REVIEW

Altered maternal micronutrients (folic acid, vitamin B12) and omega 3 fattyacids through oxidative stress may reduce neurotrophic factors in pretermpregnancy

MADHAVI DHOBALE & SADHANA JOSHI

Department of Nutritional Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune 411043,

Maharashtra, India

AbstractPreterm pregnancies account for approximately 10% of the total pregnancies and are associated with low birth weight (LBW)babies. Recent studies have shown that LBW babies are at an increased risk of developing brain disorders such as cognitivedysfunction and psychiatric disorders. Maternal nutrition, particularly, micronutrients involved in one-carbon metabolism (folicacid, vitamin B12, and docosahexaenoic acid (DHA)) have a major role during pregnancy for developing fetus and are importantdeterminants of epigenesis. A series of our studies in pregnancy complications have well established the importance of omega 3fatty acids especially DHA. DHA regulates levels of neurotrophins like brain-derived neurotrophic factor and nerve growth factor,which are required for normal neurological development. We have recently described that in one carbon metabolic pathway,membrane phospholipids are major methyl group acceptors and reduced DHA levels may result in diversion of methyl groupstoward deoxyribonucleic acid (DNA) ultimately resulting in DNA methylation. In this review, we propose that altered maternalmicronutrients (folic acid, vitamin B12), increased homocysteine, and oxidative stress levels that cause epigenetic modificationsmay be one of the mechanisms that contribute to preterm birth and poor fetal outcome, increasing risk for behavioural disorders inchildren.

Keywords: Epigenetics, docosahexaenoic acid, neurotrophins, behavioural disorders, pregnancy complications

Introduction

Pregnancy outcome is known to be influenced by duration of

gestation and rate of fetal growth. Preterm birth complicates

about 5–10% of all births resulting in low birth weight (LBW)

and increased infant morbidity and mortality [1]. LBW is

defined by WHO as birth weight less than 2500 g. The rate of

preterm birth has increased in many locations, predominantly

because of increasing indicated preterm births and preterm

delivery of artificially conceived multiple pregnancies. A

recent report suggests that 30% of total neonatal deaths in

India are due to preterm births [2].

Maternal nutrition

Pregnancy is a period of increased metabolic demands, with

changes in the woman’s physiology and the requirements of a

growing fetus [3]. Maternal nutrition that plays a critical role

in fetal growth is one of the important intrauterine environ-

mental factors that alters the expression of the fetal genome

and may have lifelong consequences. Micronutrients like folic

acid and vitamin B12 have major role in one-carbon

metabolism, since they are required for the transfer of methyl

groups for methylation of deoxyribonucleic acid (DNA),

RNA, proteins, and membrane phospholipids. Alteration in

the levels of these micronutrients can have adverse effects on

the mother, resulting in pregnancy complications and birth

defects [4].

Long-chain polyunsaturated fatty acids (LCPUFA), parti-

cularly docosahexaenoic acid (DHA), are important consti-

tuents of all cell membrane phospholipids and precursors of

eicosanoids and are critical nutritional sources for the

developing fetus. Our earlier studies have shown reduced

DHA levels in women with pregnancy complications like

preeclampsia [5] or in women delivering preterm [6]. Our

studies indicate that increased oxidative stress may be one of

the causative factors for degrading LCPUFA in women

delivering preterm [6,7]. Since DHA accretion to the fetus

takes place mainly in the last trimester of pregnancy, children

born preterm miss out on this opportunity and may have

reduced levels of DHA.

Thus, maternal micronutrients (folic acid, vitamin B12)

and omega 3 fatty acids are important intrauterine environ-

mental factors affecting placental and fetal growth and

development (Figure 1). It has been proposed that environ-

mental factors, particularly maternal undernutrition, act in

early life to programme the risks for adverse health outcomes,

such as cardiovascular disease, obesity, and the metabolic

syndrome in adult life.

(Received 2 February 2011; revised 5 March 2011; accepted 1 April 2011)

Correspondence: Dr. Sadhana Ramchandra Joshi, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune-Satara Road, Pune

411043, India. Tel: 91-20-24366929, 91-20-24366931. Fax: 91-20-24366929. E-mail: srjoshi62@gmail.com

The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(4): 317–323

� 2012 Informa UK, Ltd.

ISSN 1476-7058 print/ISSN 1476-4954 online

DOI: 10.3109/14767058.2011.579209

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Folate. Pregnancy is a period of high folate demand, estimated

to be increased 5- to 10-fold, driven by the critical importance

of folate for DNA synthesis, cellular division and proliferation,

the growth and development of the placenta and fetus, and

uterine enlargement [8]. Folate, a water-soluble vitamin, plays

an essential role as a cofactor in one-carbon metabolism,

during which it promotes the re-methylation of homocysteine

– a cytotoxic sulphur containing amino acid that can induce

the DNA strand breakage, oxidative stress, and apoptosis.

Folate provides the methyl group for the conversion of

methionine to S-adenosylmethionine (SAM), the major

methyl donor for most methyltransferases reactions for the

methylation of lipid (PC-DHA to PE-DHA), DNA, and

proteins (histones).When folate levels are low, SAM is

depleted, resulting in a reduction in the methylation of

DNA and thereby enhancing gene transcription and DNA

strand breakage and can impair DNA repair resulting in

genetic mutations or triggering apoptosis [9]. Low maternal

folate, acting to increase homocysteine levels, may provide a

functional link between many of the identified prenatal risk

factors and the hypothesized mechanisms whereby neurode-

velopmental patterning deviates toward a schizophrenic

potential [10].

Vitamin B12. Vitamin B12, also called cobalamin, is a water-

soluble vitamin with a key role in the normal functioning of

the brain and nervous system. It is normally involved in the

metabolism of every cell of the body, especially affecting DNA

synthesis and regulation, but also fatty acid synthesis and

energy production [11]. Vitamin B12 plays a crucial role in

methionine and homocysteine metabolism in most of the cell

types.

Vitamin B12 deficiency during pregnancy is known to result

in elevated levels of homocysteine in the fetus and increases

the incidence of developmental defects in its nervous system.

Vitamin B12 occurs in extensive amounts in animal-derived

foods and is essential for one-carbon metabolism. Indians

primarily consume a vegetarian diet that is Vitamin B12

deficient, which may lead to hyperhomocysteinemia. Altered

one-carbon metabolism, in addition to increasing the levels of

homocysteine, is known to alter the levels of methylation of

catecholamines, phospholipids, and chromatin (histone and

DNA), leading to epigenetic regulation of vital developmental

genes in schizophrenia [12]. Our earlier studies in animals

have shown that maternal folate levels alter brain DHA

concentrations in the offspring [13].

Omega 3-fatty acids. There are two types of PUFAs, n76

and n73 essential fatty acids. Linoleic acid (LA) is the

major n76 fatty acid, and alpha-linolenic acid (ALA) is the

major n73 fatty acid. In the body, LA is metabolized to

arachidonic acid (AA), and ALA is metabolized to

eicosapentaenoic acid (EPA) and DHA by D-5 desaturase

and D-6 desaturase enzymes (Figure 2). Nutritionally,

important essential n73 fatty acids are ALA, EPA, and

DHA. The human body cannot synthesize n73 fatty acids

de novo, but it can synthesize from ALA. These conversions

occur competitively with n76 fatty acids, which are

essential closely related chemical analogues that are derived

from LA. Both the n73 ALA and n76 LA are essential

nutrients that must be obtained from food. Synthesis of the

longer n73 fatty acids from ALA within the body is

competitively slowed by the n76 analogues. Thus, accu-

mulation of long-chain n73 fatty acids in tissues is more

effective when they are obtained directly from food [14].

In olden days, the ratio of n76 to n73 essential fatty acids

was 1 to 2:1. Today, this ratio is about 10 to 20 to 25:1,

indicating that modern day diets are deficient in n73 fatty

acids compared with the diet on which humans evolved and

their genetic patterns were established [14]. The n73 and

n76 fatty acids are not interconvertible in the human body

and are important components of all cell membranes and it

influence eicosanoid metabolism, gene expression, and inter-

cellular cell-to-cell communication.

During early life, there is limited metabolic capability to

convert ALA to DHA. Therefore, the fetus is completely

dependant on maternal source of DHA. Placental uptake of

maternal fatty acids is essential for growth and development of

the feto-placental unit. DHA and AA are critical nutritional

source for the developing fetus and infant. Throughout the

fetal life, placenta selectively and subsequently transports AA

and DHA from mother to the fetus [15].

Omega-3 fatty acids especially have shown to be essential

for normal neurological development, maintenance of learn-

ing and memory, and neuronal plasticity. DHA are also

known to influence levels of neurotrophins especially brain-

Figure 1. Role of maternal micronutrients and omega-3 fatty acids in placental and fetal growth and development.

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derived neurotrophic factor (BDNF). BDNF is associated

with alterations in neurogenesis and neuronal survival [16].

In the mammalian brain, major DHA accumulation occurs

late in gestation, parallel with maximal neuronal differentia-

tion process (neurogenesis), which consists of drastic mor-

phological and molecular changes. The formation of neurites

(axons and dendrites) is a key feature of neurogenesis, both

during development and in the adult. Several studies have

shown that DHA deficiency is critical during prenatal and

postnatal developmental stages leading to a variety of visual,

cognitive, and behavioural impairments [17].

Homocysteine. Hcy is a cytotoxic sulphur-containing amino acid

that can induce DNA strand breakage, oxidative stress, and

apoptosis. Homocysteine, a sulfhydryl-containing amino acid

that is not used in protein synthesis, originates exclusively from

the one-carbon donating metabolism of methionine, and it is

remethylated into methionine with folates acting as methyl

donors. Hcy arises during methionine metabolism in one-

carbon metabolism. Molecular mechanisms of homocysteine-

induced cellular dysfunction include increased inflammatory

cytokine expression, altered nitric oxide bioavailability, induc-

tion of oxidative stress, activation of apoptosis, and defective

methylation. Elevated maternal total homocysteine levels are

known to be associated with prematurity and LBW [18].

Hyperhomocysteinemia increases oxidative stress by indu-

cing oxidative stress promoting reactive oxygen species (ROS)

production by increasing NADPH oxidase. Oxidation is one

of the most favored postulated mechanisms explaining the

several toxic effects of homocysteine [19].

Oxidative stress

In pregnancy, the rapidly growing fetus has increased cellular

activity, which leads to increased oxidative stress. Oxidative

stress is characterized by excessive production of ROS

coupled with inadequate antioxidant defense mechanisms.

Free radicals such as ROS are formed during a variety of

biochemical reactions and cellular functions and resulting in

damages of all components of the cell. These result in

increased peroxidation of DNA, proteins/enzymes, and

membrane phospholipids, which result maternal and fetal

morbidity and mortality (Figure 3). Natural antioxidant

enzymes manufactured in the body provide an important

defense against free radicals. Glutathione peroxidase (GPx),

glutathione reductase (GR), catalase (CAT), and superoxide

dismutase (SOD) are among the most important antioxidant

enzymes.

Lipid peroxidation. Lipid peroxidation is an important mani-

festation of oxidative stress that occurs when oxygen free

radicals interact with LCPUFA in membranes or lipoproteins.

It is the process whereby free radicals take electrons from the

lipids in cell membranes, resulting in cell damage. This

process proceeds by a free radical chain reaction mechanism.

It most often affects polyunsaturated fatty acids because they

contain multiple double bonds in between where lies

Figure 2. Long-chain polyunsaturated fatty acids pathway.

Neurotrophic factors in preterm pregnancy 319

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methylene (-CH2-) groups that possess especially reactive

hydrogens. As with any radical reaction, the reaction

consists of three major steps: initiation, propagation, and

termination. In the initiation of lipid peroxidation, ROS

abstracts a hydrogen atom from an available lipid and

generates a second radical within the lipid bilayer, which

can react with another adjacent lipid. The chain reaction

spreads rapidly and can disrupt double bonds and fragment

lipids, leading to a loss of cell membrane integrity.

LCPUFA are more susceptible to lipid peroxidation

because of their high degree of unsaturation. Our earlier

studies in women delivering preterm indicate that maternal

plasma MDA levels were increased in preterm mothers as

well as in cord plasma samples [20]. Increased lipid

peroxidation and protein oxidation in both maternal and

fetal erythrocytes could be used as markers of oxygen

radical activity during intrauterine growth retardation.

Our recent studies in animals have shown that oxidative

stress is most likely triggered due to imbalance in maternal

micronutrients like folic acid and vitamin B12 during fetal

growth [21]. This may have implications for several neurode-

velopmental disorders since micronutrients and DHA are

important modulators for neural functioning. Increase in

oxidative stress can lead to reduced levels of neurotrophins

(Figure 4). Increased oxidative stress has been reported to be

associated with lower BDNF levels and neurodegenerative

disorders [22].

Neurotrophins

Neurotrophins are a unique family of polypeptide growth

factors that influence the proliferation, differentiation, survival

and death of neuronal and non-neuronal cells. There are four

family members of neurotrophins i.e. nerve growth factor

(NGF), brain-derived nerve growth factor (BDNF), neuro-

trophin-3 (NT-3), and neurotrophin-4 (NT-4). Neurotro-

phins play an important role for developing fetus during

pregnancy [23].

BDNF is abundant in peripheral nerves, affects normal

development, growth and survival and NGF promotes the

survival and functioning of cholinergic neurons in the basal

forebrain of the central nervous system. NGF and BDNF are

known to promote neuronal growth, differentiation in the

central and peripheral nervous system during fetal develop-

ment [24]. Each of these neurotrophic factors exerts its

biological activities through a family of tyrosine protein

kinases receptors (Trkases) and is responsible for mediating

neurotrophin signalling [25]. Two types of tyrosine kinase-

mediated neurotrophin receptors mediate biological activity:

high-affinity (Trk type A, B, and C) and low-affinity p75

receptor, a member of the tumor necrosis factor receptor

super-family. NGF selectively binds TrkA while, BDNF binds

Trk B, although some nonselective binding also occurs.

Our earlier studies, in first-episode schizophrenia, showed

significantly reduced levels of DHA [26] and BDNF, and

NGF levels in first-episode schizophrenia patients were also

significantly lower [27,28] in plasma as well as in cerebrosp-

inal fluid of schizophrenia patients compared to control

subjects suggesting that reduced levels of membrane DHA

may affect the neuronal plasticity as indicated by the reduced

levels of neurotrophins in schizophrenia.

Therefore, based on our earlier studies and reported data,

we propose that in mothers delivering preterm, changes in the

levels of micronutrients and omega 3 fatty acids especially

DHA during pregnancy leads to altered levels of homocys-

teine, which may result in methylation of neurotrophic factor

genes especially BDNF. These changes in levels of neuro-

trophins may be responsible for risk for neurodevelopmental

disorders in infants born preterm.

Very few studies have examined the levels of neurotrophins

in mother and cord samples during pregnancy complications.

There are limited studies that have examined levels of BDNF

during pregnancy [29,30]. Most of these studies are on a small

sample size and also could be confounded by the use of

antenatal steroids, which are known to alter the levels of

BDNF.

More systemic studies need to examine levels of neuro-

trophins from cord blood and maternal blood in women

delivering preterm pregnancy. This work will be useful in

predicting the risk for psychiatric disorders in childhood and

later life.

Consequences of the hypothesis: implications forneurodevelopment

Recent studies have shown that children born preterm are

associated with increased risk for developing attention deficit

hyperactivity disorder in childhood [31] and schizophrenia

later life [32].

Figure 3. Role of oxidative stress in pregnancy.

Figure 4. Increased oxidative stress and reduced levels of neuro-

trophins.

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It is well established that 50% of the brain is made up of

DHA and AA, which play major role in brain development.

Studies also suggest that DHA regulate the levels of

neurotrophic factors. Neurotrophic factors like BDNF are

proteins abundant in brain and peripheral nerves, which affect

development, growth, survival, and differentiation of neural

cells. It has also been reported that maternal plasma vitamin

B12 status during pregnancy is a major determinant of the

child’s cognitive function at 9 years of age [33].

Influences of maternal nutrition on epigenetic programming

are most important during prenatal and early postnatal develop-

ment, when epigenetic mechanisms undergo establishment and

maturation. Disruption of normal gene-specific methylation

patterns by perturbations in maternal nutrition may affect the

pregnancy outcome having long-term implications in the

offspring. Recent attention has also focused on the potential role

of the amino acid homocysteine, in adverse pregnancy outcomes

[18]. Recently, homocysteine has also been shown to impair

short- and long-term memories and reduce BDNF levels in the

rat hippocampus. Recent reports also suggest important auto-

crine/paracrine roles of the BDNF/TrkB signalling system

during implantation, subsequent placental development, and

Figure 5. Interaction between micronutrients in one-carbon cycle with impact on oxidative stress and epigenesis in (a) normal and (b) preterm

birth. DHF, di hydro folate; THF, tetra hydro folate; MTHF, methyl tetra hydro folate; MTFHR, methylene tetra hydro folate reductase; PEMT,

phosphatidylethanolamine N methyl transferase; MS, methyl synthase; PC-DHA, phosphatidyl choline DHA; PE-DHA, phosphatidyl

ethanolamine.

Neurotrophic factors in preterm pregnancy 321

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fetal growth by increasing trophoblast cell growth and survival

[34]. However, the possible relationship between IUGR and

BDNF function remains unclear. In developing countries like

India, micronutrient deficiencies such as folic acid, vitamin B12,

and DHA are common and associated with poor pregnancy

outcomes such as LBW.

Our group has shown decreased DHA levels in pregnancy

complications like preterm and preeclampsia, which may result

in LBW babies [5,6]. It is known that low DHA levels are

associated with decreased levels of BDNF, which is crucial for

maintaining neuronal plasticity. Further, high levels of homo-

cysteine are associated with reduced DNA methylation

potential, whereas folate and vitamin B12 increase this potential.

Further, we have also reported in the one carbon cycle that when

DHA levels are low, influx of methyl groups may divert toward

histone and DNA [27]. It is possible that increased homo-

cysteine and reduced DHA status epigenetically alter the

BDNF gene resulting in altered expression at birth that persists

in later years. Influences of maternal nutrition on epigenetic

programming are most important during prenatal and early

postnatal development, when epigenetic mechanisms undergo

establishment and maturation. Disruption of normal gene-

specific methylation patterns by perturbations in maternal

nutrition may affect the pregnancy outcome having long-term

implications in the offspring.

Our recent several studies have shown that reduced

antioxidants and increased oxidative stress leads to impaired

essential polyunsaturated fatty acid levels that may be the key

factors involved in the development of preeclampsia [5,7].

Recent studies have shown that children born preterm are

associated with increased risk for neurodevelopmental beha-

vioural and cognitive disorders in childhood and continue in

adult life [31]. In our study, on drug-naıve patients with early

onset of psychosis and confirmed as schizophrenics showed

reduced levels of DHA, BDNF, and NGF in blood as well as

CSF at the onset of psychosis. Schizophrenia is well established

as the neurodevelopmental disorder. Thus, our data on

pregnancy complications and schizophrenia strongly support

the hypothesis that altered micronutrients like folic acid,

vitamin B12, and DHA, through the one-carbon cycle, may

cause epigenetic modifications of neurotrophins. This may

further contribute to risk for neurodevelopmental disorders in

children born preterm (Figure 5). Understanding the role of

neurotrophins like BDNF is timely and may provide important

clues to prevent such risk for neurodevelopmental disorders.

Conclusion

Therefore, based on this review, we conclude that in mothers

delivering preterm, altered levels of micronutrients (folate and

vitamin B12) and omega 3 fatty acids especially DHA during

pregnancy leads to altered one-carbon metabolism and

increased oxidative stress, affecting expression of neurotrophic

factors. These changes may be responsible for risk for the

metabolic and neurodevelopmental disorders in infants born

preterm. Further, we hypothesize that altered one-carbon

metabolism and oxidative stress may lead to altered epigenetic

regulation of neurotrophic factors in preterm pregnancy.

Acknowledgment

The authors acknowledge Indian Council of Medical Re-

search for giving the senior fellowship to one of the authors

(MD).

Declaration of interest: The author reports no conflicts of

interest. The authors alone are responsible for the content and

writing of the paper.

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