA and their association with placental weight and birth outcome in 58 women delivering
preterm and 44 women delivering at term. Docosahexaenoic acid (DHA) and arachidonic acid (ARA)
Keywords: levels were lower (p o 0.01) in women delivering preterm. There was a positive association of placental
Preterm pregnancy DHA with placental weight (p ¼0.036) and nervonic acid with head circumference (p ¼ 0.040) in the
Omega-3 fatty acids
preterm group. Altered placental LCPUFA status exists in Indian mothers delivering preterm, which may
Nervonic acid
influence the birth outcome.
Birth outcome
& 2011 Elsevier Ltd. All rights reserved.

1. Introduction and conformation of all cell membranes. They are precursors

Preterm births are those occurring at less than 37 weeks of
gestation and result in 10 percentages of deaths in the neonatal
period [1]. However, in developing countries like India, 30% of the
total neonatal deaths are due to preterm delivery [2]. It is well
established that the placenta provides the fetus with nutrients
needed for growth and also serves as an excretory organ to
eliminate wastes from fetal metabolism [3]. Epidemiologic stu-
dies have suggested that altered brain development following
preterm birth may be associated with psychiatric disorders [4].
Reports suggest that the placenta in preterm birth is not only a
record of adverse conditions during intrauterine life that led to
preterm birth, but it also probably holds clues to predicting which
individuals will be at risk for developing chronic diseases in
childhood, or as adults [5].
The human fetus relies on maternal supply and placental
delivery of long-chain n  3 polyunsaturated fatty acids for opti-
mal development and function, particularly of the central nervous
system. In view of this understanding the levels of placental long
chain polyunsaturated fatty acids (LCPUFA) in the preterm pla-
centa may throw light on the neurodevelopmental risk for the
child. Nutrients like LCPUFA maintain the fluidity, permeability
$
Funding: This research did not receive any specific grant from any funding
agency in the public, commercial or not-for-profit sector.
n
Corresponding author. Tel.: þ020 24366929/31; fax: þ 020 24366929.
E-mail address: srjoshi62@gmail.com (S.R. Joshi).
of important bioactive compounds such as the prostacyclins,
prostaglandins, thromboxanes and leukotrienes and as a source
of energy [6]. Elongation and desaturation enzymes for LCPUFA
conversion are present in the fetal liver early in gestation, but
their activity appears to be low before birth [7]. Therefore, the
LCPUFA that the fetus accumulates in utero are derived predomi-
nantly through placental transfer, which in turn, is influenced by
maternal diet and metabolism [8,9], which consequently impacts
post-natal development of brain and visual functions [10].
A term process of parturition involves a cascade of activations
of cellular components and mediators of an inflammatory
pathway(s) that result in the onset of labor and membrane
rupture and any abnormalities can result in preterm birth [5].
A recent review indicates that the data on the effect of n 3 fatty
acids on gestational length, risk of preterm birth is controversial
[11] with most studies being reported from Europe and North
America [12]. We have earlier reported increased oxidative stress
and lower maternal erythrocyte docosahexaenoic acid (DHA)
(precursors to prostaglandins) levels in preterm deliveries as
compared to term deliveries [13,14].
Our recent study in placental tissue samples has shown DHA
and n  3 fatty acid levels were significantly lower while arachi-
donic acid (ARA) and n  6 fatty acid levels were higher in
preeclamptic women as compared to normotensive women,
indicative of altered membrane lipid fatty acid composition
leading to altered placental development [15]. However, the level
of LCPUFA and their role in placental and fetal development in

0952-3278/$ - see front matter & 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.plefa.2011.06.003
150 M.V. Dhobale et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 85 (2011) 149–153

preterm deliveries are not clear. The only study that has exam-
ined the levels of fatty acids from placenta in preterm pregnancies
is from women from an extremely diverse population, which
differed in religion, culture and ethnicity [16].
The present study compares the levels of LCPUFA from
placental tissue in preterm deliveries with term deliveries. All
women were matched for race, age, sex, socioeconomic status,
diet and lifestyle to minimize the confounds to variability in fatty
acids. Further, the study for the first time also examines the
association of placental LCPUFA with placental weight and
weight, length, head and chest circumference of the baby at birth.
chromatograph (SP 2330, 30 m capillary Supelco column). Helium
was used as carrier gas at 1 ml/min. Oven temperature was held
at 150 1C for 10 min, programmed to rise from 150 to 220 1C at
10 1C/min and at 220 1C for 10 min. The detector temperature was
275 1C and the injector temperature was 240 1C. Retention times
and peak areas were automatically computed. Peaks were identi-
fied by comparison with standard fatty acid methyl esters
(Sigma). Fatty acids were expressed as g/100 g fatty acid, i.e.,
percentage of total fatty acids as 100%.
2.3. Statistical analysis

2. Patients and methods Values are reported as mean 7SD. The data were analyzed
using SPSS/PC þpackage (Version11.0, Chicago, IL). Mean values of
This study was conducted at the Dept. of Obstetrics and the estimates of various parameters were compared using ‘one
Gynaecology, Bharati Hospital, Pune during the year 2008–2010. way ANOVA’ test for possible statistical significant difference
This study was approved by Institutional Ethical Committee and a (p o0.05 and 0.01). Skewed variables were transformed to nor-
written informed consent was taken from each subject. All the mality using the following transformations: log to the base 10
experiments were conducted with the understanding and the (DHA, nervonic acid, placenta weight and birth outcome). Corre-
consent of each participant. A total number of 58 women lation between variables was studied using Pearson’s correla-
delivering preterm (o37 weeks gestation) and 44 women deli- tion analysis after adjusting for gestation, age and body mass
vering at control (control group) were recruited (Z37 weeks index (BMI).
gestation) for this prospective study. Women were excluded from
the study if there was evidence of other pregnancy complications
like multiple gestation, pre-eclampsia, chronic hypertension, type
3. Results
I or type II diabetes mellitus, seizure disorder and renal or liver
disease. Pregnant women with alcohol or drug abuse were also
3.1. Maternal and neonatal characteristics
excluded from the study. Women delivering at control consisted
of pregnant women with no medical or obstetrical complications.
Table 1 shows the maternal and neonatal characteristics. All
Gestational age was calculated by the last menstrual period and
women had similar age, income, education and parity. The body
then confirmed by ultrasound. Women from both groups were
mass index (BMI) of women delivering preterm was significantly
from the lower socioeconomic group and had similar levels of
lower than that of women delivering at term (control) (po0.01).
education, parity and lifestyle. Income is given as Indian Rupees
The baby weight, length, head and chest circumference were
and the conversion factor for Indian Rupees (INR) to US Dollar
lower (p o0.01 for all) in the preterm group as compared to term.
(USD) is 50.

2.1. Sample collection and processing 3.2. Placental fatty acid concentrations

Fresh placental tissues were obtained from normal and pre-
term pregnancies immediately after delivery. Fetal membranes
were trimmed off and the placenta was weighed. Small pieces
(approximately 1 cm (l)  1 cm (w)  0.5–1 cm (h)) of villous
explants were cut out from five different regions of the placenta
while avoiding infracted areas. These pieces were pooled per
patient for lipid analyses. The tissue pieces were individually
rinsed in DEPC-treated PBS to wash off maternal and fetal blood.
Tissue pieces were collected in liquid nitrogen and stored at
80 1C until assayed. In the control group 3 (6.8%) placentas were
collected from women who delivered by cesarean section, while
41 (93.1%) placentas were collected from women who had normal
parturition. In the preterm group 13 (22.4%) placentas were
collected from women who delivered by cesarean section, while
DHA level was lower (p o0.01) in preterm deliveries as
compared to term deliveries while eicosapentaenoic acid (EPA)
and a-linolenic acid (ALA) levels were higher (p o0.01 for both).
The data on placental PUFA levels on control women (n ¼40) has
been reported earlier [15]. n  6 fatty acids arachidonic acid (ARA),
linoleic acid (LA), di-g-linoleic acid (DGLA) and docosapentaenoic
acid (DPA) levels were significantly reduced (p o0.01 for all) in
preterm deliveries as compared to term deliveries. There was no
difference seen in case of g-linoleic acid (GLA) levels.
Table 1
Maternal and neonatal characteristics.
Term (n ¼44) Preterm (n¼ 58)

45 (77.5%) placentas were collected from women who had normal Maternal characteristics
parturition. Age (yr) 23.7 7 3.6 22.3 7 4.1
BMI (kg/m2) 23.0 7 3.9 20.07 3.2nn
Gestation (wks) 39.3 7 1.1 34.4 7 2.0nn
2.2. Fatty acid estimation from placental membrane fatty acids
Education (grade) 10.3 7 3.1 9.3 7 3.2
Income (Rs.) 5227.27 2914.3 4592.57 2134.7
The procedure for fatty acid analysis used in our study was Parity g 1.6 7 0.7 1.3 7 0.7
revised from the original method of Manku et al. [17] and is also Neonatal characteristics
reported by us earlier in separate studies [12,15,18,19]. Briefly, Baby wt. (kg) 2.8 7 0.2 1.9 7 0.4nn
Baby length (cm) 48.6 7 2.4 44.7 7 3.5nn
placental tissue was homogenized with chilled PBS and spinned
Baby head circumference 33.7 7 1.33 31.3 7 2.0 nn
at 4000 rpm at 4 1C for 20 min. Supernatant and cell membrane Baby chest circumference 32.2 7 1.2 28.4 7 3.0nn
fractions were separated. Transesterification of cell membrane
phospholipid fraction was carried out using hydrochloric acid– Values given are mean 7 SD.
methanol. These were separated using a Perkin Elmer gas nn
po 0.01 when compared to term.
 M.V. Dhobale et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 85 (2011) 149–153 151

Total saturated fatty acids were higher (p o0.01) and MUFA Table 3
were lower (p o0.05) in case of preterm deliveries as compared to Association between placental weight and birth outcome.
term deliveries (Table 2).
Term group Preterm group

n r p n r p
3.3. Placental weight and their association with docosahexaenoic
acid Placental weight
Baby weight (kg) 44 0.280 0.080 52 0.420 0.019n
Placental weight was lower (p o0.01) in preterm deliveries as Baby length (cm) 44  0.055 0.738 52 0.371 0.044n
compared to term deliveries. There was a positive association Head circumference (cm) 44 0.066 0.688 51 0.369 0.040n
Chest circumference (cm) 44  0.009 0.958 52 0.344 0.058n
between placental DHA with placental weight in preterm group
(r ¼0.413, p ¼0.036, n ¼45) (Fig. 1). However, this association was n
p o0.05 when compared to term.
not seen in the term group.

Table 4
3.4. Association of placental weight with birth outcome Association between nervonic acid and birth outcome.

There was a positive association seen between placental weight Term group Preterm group
and baby weight (r¼0.420, p¼0.019, n¼52), length (r¼0.371,
n r p n r p
p¼0.044, n¼52), head circumference (r¼0.369, p¼0.040, n¼51)
Nervonic acid
Table 2 Baby weight (kg) 44  0.237 0.140 51 0.383 0.048n
Placental fatty acid levels in preterm and term deliveries. Baby length (cm) 44 0.063 0.699 51 0.085 0.675
Head circumference (cm) 44  0.002 0.992 52 0.391 0.040n
Fatty acid (g/100 g fatty acids) Term (n¼ 44) Preterm (n¼ 58) Chest circumference (cm) 44  0.020 0.904 55  0.047 0.799

Myristic acid 0.547 0.52 0.367 0.28n n

p o0.05 when compared to term.
Myristoleic acid 0.367 0.48 0.137 0.15nn
Palmitic acid 23.68 7 3.44 29.24 7 6.87nn
Palmetoleic acid 0.317 0.27 0.357 0.42 and chest circumference (r¼ 0.344, p¼0.058, n¼52) in the pre-
Stearic acid 14.16 7 2.64 16.47 7 5.31nn term group. However these associations were not seen in term
Oleic acid 6.657 2.02 6.85 7 1.91 group (Table 3). There was no association between any of the
Linoleic acid 11.31 7 2.02 10.17 7 2.95n other fatty acids and birth outcome.
g-Linoleic acid 0.187 0.24 0.17 7 0.18
a-Linolenic acid 0.197 0.15 0.387 0.36nn
Di-g-linoleic acid 4.457 1.17 3.53 7 1.20nn 3.5. Association of nervonic acid with birth outcome
Arachidonic acid 22.44 7 3.43 19.51 7 6.15nn
Eicosapentaenoic acid 0.117 0.16 0.327 0.29nn
There was a positive association of nervonic acid with baby
Nervonic acid 2.467 1.43 1.507 0.75nn
Docosapentaenoic acid 0.627 0.45 0.377 0.27nn
weight (r ¼0.383, p ¼0.048, n ¼51) as well as with head circum-
Docohexaenoic acid 3.197 0.94 2.057 0.97nn ference (r ¼0.391, p¼0.040, n ¼52) in preterm group (Table 4).
Saturated fatty acids 38.38 7 5.08 46.07 7 11.28nn
Monounsaturated fatty acids 9.787 2.16 8.83 7 2.26n
Total n  3 fatty acids 3.497 0.95 2.75 7 1.10nn 4. Discussion
Total n  6 fatty acids 38.99 7 5.26 33.74 7 9.21nn
n  6/n 3 ration 11.98 7 3.60 13.46 7 4.73
The present study reveals several novel and interesting find-
Values given are mean 7 SD. ings in placenta from preterm deliveries: (1) lower DHA but
n
p o 0.05 when compared to term group. higher EPA & ALA levels; (2) lower ARA, LA, DGLA and DPA;
nn
p o0.01 when compared to term group. (3) positive association of DHA with placental weight and
(4) positive association of nervonic acid with baby weight and head
circumference.
In our study, placental levels of ALA and EPA were higher but
DHA levels were lower in women delivering preterm. In the body,
4.50 ALA is metabolized to EPA and DHA while LA is metabolized to
ARA by D-5 desaturase and D-6 desaturase enzymes [20]. The
DHA (g / 100g fatty acids)

changes in levels of fatty acids observed in our study can be

attributed either to altered intake or metabolism. A study in rats
indicates that increase in amounts of ALA leads to accumulation
3.00
of EPA [21]. However, in our earlier study we have reported no
difference in the intakes of ALA rich foods between women
delivering preterm and at control [13]. We have already reported
earlier that in women delivering preterm the frequency of
1.50 consumption of foods rich in alpha linolenic acid, a precursor of
DHA was about 4–5 times a week, and this was similar to the
reported frequency of consumption by pregnant women deliver-
ing at term due to a strong traditional practice and availability of
same foods [13,22].
200 300 400 500 600 Our findings suggest that ALA may be getting converted to EPA
Placenta weight (gm) but EPA is not further metabolized to DHA since we have seen
reduced placental DHA levels. This may be due to the reduced
Fig. 1 D5-desaturase enzyme activity, which is known to be regulated at
152 M.V. Dhobale et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 85 (2011) 149–153
transcription And translational levels [23]. Future studies need to
examine D5-desaturase enzyme levels as well as expression from
preterm placentae.
In our study low levels of ARA were seen in preterm placentae.
This is in contrast to the high amounts of ARA reported earlier
[16]. The reduced levels of ARA in our study may be as a result of
increased oxidative stress in preterm pregnancies. It is known
that ARA, a major unsaturated fatty acids present in mammalian
cells, is the major target of free radical attack, which induces lipid
peroxidation [24]. Although in the present study we did not
examine the association between oxidative stress and ARA levels
we have earlier reported increased oxidative stress in preterm
deliveries [11].
LCPUFAs have numerous physiological functions (metabolic,
energetic and structural) and influence placental and fetal devel-
opment [25]. LCPUFAs, especially ARA and DHA, are major
components of all cell membranes and are of special importance
to the brain and blood vessels. In particular, DHA accounts for
about 40% of the membrane phospholipids in the brain. It has
been widely investigated for its critical importance on fetal
growth and development of the central nervous system [25].
EPA and DHA are reported to have an effect on membrane
receptor function and even neurotransmitter generation and
metabolism [26].
In utero, the placenta selectively and substantially extracts
ARA and DHA from the mother and enriches the fetal circulation.
We have earlier reported higher DHA and ARA levels in cord blood
compared to their mothers, suggesting a special mechanism to
meet the increased demand of the fetus [13]. Placental synthesis
of ARA and DHA has been proposed as one mechanism to explain
the higher concentrations of these LCPUFAs in the fetal circulation
[27]. Reduced levels of both DHA could be attributed to reduced
fatty acid synthesis in the placenta. Alternatively it may also be
possible that the placenta also plays a role in regulating its own
levels in response to the fetal demand.
In the present study individual fatty acids were expressed as
proportions of total fatty acids and are interdependent. Thus an
increase in one fatty acid that makes up a large percentage of the
total will cause the relative contribution of other fatty acids to be
lower, even when the absolute amount remains unaltered. That is,
a high percentage of saturated fatty acids will automatically
reflect a low percentage of unsaturated fatty acids. This makes
it difficult to interpret the effect of single fatty acid constituents,
independent of other fatty acids.
We report here for the first time a positive association
between placental weight and placental DHA in preterm deliv-
eries. This finding is of significance in view of the fact that 98% of
the growth of the baby occurs when the fetus is entirely
dependent on the placenta for its supply of nutrients/oxygen. It
has been speculated that the placenta plays an important role in
regulating fetal growth and ‘programming’ the development of
the fetus [28]. These associations are similar to those seen with
plasma concentrations DHA and placental weight in normal
pregnancy [29]. Bonds et al. [30] have showed close correlation
between placental weight and birth weight. We also report here a
positive correlation of placental weight with baby weight, length
and head circumference. This indicates that fetal growth may be
hampered due to composition of placental fatty acids and their
transfer via placenta during pregnancy.
Nervonic acid is an important monounsaturated n  9 fatty
acid in sphingomyelin and has been identified as important in the
biosynthesis of nerve cell myelin in the brain [31]. Nervonic acid
level is thought to reflect brain maturation and there is a
concordance in the proportions of the fatty acid in red cell and
brain sphingomyelin [32]. The accretions of nervonic acid are a
good marker to track myelinogenesis [33]. In our study levels of
nervonic acid were lower in preterm placentae. Further, nervonic
acid was positively associated with baby head circumference,
which may lead for poor fetal brain development. Recent reports
suggest that plasma and erythrocyte nervonic acid levels are
lower in major depressive disorder patients [34].
Biological effects of LCPUFAs on brain function are assumed to
be mediated by the availability of these LCPUFA with 420 carbon
atoms and 43 double bonds (i.e. ARA, EPA and DHA) [35]. It has
recently been suggested that DHA supplementation during the
complementary feeding period is effective in improving neuro-
functional and visual performance [36]. Bouwstra et al. [37] have
also reported associations between umbilical cord fatty acid
composition and neurodevelopmental status at 18 months and
suggest that the umbilical cord fatty acid compositions reflect
long-control of LCPUFA status, and are therefore more likely to
show a relationship with neurodevelopment. The recent Cochrane
database systematic reviews evaluating the effects of LCPUFA
supplementation on breast feeding mothers and their infant,
which included six randomized controlled trials indicate that in
2 trials LCPUFA supplementation was associated with increased
head circumference [38].
Micronutrients like folic acid, vitamin B12 and LCPUFA interact
in the one carbon cycle. Membrane phospholipids are major
methyl group acceptors and reduced DHA levels may result in
diversion of methyl groups towards DNA ultimately resulting in
DNA methylation as we have recently described in one carbon
metabolic pathway [39,40]. We have recently reported gestation-
dependent changes in human placental global DNA methylation
levels [41]. In view of this, our results indicating reduced levels of
placental LCPUFA may have implications for fetal programming of
adult diseases.
In conclusion, our study for the first time reports the levels and
association of placental LCPUFA with placental weight and birth
weight, length, head and chest circumference in women deliver-
ing preterm babies. Our results although observational and only
indicative of causal relations suggest that altered placental
LCPUFA status exist in Indian mothers delivering preterm, which
may influence the birth outcome. Future studies need to examine
whether these altered levels of placental fatty acids, which affect
birth outcome, lead to increased risk of neurodevelopmental
disorders and non-communicable diseases in childhood and later
life.
Acknowledgment
The authors would like to thank all the subjects for volunteer-
ing in this study and nurses of Bharati hospital who helped in
collecting the samples.
References
[1] J. Bryce, C. Boschi-Pinto, K. Shibuya, R.E. Black, WHO Child Health Epidemiol-
ogy Reference Group, WHO estimates of the causes of death in children,
Lancet 365 (2005) 1147–1152.
[2] World Health Organization, Report: World Health Statistics, World Health
Organization, Geneva, 2006.
[3] P. Shekhawat, M.J. Bennett, Y. Sadovsky, D.M. Nelson, D. Rakheja,
A.W. Strauss, Human placenta metabolizes fatty acids: implications for fetal
fatty acid oxidation disorders and maternal liver diseases, Am. J. Physiol.
Endocrinol. Metab. 284 (2003) 1098–1105.
[4] S. Johnson, N. Marlow, Preterm birth and childhood psychiatric disorders,
Pediatr. Res. (2011) (Epub ahead of print).
[5] O.M. Faye-Petersen, The placenta in preterm birth, J. Clin. Pathol. 61 (2008)
1261–1275.
[6] P. Haggarty, Placental regulation of fatty acid delivery and its effect on fetal
growth: a review, Placenta 23 (2002) S28–S38.
[7] R. Uauy, P. Mena, B. Wegher, S. Nieto, N. Salem, Long chain polyunsaturated
fatty acid formation in neonates: effect of gestational age and intrauterine
growth, Pediatr. Res. 47 (2000) 127–135.
 M.V. Dhobale et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 85 (2011) 149–153
[8] B. Koletzko, E. Larque, H. Demmelmair, Placental transfer of long-chain
polyunsaturated fatty acids (LC-PUFA), J. Perinat. Med. 35 (2007) S5–S11.
[9] S. Krauss-Etschmann, R. Shadid, C. Campoy, et al., Effects of fish-oil and folate
supplementation of pregnant women on maternal and fetal plasma concen-
trations of docosahexaenoic acid and eicosapentaenoic acid: a European
randomized multicenter trial, Am. J. Clin. Nutr. 85 (2007) 1392–1400.
[10] P. Guesnet, J.M. Alessandri, Docosahexaenoic acid (DHA) and the developing
central nervous system (CNS)—implications for dietary recommendations,
Biochimie 93 (2011) 7–12.
[11] J.M. Coletta, S.J. Bell, A.S. Roman, Omega-3 fatty acids and pregnancy, Rev.
Obstet. Gynecol. 3 (2010) 163–171.
[12] L. Lauritzen, S.E. Carlson, Maternal fatty acid status during pregnancy and
lactation and relation to newborn and infant status, Matern. Child. Nutr. 7
(2011) 41–58.
[13] S.R. Joshi, S.S. Mehendale, K.D. Dangat, A.S. Kilari, H.R. Yadav, V.S. Taralekar,
High maternal plasma antioxidant concentrations associated with preterm
delivery, Ann. Nutr. Metab. 53 (2008) 276–282.
[14] A.S. Kilari, S.S. Mehendale, K.D. Dangat, et al., Long chain polyunsaturated
fatty acids in mothers of preterm babies, J. Perinat. Med. 38 (2010) 659–664.
[15] A.V. Kulkarni, S.S. Mehendale, H.R. Yadav, S.R. Joshi, Reduced placental
docosahexaenoic acid levels associated with increased levels of sFlt-1 in
preeclampsia, Prostaglandins Leukot. Essent. Fatty Acids 84 (2011) 51–55.
[16] D. Bitsanis, M.A. Crawford, T. Moodley, H. Holmsen, K. Ghebremeskel,
O. Djahanbakhch, Arachidonic acid predominates in the membrane phos-
phoglycerides of the early and term human placenta, J. Nutr. 135 (2005)
2566–2571.
[17] M.S. Manku, D.F. Horrobin, S. Huang, N. Morse, Fatty acids in plasma and red
cell membranes in normal humans, Lipids 18 (1983) 906–908.
[18] S. Mehendale, A. Kilari, K. Dangat, V. Taralekar, S. Mahadik, S. Joshi, Fatty
acids, antioxidants, and oxidative stress in preeclampsia, Int. J. Gynaecol.
Obstet. 100 (2008) 234–238.
[19] K. Dangat, S. Mehendale, H. Yadav, et al., Long chain polyunsaturated fatty
acid composition of breast milk in pre-eclamptic mothers, Neonatology 97
(2010) 190–194.
[20] M. Singh, Essential fatty acids, DHA and human brain, Indian J. Pediatr. 72
(2005) 239–242.
[21] W.C. Tu, R.J. Cook-Johnson, M.J. James, B.S. Mühlhäusler, R.A. Gibson, Omega-
3 long chain fatty acid synthesis is regulated more by substrate levels than
gene expression, Prostaglandins Leukot. Essent. Fatty Acids 83 (2010) 61–68.
[22] A.S. Kilari, S.S. Mehendale, K.D. Dangat, et al., Long chain polyunsaturated
fatty acids in mothers and term babies, J. Perinat. Med. 37 (2009) 513–518.
[23] D.B. Jump, Fatty acid regulation of hepatic lipid metabolism, Curr. Opin. Clin.
Nutr. Metab. Care 14 (2011) 115–120.
[24] M. Marmunti, A. Catalá, Arachidonic acid hydroperoxide stimulates lipid
peroxidation in rat liver nuclei and chromatin fractions, Mol. Cell. Biochem.
298 (2007) 161–168.
[25] I. Cetin, G. Alvino, M. Cardellicchio, Long chain fatty acids and dietary fats in
fetal nutrition, J. Physiol. 587 (2009) 3441–3451.
153
[26] A.P. Simopoulos, Evolutionary aspects of diet: the omega-6/omega-3 ratio
and the brain, Mol. Neurobiol. (2011) (Epub ahead of print).
[27] P. Haggarty, Fatty acid supply to the human fetus, Annu. Rev. Nutr. 30 (2010)
237–255.
[28] T. Jansson, T.L. Powell, Role of the placenta in fetal programming: underlying
mechanisms and potential interventional approaches, Clin. Sci. (Lond.) 113
(2007) 1–13.
[29] M.D. Al, A.C. van Houwelingen, A.D. Kester, T.H. Hasaart, A.E. de Jong,
G. Hornstra, Maternal essential fatty acid patterns during normal pregnancy
and their relationship to the neonatal essential fatty acid status, Br. J. Nutr. 74
(1995) 55–68.
[30] D.R. Bonds, B. Mwape, S. Kumar, S.G. Gabbe, Human fetal weight and
placental weight growth curves. A mathematical analysis from a population
at sea level, Biol. Neonate 45 (1984) 261–274.
[31] J.R. Sargent, K. Coupland, R. Wilson, Nervonic acid and demyelinating disease,
Med. Hypotheses 42 (1994) 237–242.
[32] F. Babin, P. Sarda, B. Limasset, et al., Nervonic acid in red blood cell
sphingomyelin in premature infants: an index of myelin maturation, Lipids
28 (1993) 627–630.
[33] M. Martinez, Tissue levels of polyunsaturated fatty acids during early human
development, J. Pediatr. 120 (1992) S129–S138.
[34] J. Assies, F. Pouwer, A. Lok, et al., Plasma and erythrocyte fatty acid patterns
in patients with recurrent depression: a matched case-control study, PLoS
One 5 (2010) e10635.
[35] J.P. Schuchardt, M. Huss, M. Stauss-Grabo, A. Hahn, Significance of long-chain
polyunsaturated fatty acids (PUFAs) for the development and behaviour of
children, Eur. J. Pediatr. 169 (2010) 149–164.
[36] C. Agostoni, Docosahexaenoic acid (DHA): from the maternal-foetal dyad to
the complementary feeding period, Early Hum. Dev. 86 (2010) 3–6.
[37] H. Bouwstra, D.A. Dijck-Brouwer, T. Decsi, et al., Neurologic condition of
healthy control infants at 18 months: positive association with venous
umbilical DHA status and negative association with umbilical trans-fatty
acids, Pediatr. Res. 60 (2006) 334–339.
[38] M.F. Delgado-Noguera, J.A. Calvache, X. Bonfill Cosp, Supplementation with
long chain polyunsaturated fatty acids (LCPUFA) to breastfeeding mothers for
improving child growth and development, Cochrane Database Syst. Rev. 8
(2010) CD007901.
[39] A. Kale, S. Joshi, N. Naphade, et al., Reduced folic acid, vitamin B12 and
docosahexaenoic acid and increased homocysteine and cortisol in never-
medicated schizophrenia patients: implications for altered one-carbon
metabolism, Schizophr. Res. 98 (2008) 295–301.
[40] A. Kulkarni, K. Dangat, A. Kale, P. Sable, P. Chavan-Gautam, S. Joshi, Effects of
altered maternal folic acid, vitamin b(12) and docosahexaenoic acid on
placental global DNA methylation patterns in wistar rats, PLoS One 6
(2011) e17706.
[41] P. Chavan-Gautam, D. Sundrani, H. Pisal, V. Nimbargi, S. Mehendale, S. Joshi,
Gestation-dependent changes in human placental global DNA methylation
levels, Mol. Reprod. Dev. 78 (2011) 150.