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4 doi: 10.1111/j.1365-3016.2012.01291.x

Biological Mechanisms for Nutritional Regulation of Maternal

Health and Fetal Development ppe_1291 4..26

Guoyao Wu,a,b Beth Imhoff-Kunsch,c Amy Webb Girardc

a
Faculty of Nutrition and Department of Animal Science, Texas A&M University, bCardiovascular Research Institute and Department of Systems
Biology and Translational Medicine, Texas A&M Health Science Center, College Station, TX, and cHubert Department of Global Health, Rollins
School of Public Health, Emory University, Atlanta, GA, USA

Abstract
This review paper highlights mechanisms for nutritional regulation of maternal health and fetal development.
Malnutrition (nutrient deficiencies or obesity) in pregnant women adversely affects their health by causing or
exacerbating a plethora of problems, such as anaemia, maternal haemorrhage, insulin resistance, and hyperten-
sive disorders (e.g. pre-eclampsia/eclampsia). Maternal malnutrition during gestation also impairs embryonic
and fetal growth and development, resulting in deleterious outcomes, including intrauterine growth restriction
(IUGR), low birthweight, preterm birth, and birth defects (e.g. neural tube defects and iodine deficiency disor-
ders). IUGR and preterm birth contribute to high rates of neonatal morbidity and mortality. Major common
mechanisms responsible for malnutrition-induced IUGR and preterm birth include: (i) abnormal growth and
development of the placenta; (ii) impaired placental transfer of nutrients from mother to fetus; (iii) endocrine
disorders; and (iv) disturbances in normal metabolic processes. Activation of a series of physiological responses
leading to premature and sustained contraction of the uterine myometrium also results in preterm birth. Recent
epidemiologic studies have suggested a link between IUGR and chronic metabolic disease in children and adults,
and the effects of IUGR may be carried forward to subsequent generations through epigenetics. While advanced
medical therapies, which are generally unavailable in low-income countries, are required to support preterm
and IUGR infants, optimal nutrition during pregnancy may help ameliorate many of these problems.
Future studies are necessary to develop effective nutritional interventions to enhance fetal growth
and development and alleviate the burden of maternal morbidity and mortality in low- and middle-income
countries.

Keywords: fetus, infant, mother, nutrition, micronutrients, pregnancy.

Multiple genetic and environmental factors, including
maternal nutrition, regulate fetal survival, growth and
development.1,2 Studies with animal models have
demonstrated that fetal growth and development is
most vulnerable to maternal nutrient deficiencies
in early gestation, specifically during the peri-
implantation period and the period of rapid placental
development.3 Neural tube defects, cretinism, intrau-
terine growth restriction (IUGR), and preterm birth
are well-known adverse outcomes of general and spe-
cific nutrient deficiencies in human pregnancy.1
Correspondence: Guoyao Wu, Rm. 212, Kleberg Center, Texas
A&M University, 2471 TAMU, College Station, TX 77843-2471,
USA.
E-mail: g-wu@tamu.edu
In addition to effects on fetal development, maternal
malnutrition contributes to poor maternal health as
well as high rates of morbidity and mortality. For
example, maternal stunting, the result of chronic
malnutrition during childhood, increases the risk of
obstructed labour and obstetric fistula.4 Calcium defi-
ciency is a risk factor for hypertensive disorders of
pregnancy,1 while anaemia may increase the risk of
maternal mortality because of haemorrhage.5,6
In October 2010, the United Nations Food and Agri-
culture Organization reported that 925 million people
worldwide, including a large proportion of women of
reproductive age, suffered from hunger; nearly all of
the undernourished reside in low- and middle-income
countries.7 Deficiencies of protein, vitamin A, iron,
zinc, folate, and other micronutrients remain major

© 2012 Blackwell Publishing Ltd

Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

nutritional problems in poor regions of the world.8–10
Fetal undernutrition can occur in adolescent pregnan-
cies because of competition between the fetus and the
mother for nutrients. Low birthweight and preterm
delivery are twice as common and neonatal mortality
is almost three-times higher in adolescent pregnancies
than in adult pregnancies.2,10 Furthermore, suboptimal
nutrition may result from short interpregnancy inter-
vals (<18 months) which are associated with miscar-
riage, IUGR and preterm delivery.11,12
While maternal undernutrition has substantial
implications for maternal and fetal health, overweight
and obesity in pregnancy similarly increase the risk
of poor health outcomes.13 Maternal obesity or over-
nutrition before or during pregnancy may result
in IUGR and increased risk of neonatal mortality
and morbidity, as well as adverse maternal health
including insulin resistance, maternal haemorrhage,
and hyperglycaemia.13,14 Currently one billion adults,
worldwide, are overweight and more than 300 million
are obese.1 Given the increasing epidemic of over-
weight and obesity in low-, middle- and high-income
nations, overnutrition has emerged as a major public
health problem globally.13
Over the past two decades, compelling epidemio-
logical studies have linked both over- and under-
nutrition in pregnancy with maternal, fetal, and infant
morbidity and mortality.1 Additionally, substantial
evidence links IUGR with the aetiology of many
chronic diseases in adult humans.15 These findings
have prompted extensive animal studies to identify
the biological mechanisms for nutritional regulation
of fetal growth and development as well as long-term
health consequences of IUGR, preterm birth, and
other poor pregnancy outcomes.16–21 This paper high-
lights the recent advances in this area of biomedical
research, with a focus on effects of macronutrients
and micronutrients on adverse pregnancy outcomes,
including maternal morbidity and mortality, infant
morbidity and mortality, as well as fetal and infant
growth and development. Specifically, our work
focuses on nutritional needs for fetal growth and
development, consequences of maternal malnutrition
on maternal and fetal health outcomes, implications of
IUGR, and future research priorities. Furthermore, we
provide an overview of the biological mechanisms of
nutritional needs in pregnancy, while the other papers
contained within this supplement summarise the
effects of specific nutrition interventions on maternal,
newborn, and child health outcomes.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 5
Nutritional needs for fetal growth
and development
Macronutrients required for fetal growth
and development
Energy [primarily as adenosine triphosphate (ATP)] is
required for a variety of physiological processes in the
fetus, including nutrient transport, cell motility, and
synthetic pathways.22 Dietary macronutrients are the
ultimate sources of energy substrates during fetal
growth although the specific sources of substrates for
ATP production in the conceptus are cell- and tissue-
specific. In pregnant women and the developing
fetuses, glucose is the major fuel for red blood cells,
brain, retinal cells, and kidney medulla cells, while
the maternal and fetal hearts utilise both glucose and
lactate. The small intestine of both the mother and the
fetus oxidises the amino acids glutamate, aspartate,
and glutamine to provide most energy requirements
of these tissues.21 Through b-oxidation, fatty acids are
the major energy substrates for the maternal liver,
skeletal muscle, heart and kidneys. The fetal liver
also oxidises long-chain fatty acids (LCFA) to CO2 at
relatively high rates. Thus, a balanced and adequate
supply of carbohydrates, lipids and proteins is critical
to meet fetal and maternal needs for energy. In the
next sections we discuss the contributions of each of
the macronutrients in more detail.
Carbohydrates
Glucose is a major energy substrate for the mother and
the developing fetus. Glucose is also the predominant
source of reduced nicotinamide adenine dinucleotide
phosphate (NADPH), which is an essential cofactor
for antioxidative enzymes and diverse metabolic path-
ways in all cell types.22 Thus, a deficiency of glucose
will immediately result in neurological dysfunction
and disorders of the circulatory system. The metabolic
functions of glucose to maintain whole-body homeo-
stasis cannot be served by any other nutrient. Fetal
glucose is primarily derived from the uptake of mater-
nal glucose by the placenta.23 The fetal liver and kidney
synthesise only a small amount of glucose from gluco-
neogenic amino acids.23 Dietary starch is the primary
source of glucose for the mother (Table 1). In the post-
absorptive state or in response to starvation or under-
nutrition, pregnant women mobilise glucose from (1)
glycogen stores in the liver and muscle; (2) glycerol
 6

Table 1. Needs of macronutrients for maternal health and fetal growth and development

Consequences of insufficiency
G. Wu et al.

Uptake by the fetus Action on fetal growth and development in pregnancy

Carbohydratesa Glucose from (1) hydrolysis of maternal dietary starch; (2)
glycogen from diet as well as stores in liver and muscle;
(3) glycerol from lipolysis in adipose tissue; and (4) amino
acids from protein degradation. Maternal glucose is
transferred to fetus via the placenta.
Lipidsb Saturated and monounsaturated fatty acids can be
synthesised from glucose and amino acids in mother and
fetus; fetus accumulates relatively small amounts of lipids
before gestation week 25, but relatively large amounts
thereafter; EFA must be supplied through maternal diet;
placenta is permeable to long-chain PUFA and can
transport EFA from mother to fetus.
Proteinc Some amino acids can be synthesised from EAA via
inter-organ metabolism; multiple amino acid transport
systems in the uterus and placenta; uptake of glutamine,
glutamate, and other amino acids by fetus through
swallowing of amniotic fluid (enteral nutrition).
A major energy substrate for mother and fetus; the
exclusive source of ATP for red blood cells; the
predominant source of NADPH via the pentose cycle
for NO and superoxide synthesis, one-carbon-unit
metabolism, production of pregnancy hormones, and
antioxidative reactions.
Long-chain PUFA maintain membrane fluidity and
permeability; serve as metabolic fuels for liver, skeletal
muscle and heart; are important for retinal and neural
development; act as bioactive signalling molecules;
play an important role in the absorption of
lipid-soluble vitamins by the small intestine.
Amino acids are the building blocks of proteins and
peptides; precursors for the synthesis of nitrogenous
hormones; substrates for the production of numerous
substances, including DNA, neurotransmitters,
vasodilators, and signalling molecules; major
metabolic fuels for the small intestine and cells of the
immune system; contribute substantially to fetal
growth.
Neurological damage; ketosis; fetal
growth retardation; maternal weight
loss; impaired blood flow; weakness;
fatigue; reduced intestinal motility in
both mother and fetus; suboptimal
health of the colon in mother.
Maternal weight loss; hyperglycaemia;
deficiency of EFA can detrimentally
impair the growth and development
of fetal organs (including the brain,
eyes, and heart); deficiencies of
lipid-soluble vitamins.
Neurological damage; anaemia; fetal
growth retardation; maternal weight
loss; impaired blood flow; weakness;
fatigue; reduced intestinal motility;
intestinal atrophy; kidney
dysfunction; cardiac failure; oxidative
stress.

a
Complex carbohydrates for enteral nutrition (starch, glycogen and fibre) and simple carbohydrate for parenteral nutrition (glucose).
b
PUFA that cannot be synthesised de novo by mother and fetus are linoleic acid (18:2w6) and a-linolenic acid (18:3w3); PUFA that cannot be adequately synthesised by mother and
fetus from preformed precursors include arachidonic acid (20:4w6), eicosapentaenoic acid (20:5w3), and docosahexaenoic acid (20:6w3); MUFA that can be adequately synthesised by
mother and fetus include palmitoleic acid (16:1w7), cis-vaccenic acid (18:1w7), and oleic acid (18:1w9); saturated LCFA that can be adequately synthesised by mother and fetus include
palmitic acid (16:0), stearic acid (18:0), and arachidic acid (20:0); short-chain fatty acids include butyrate, propionate, and acetate.
c
EAA that cannot be synthesised by mother and fetus are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine; amino acids that are
inadequately synthesised by gestating mother and her fetus include arginine and glutamine; NEAA that can be synthesised presumably in adequate amounts by mother and fetus
include alanine, asparagine, aspartate, cysteine, glutamate, glycine, proline, serine, taurine, and tyrosine.28,29
ATP, adenosine triphosphate; EAA, essential amino acids; EFA, essential fatty acids (n-3 and n-6 PUFA); LCFA, long-chain fatty acids; MUFA, monounsaturated fatty acids;
NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; PUFA, polyunsaturated fatty acids.

Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

© 2012 Blackwell Publishing Ltd
 Maternal nutrition and healthy pregnancy 7

from lipolysis in adipose tissue; and (3) amino acids of a variety of physiologically important molecules,
released by skeletal muscle.22 However, sole depen- including hormones, neurotransmitters, NO, creatine,
dence of these mechanisms to provide glucose in the glutathione, carnitine and polyamines.31,32 Addition-
maternal circulation will cause maternal wasting. ally, through multiple cell signalling pathways, amino
acids regulate key metabolic pathways that are vital
Lipids to human health, growth, development and reproduc-
tion.33 Based on nitrogen balance and growth, amino
The human placenta is permeable to LCFA and trans-
acids are traditionally classified as either nutritionally
fers them to the fetus for metabolic utilisation.24 Liver,
essential or nonessential (Table 1). However, the clas-
skeletal muscle, and heart in the mother and the
sification of nutritionally nonessential amino acids
fetus depend on LCFA as major metabolic fuels. Con-
(NEAA) has conceptual limitations because there is no
versely, short-chain fatty acids are the primary energy
compelling evidence that certain NEAA (e.g. arginine
sources for colonocytes. Prior to 25 weeks of gestation,
and glutamine) can be adequately synthesised by the
the human fetus accumulates only a small amount of
mother or fetus to support optimal fetal growth and
lipids. After 25 weeks of pregnancy, the fetus expo-
development.33–35 The synthesis of fetal proteins
nentially accumulates a relatively large amount of lip-
depends on the balanced provision of all the constitu-
ids.24 Placental and fetal tissues are able to synthesise
ent amino acids, namely both nutritionally essential
the w9 (oleic acid) family of unsaturated fatty acids.
amino acids (EAA) and NEAA. To meet the needs
However, humans cannot synthesise the w6 or w3
for amino acids by the developing fetus, pregnant
fatty acids, linoleic acid and a-linolenic acid. There-
women should consume diets containing adequate
fore, these two unsaturated fatty acids must be pro-
amounts of high-quality proteins. Because most
vided in the diet to synthesise the long-chain w-6
staple grains are deficient in several EAA (e.g. lysine,
and w-3 polyunsaturated fatty acids (PUFA; Table 1).
methionine, threonine and tryptophan), the consump-
Physiologically and nutritionally important long-
tion of animal source foods is recommended.36 Veg-
chain w-6 and w-3 PUFA include arachidonic acid
etarian and vegan women must carefully balance their
(20:4w6), eicosapentaenoic acid (EPA 20:5w3), and
intakes of grains, legumes, and other sources of
docosahexaenoic acid (DHA 20:6w3) (Table 1). Beyond
protein to ensure they meet their EAA requirements;
serving as an energy source, long-chain PUFA play an
when this is not possible, supplements with specific
important role in maintaining the fluidity, permeabil-
amino acids will be needed to ensure adequate EAA
ity and conformation of cell membranes. They are also
intakes.
precursors for the synthesis of bioactive lipid mol-
ecules, including prostaglandins, thromboxanes and
leukotrienes.24 Additionally, some long-chain PUFA Minerals
(e.g. DHA) are regulators of eicosanoid metabolism
Nutritionally significant micro-minerals cannot be
and the synthesis of nitric oxide (NO), a signalling
synthesised by the body and, therefore, must be pro-
molecule and a neurotransmitter in multiple tissues,
vided in the diet (Table 2). These inorganic nutrients
including the brain).25,26 Among PUFA, DHA has
are the backbone of the skeleton system, serve as
received the most attention over the past decade for
second messengers in cell signalling, and maintain the
its role in development. DHA modulates appropriate
polarity of the plasma membrane. Minerals also regu-
neuronal sheath mylenation and differentiation of
late extracellular and intracellular osmolality, which
neural stem cells to neurons and promotes the devel-
is important for maintaining cell and blood volume
opment of the brain, nerves, retinal photoreceptors,
as well as cell viability and shape. Most minerals are
and the immune system in the fetus.27–30 However,
either cofactors for enzymes or components of metallo
rates of the synthesis of DHA from a-linolenic acid in
proteins, and also participate in electron transport and
the human placenta and fetal brain are low relative to
redox reactions. The metabolic functions of the miner-
the needs of DHA by the rapidly growing fetus.24
als are summarised in Table 2. We review those most
commonly implicated in fetal and maternal health
Proteins
outcomes.
Amino acids serve not only as building blocks for pro- Calcium is a major component of the skeleton,
teins but also as essential precursors for the synthesis cytoskeleton and teeth.37 Calcium-activated enzymes

© 2012 Blackwell Publishing Ltd

Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
 Table 2. Nutritional needs of minerals for maternal health and fetal growth and development
8
Special importance during Consequences of insufficiency
Rich dietary sources General actions pregnancy in pregnancy

Calcium Dairy foods Component of the bone; second messenger that regulates Cell-to-cell adhesion; implantation; and placentation PIH, pre-eclampsia, eclampsia; preterm
numerous biochemical pathways. delivery
G. Wu et al.

Chlorine Meat, dairy Principal anion in the extracellular fluid; required for Maintenance of osmolality in blood protein digestion Disturbance of whole-body homeostasis;
foods, salt production of gastric acid; maintain a hydrated state of the embryonic and fetal death
mucus on epithelial cells
Chromium Meat, vegetables Potentiate insulin sensitivity Glucose transport; toxic at high intake Contributes to insulin resistance
Cobalt Meat A component of vitamin B12 One-carbon-unit metabolism; toxic at high intake Anaemia, neurological disorders
Copper Meat Function of mitochondrial ETS; cofactor of cytosolic Cu/Zn-SOD; ATP production in mitochondria; toxic at high intake Weakness, fatigue, impaired fetal growth
regulation of iron and molybdenum absorption by the small and contribute to iron-deficiency anaemia and and development
intestine impairment of zinc absorption
Fluorine Meat, bones A component of teeth Strength of teeth; toxic at high levels Reduced fertility (animal studies)
Iodine Sea vegetables, Production of thyroid hormones Important for the proper development of central Iodine deficient disorders, including
seafood, iodised salt nervous system in fetuses cretinism
Iron Meat, legumes, Oxygen binding, transport and storage; metabolism, generation Strain on maternal iron supply in pregnancy to meet Iron deficiency anaemia can increase risk
fortified foods of ATP maternal haemo-expansion; toxic at high intake of maternal haemorrhage; maternal
mortality; preterm birth; IUGR
Magnesium Meat Required for glucose and protein metabolism ATP production by red blood cells; cofactor for some Pre-eclampsia and preterm birth
ATP-dependent enzymes
Manganese Meat Required by Mn-dependent enzymes (including arginase and Ammonia detoxification by liver anti-oxidative Neurological damage, oxidative stress,
mitochondrial Mn-SOD) reactions and death
Molybdenum Meat, vegetables Component of molybdopterin, sulfite oxidase, and xanthine Toxic at high levels and contribution to iron-deficiency Increase of risk for copper toxicity;
oxidoreductase; regulation of copper and iron absorption anaemia; prevention of copper toxicity impaired metabolism of purines
Nickel Meat, vegetables Cofactor for microbial enzymes (e.g. urease, glyoxylase, and Normal microbial activity in the intestine; toxic at high Maintenance of the normal microbiota in
Ni-SOD); required for microbial metabolism in the lumen of levels the intestine
the intestine
Phosphorus Meat, dairy products ATP production, cell signalling, component of the bone Embryonic survival; fetal growth and development Weakness; fatigue; embryonic and fetal
energy metabolism death; IUGR
Potassium Meat, dairy products, Most abundant cation in intracellular fluid Maintenance of intracellular osmolality; function of Cardiac arrest; weakness; fatigue; IUGR
vegetables the nerve and muscle; fetal growth and development
Selenium Meat Cofactor for antioxidant enzymes Protect mother and fetus from oxidative stress; toxic Cardiac dysfunction; oxidative stress
at high levels
Silicon Meat, vegetables Mediate association between cells and macromolecules Required for the growth of connective tissue and Abnormal joint structure; soft-bone
(e.g. osteonectin); required for cartilage calcification bones; toxic at high intake syndrome;
Sodium Meat, dairy products; Principal cation in extracellular fluid; sodium pump; nutrient Maintenance of extracellular osmolality; function of Malnutrition; multiple organ dysfunction;
salt transport the nerve and muscle; fetal growth and development IUGR
Sulfur Meat, milk, egg Component of sulfur-containing amino acids metabolism of Inorganic sulfur cannot be used by mother or fetus; Oxidative stress; IUGR
intestinal bacteria toxic at high levels
Vanadium Meat, vegetables React with H2O2 to form a pervanadate to stimulate Cell signalling; glucose transport Contribute to insulin resistance
phosphorylation of receptor proteins; potentiate insulin
sensitivity
Zinc Meat, legumes Gene expression; cofactor of cytosolic Zn/Cu-SOD; immune Fetal growth and development; regulation of food Malnutrition; potential detrimental effect
function; cell signalling intake; impairment of copper absorption at high levels on immune function; IUGR

Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

© 2012 Blackwell Publishing Ltd
ATP, adenosine triphosphate; ETS, electron transport system; IUGR, intrauterine growth restriction; PIH, pregnancy-induced hypertension; SOD, superoxide dismutase.

and calcium-binding proteins include pancreatic
a-amylase, pancreatic phospholipases A2 and C,
protein kinase C, phosphorylase kinase, calmodulin,
troponin C, NO synthase, calcium-ATPase, and blood
clotting proteins.38 Thus, calcium is required for diges-
tion of dietary starch, blood clotting, intracellular
proteolysis, cell-to-cell adhesion, and NO synthesis
in nearly all cell types, including endothelial cells and
uterus.39,40 Furthermore, calcium is a second messen-
ger and in this role regulates uterine contraction. By
maintaining the uterus in a quiescent state through an
NO-dependent mechanism,40 calcium supplementa-
tion may modulate the risk of preterm labour.41
Iodine is an essential component of the thyroid hor-
mones (triiodothyronine and thyroxine). Thyroid hor-
mones regulate gene expression, energy metabolism,
growth, development and reproduction.42 During fetal
development, thyroid hormones are required for
migration of radial neurons and appropriate neuronal
mylenation. As discussed later and in the review in
this supplement by Zimmermann,43 severe maternal
iodine deficiency, which causes a hypothyroid
condition, is associated with cretinism while milder
forms of iodine deficiency can impair cognitive
development in the infant. To meet the demand for
thyroid hormone by the rapidly developing fetus, the
recommended daily allowance for iodine increases
by approximately 1/3 from 150 mg/day to 220 mg/day
during pregnancy.44
Iron is the most abundant trace element in the
body.45 It is a component of haeme and haeme pro-
teins, including haemoglobin, myoglobin, and cyto-
chromes. Iron is also required for the activities of
non-haeme proteins. Thus, physiological levels of iron
play important roles in: (1) oxygen binding, transport,
storage, and sensing; (2) the metabolism of nutrients
(including proteins, lipids, and glucose); (3) mito-
chondrial electron transport and ATP production;
(4) DNA synthesis; (5) immunity; and (6) antioxida-
tive reactions. A deficiency of iron can result in
anaemia, hypoxia, increased risk for maternal mortal-
ity, as well as preterm birth and IUGR.46 Iron require-
ments almost double during pregnancy, namely from
15 mg/day to 27 mg/day.44 This increase is necessary
to meet the iron requirements of the mother and the
developing fetus as well as the haemodilution which
occurs in the second and third trimesters. These
increases in iron needs are partially compensated for
by a progressive rise in iron absorption during preg-
nancy; however, the amounts that can be absorbed
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 9
from even an optimal diet are less than the iron
requirements in later pregnancy.6,47 Therefore, a
woman must have adequate iron stores when entering
pregnancy. This is unlikely for many women espe-
cially in developing countries, where 60% of pregnant
women are anaemic.1
Magnesium has multiple metabolic functions.
Magnesium, the second most abundant cation in cells,
is a cofactor for many enzymes in multiple metabolic
pathways, including glycolysis, the pentose cycle, the
urea cycle, gluconeogenesis, purine and pyrimidine
synthesis, fatty acid oxidation, and a-ketoacid decar-
boxylation.48 This mineral regulates nutrient metabo-
lism, antioxidative reactions, signalling pathways, and
ion channels. Notably, because magnesium promotes
the relaxation of vascular smooth muscle cells and
inhibits the contraction of the uterine myometrium,
magnesium sulfate has long been used in treatment of
pre-eclampsia, preterm labour, and preterm birth in
clinical medicine.49
Zinc plays a key role in nutrient metabolism as
well as the structures of DNA and protein.50 Although
zinc is not directly involved in oxidation–reduction
reactions, it tightly binds to proteins in cells. There
are probably 100 zinc enzymes associated with the
mammalian genome. Zinc-dependent enzymes and
zinc-binding proteins include carbonic anhydrase,
carboxypeptidases A and B, protein kinase C, phos-
pholipase C, insulin, superoxide dismutase (cytosol),
thymulin, and poly(ADP-ribose) polymerase. Thus,
zinc plays an important role in regulating food intake,
nutrient metabolism, DNA and protein synthesis,
antioxidative reactions, neurological function, immu-
nity, growth and development.51,52
Vitamins
Vitamins are required in small amounts as cofactors in
biochemical reactions and classified into two types
(water- or lipid-soluble) based on their solubility
(Table 3). Water-soluble vitamins are absorbed by the
small intestine into the portal circulation, whereas
lipid-soluble vitamins can only be absorbed efficiently
by the intestine into the lymph circulation when
normal fat absorption occurs. Except for niacin and
vitamin D which are formed from tryptophan and
cholesterol, respectively, vitamins cannot be synthe-
sised in human cells. The functions of all vitamins are
summarised in Table 3. Deficiencies of vitamins gen-
erally result in metabolic disorders and diseases with
 10
Table 3. Nutritional needs of vitamins for maternal health and fetal growth and development

Special importance during Consequences of insufficiency

Rich dietary sources General actions pregnancy in pregnancy

Biotin Meat, fresh vegetables Coenzyme A for ATP-dependent carboxylases Embryonic survival and development; Anorexia, depression, dermatitis, muscle
G. Wu et al.

consumption of raw eggs increases risk pain

for biotin deficiency
Folate Green leafy vegetables, Essential for one-carbon-unit metabolism and Formation of neural tube; formation of Neural tube defects (spina bifida and
legumes, fortified foods DNA synthesis; removal of homocysteine red blood cells anencephaly)
(folic acid)
Vitamin A (retinol Whole milk, liver, eggs, dark Component of visual pigment in retina; regulates Embryonic and fetal survival; regulate Maternal ocular problems (e.g. night
and carotenoids) coloured fruits and gene expression; plays an important role in haematopoiesis; fetal growth and blindness); potential detrimental impact
vegetables development and function of immune system; development; potential teratogenicity at on maternal and fetal immune function;
epithelial cell function high intake of vitamin A higher risk of maternal anaemia
Vitamin B1 Meat, unrefined cereal Coenzyme for decarboxylase complexes in Production of ATP from glucose in the Anorexia, maternal weight loss,
(thiamin) glucose and amino acid degradation brain; fetal growth and development; neurological symptoms, muscle
maternal health degeneration, IUGR
Vitamin B2 Meat, grains, legumes Component of FAD and FMN required for Nutrient metabolism; fetal growth and Maternal skin lesion, dermatitis, nerve
(riboflavin) oxidoreductases, amino acid oxidases, and development; maternal health degeneration, IUGR
other flavoprotein enzymes
Vitamin B3 (niacin) Meat, fresh vegetables Component of NAD and NADP required for Nutrient metabolism; embryonic and fetal Four-D syndromes: dermatitis, diarrhoea,
oxidoreductases; post-translational survival; fetal growth and dementia, and death; IUGR
modifications of a variety of proteins via development; maternal health
poly(ADP-ribose) polymerases
Vitamin B5 Meat, whole grain cereals, Component of coenzyme A for numerous key Nutrient metabolism; embryonic and fetal Loss of appetite, skin lesion, depression,
(pantothenic legumes, fresh vegetables enzymes (including dehydrogenases); a survival; fetal growth and weakness, fatigue, IUGR
acid) prosthetic group in acyl carrier protein of the development; maternal health
fatty acid synthase complex
Vitamin B6 Meat, dairy products, nuts, Coenzyme for amino acid transaminases and Amino acid metabolism, removal of Anaemia, skin lesion, depression, seizure,
(pyridoxal fresh vegetables decarboxylases, as well as threonine aldolase; ammonia, muscle function nausea, vomiting
phosphate) covalently bound to muscle glycogen
phosphorylase
Vitamin B12 Meat Participate in one-carbon-unit metabolism and Neurological development and function; Anaemia, homocysteinemia,
(cobalamin) conversion of homocysteine into methionine formation of red blood cells cardiovascular dysfunction,
neurological disorders, oxidative stress
Vitamin C Fresh vegetables, fruits Hydroxylation of protein-bound proline and Connective tissue growth and Subcutaneous haemorrhage; defective
lysine; antioxidant; promote iron absorption development; protect mother and fetus collagen structure
from oxidative stress
Vitamin D Can be synthesised de novo Steroid pro-hormone; influences innate and Absorption of dietary calcium and Impaired skeletal growth; IUGR; rickets
by humans in exposure to adaptive immune function; stimulates growth phosphorus to support fetal growth
sunlight; fatty fish; fortified of osteoclasts; allows body to absorb calcium and development; potential toxicity at
milk and phosphorus high intake
Vitamin E Vegetable oils; animal fats; Antioxidant; stabilise cell membrane Embryonic and fetal survival life-span of Maternal and fetal anaemia; muscle
meat; fresh vegetables red blood cells weakness
Vitamin K Vegetables; animal products; Generation of biologically active clotting factors Stop bleeding when a blood vessel is cut. Risk for maternal haemorrhage
intestinal synthesis by
bacteria

ATP, adenosine triphosphate; FAD, Flavin adenine dinucleotide; FMN, Flavin mononucleotide; IUGR, intra-uterine growth restriction; NAD, Nicotinamide adenine dinucleotide; NADP, Nicotinamide adenine
dinucleotide phosphate.

Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

© 2012 Blackwell Publishing Ltd
 Maternal nutrition and healthy pregnancy 11

characteristic syndromes. In this section, we review the conversion of N5-methyl-tetrahydrofolate into

those vitamins whose deficiencies in pregnancy
are most commonly associated with poor maternal
and fetal outcomes, namely vitamins A, B6, B12, D, and
folate.
Pyridoxal phosphate (the active form of vitamin B6),
folic acid (the synthetic form of folate), and vitamin
B12 (methylcobalamin) are of considerable importance
in fetal development because of their role in one-
carbon-unit metabolism (Figure 1). These reactions are
critical for the production of DNA bases, the conver-
sion of homocysteine into methionine, neurological
and immunological function, growth and develop-
ment, and the formation of red blood cells.53–55 Addi-
tionally, vitamin B6 is required for the synthesis of
neurotransmitters, polyamines and histamine, as well
as the removal of ammonia from the body.53 Of particu-
lar interest, vitamin B6 has been used to treat women
for pregnancy-associated nausea and vomiting.56
Folate has a close metabolic inter-relationship with
vitamin B12 (cobalamin).57 Vitamin B12 is required for
tetrahydrofolate, which is the active form of folate
involved in the synthesis of DNA, and the metabolism
of homocysteine. Folate is essential to embryonic, fetal
and infant growth and development58, and deficiency
in early pregnancy can disrupt neural tube formation.
As well, deficiencies of folate or B12 disrupt red blood
cell production resulting in megaloblastic anaemia.54
However, because of the re-absorption of bile-derived
vitamin B12 by the small intestine, acute deficiency is
not common in women who enter pregnancy with
adequate stores.55 Nonetheless, because vitamin B12 is
only found in animal source foods, vegans, vegetar-
ians, and those who do not have the resources to
obtain animal source foods (i.e. very poor women) are
at risk for B12 deficiency.
Vitamin A (retinol) and its metabolites exhibit
metabolic and regulatory versatilities in humans.
Retinal, an isomer of retinol, is a component of
rhodopsin, the visual pigment that is responsible for
vision under low-light conditions. Second, retinol and

-CH3 8 SAM 7 Methionine 6 Homocysteine

Vit B12

Folate
NADPH+H+ Dihydrofolate
NADPH+H+
1 1 dTMP DNA synthesis
NADP+ 13
NADP+ dUMP

H4-Folate 4 N5-N10-Methylene H4-folate 5 N5-Methyl H4-folate

ATP + Formate Vit B6
Ser Gly + H2O NADP+ NADH+H+ NAD+
2
NADPH+H+ + CO2 2
ADP + Pi 3 NADPH+H+
NADP+ H2O NH4+
N10-Formyl H4-folate N5-N10-Methenyl H4-folate N5-Formimino H4-folate
2 9
H2O ADP + L-Glutamate
14 11Pi
10 ATP 9
H4-folate
Purine N5-Formyl H4-folate 12 N-Formiminoglutamate
synthesis (folinic acid) L-Histidine

Figure 1. Metabolism of one-carbon units in mammals. Folate, histidine, methionine, glycine and serine participate in the transfer of
one-carbon units for the synthesis of purines and DNA as well as methylation reactions in mammals. The enzymes catalysed the
indicated reactions are: (1) folate reductase; (2) N5-N10-methylene H4-folate dehydrogenase (a trifunctional enzyme possessing N10-
formyl H4-folate synthetase, N5-N10-methylene H4-folate dehydrogenase, and N5-N10-methenyl H4-folate cyclohydrolase activities);
(3) N10-formyl H4-folate dehydrogenase; (4) serine hydroxymethyl transferase; (5) N5-N10-methylene H4-folate reductase; (6) methionine
synthase; (7) S-adenosylmethionine synthase; (8) S-adenosylmethionine as a major methyl group donor in methyltransferase-catalyzed
reactions; (9) formiminotransferase-cyclodeaminase (a bifunctional enzyme possessing glutamate formiminotransferase and formim-
idoyl H4-folate cyclodeaminase activities); (10) serine hydroxymethyl transferase, N5-N10-methenyl H4-folate cyclohydrolase, and spon-
taneous reaction at pH 4–7.0; (11) N5-N10-methenyl H4-folate synthetase; (12) a sequential series of enzymes: histidase, urocanase, and
imidazolone propionate hydrolase; (13) thymidylate synthase; and (14) formyltransferase. ATP, adenosine triphosphate; dTMP, deox-
ythymidine 5′-monophosphate; dUMP, deoxyuridine 5′-monophosphate; Gly, glycine; H4-folate, tetrahydrofolate; NADPH, nicotina-
mide adenine dinucleotide phosphate; SAM, S-adenosylmethionine; Ser, serine; Vit, vitamin.

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Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
12 G. Wu et al.
its derivatives (including retinoic acid) bind nuclear
proteins to regulate gene expression, cell proliferation,
and differentiation in diverse cell types, including
immunocytes and epithelial cells.59 Third, vitamin
A and its metabolites play an important role in deve-
lopment and function of the immune system by
promoting: (1) proliferation and differentiation of
lymphocytes; (2) activation of T-cells to synthesise
cytokines; (3) tissue-specific lymphocyte homing;
(4) production of antigen-specific antibodies; and (5)
generation of a large amount of NO (a mediator of
the immune response) by activated macrophages.60
Fourth, retinol is necessary for alveolar formation and
lung development in early gestation. Fifth, retinoic
acid participates in the synthesis of glycoproteins,
which accounts for, in part, its effect on enhancing cell
growth and differentiation, as well as functional integ-
rity of all epithelial cells. Last, vitamin A regulates
haematopoiesis by stimulating the differentiation of
stem cells into red blood cells. Thus, a deficiency of
vitamin A can cause embryonic death and impair fetal
survival, growth and development.61 Night blindness
in pregnancy, a consequence of severe vitamin A defi-
ciency, is associated with maternal and neonatal mor-
tality and IUGR. However, it should be noted that
high doses of vitamin A, especially in early gestation,
are teratogenic.62 Thus, caution should be taken in
supplementing pregnant women with high doses of
vitamin A. b-Carotene is a good source of vitamin A
for humans and is not known to be teratogenic.63
Vitamin D is a steroid prohormone. In humans,
when the skin is exposed to sunlight, 7-
dehydrocholesterol is converted to cholecalciferol
(vitamin D3).64 Vitamin D is metabolised to 1,25-
dihydroxyvitamin D3 (calcitriol, a hormone) which
plays a central role in calcium and phosphate metabo-
lism and, therefore, bone accretion and minera-
lisation.64 Specifically, through regulation of gene
expression, calcitriol has three effects: (1) activating
the vitamin D-dependent calcium and phosphate
transport systems in the small intestine; (2) stimulat-
ing the growth of osteoclasts; and (3) enhancing
calcium resorption by the kidney. Additional regula-
tory functions for calcitrol in non-skeletal tissues
have been identified in recent years. One of the first
extra-skeletal tissues identified was the placenta.65,66
Although evidence is limited, it has been hypoth-
esised that the immunosuppressive effects of calcitrol
dampen the immune response against the early con-
ceptus to promote successful implantation.67,68
Consequences of maternal malnutrition on
maternal and fetal health outcomes
Overall negative impacts
Both undernutrition and overnutrition can be classi-
fied as malnutrition because these two extremes of
nutrition are commonly characterised by (1) imbal-
ances of nutrients (e.g. amino acids, PUFA, vitamins
and minerals); (2) elevated levels of cortisol in blood;
and (3) oxidative stress.2,16 Maternal malnutrition
during pregnancy can result in a plethora of problems
in both mother and fetus (Figure 2). In the following
sections, we will focus on the implications of malnu-
trition in pregnancy for fetal growth and development
and maternal health.
Impact of maternal undernutrition
The prenatal growth trajectory of all species is
sensitive to direct and indirect effects of maternal
nutrition at all stages between oocyte maturation and
birth.64 Epidemiological studies of the Dutch famine
(November 1944–May 1945) have shown that maternal
undernutrition of women during the second or third
trimester, but not the first trimester, reduced birth-
weight, birth length, and head circumference of
infants.69 Because of ethical concerns, animal models
have often been used to gain clarification on how the
timing of exposure modifies the effects of maternal
Impairment of
Offspring Growth and
Development
Maternal Insulin
Maternal Resistance
Haemorrhage
Cretinism
Preterm Birth Maternal
IUGR
Malnutrition
During
Maternal Anaemia Birth Defects
Pregnancy
Pre-eclampsia Cognition and
and Eclampsia Behaviour
Postpartum Fetal and Neonatal
Complications Long-Term Complications
Adverse Effects
on Mother and
Offspring Health
Figure 2. Major negative impacts of maternal malnutrition on
mother and fetus. Either undernutrition or overnutrition of
pregnant women can negatively affect maternal and fetal health,
pregnancy outcome, and offspring well-being in the neonatal
period, childhood and adulthood. Maternal malnutrition also
has long-term adverse effects on the health of both mother and
offspring. IUGR, intrauterine growth restriction.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

undernutrition on fetal development.70–81 Results
from these studies indicate that deficiencies of energy
or macronutrients during the first trimester of preg-
nancy have a greater detrimental effect on fetal devel-
opment than during late gestation.82–88 For example,
severe global undernutrition during the peri-
conceptual period accelerates maturation of the fetal
hypothalamic–pituitary–adrenal axis and causes
preterm delivery in ewes.71 Also, low pre-pregnancy
body weight, followed by global undernutrition
during mid pregnancy, reduces placental growth and
birthweight in adult sheep.73 Depending on nutritional
status before breeding, maternal undernutrition
during early and mid-gestation may result in variable
effects on the placental and fetal growth trajectory in
sheep;75–77 however, all studies have shown that, if
undernutrition is prolonged to late pregnancy, fetal
growth is greatly reduced, particularly in twin preg-
nancies.73,78 Regarding specific nutrients, the animal
studies suggest that the embryo/fetus is most vulner-
able to maternal deficiency of protein or amino acids
during the peri-implantation period and the period of
rapid placental development.3 Furthermore, the early
to mid gestation is the critical period when a defi-
ciency of micronutrients (vitamins and minerals)
has greatest adverse impacts on fetal growth and
development.79–81 For example, adequate folate during
the first trimester is important for the formation,
development, and closing of the neural tube in
humans.9
Impact of maternal obesity
While the majority of this review focuses on undernu-
trition, overnutrition in pregnancy has distinct meta-
bolic consequences during pregnancy that increase
the risk for poor maternal, fetal and neonatal/infant
outcomes.2 Obese women at any period of gestation
may experience a metabolic syndrome that is charac-
terised by elevated levels of glucose, hyperinsuli-
naemia, hyperlipidaemia, hypertension and insulin
resistance.16 With regards to timing of overnutrition,
evidence shows that maternal obesity before or during
pregnancy has negative impacts on fetal growth and
development.13 However, the presence of obesity in
the first trimester of gestation appears to be most det-
rimental to embryonic/fetal survival and growth.3
Interestingly, obese mothers who lose weight during
part or all of the gestation have increased risk for
IUGR. This apparent paradox may be explained by:
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 13
(1) ketosis resulting from the mobilisation of white fat
stores and partial oxidation of fatty acids in the liver;
(2) deficiencies of nutrients (e.g. glutamine and micro-
nutrients) in the fetus because of increased utilisation
by maternal tissues (e.g. kidneys) and impaired utero-
placental blood flow; and (3) elevations of cortisol that
inhibit fetal protein synthesis. During the perinatal
period, infants of obese women are at increased risk
for metabolic distress, stillbirths, neonatal hypoglycae-
mia, neonatal deaths, congenital abnormalities, and
cardiac dysfunction.13
Specific effects of maternal undernutrition on
birth outcomes
Effects of maternal undernutrition on the fetal
immune system
The immune system protects the host from various
pathogens and consists of the innate (natural, non-
specific) and the acquired (adaptive, specific) sys-
tems.89 The innate immune system provides the early
response to invading microbes, but it is non-specific
and lacks a memory effect. After a few days, if infec-
tion cannot be fully cleared by the innate immunity,
the adaptive immune system is activated. At birth,
the innate and acquired immune systems are largely
present in infants but remain functionally immature.89
As pointed out earlier in this review, the development
of both innate and acquired immune systems in the
fetus is highly dependent upon an adequate availabil-
ity of macro and micro nutrients.27,90,91 Epidemiologi-
cal and experimental data from both human and
animal studies suggest that maternal deficiencies of
energy, protein, fatty acids and micronutrients during
gestation seriously compromises development of the
fetal immune system, increase the risk of infectious
diseases in infants, and have long-term adverse effects
on the adults.1,89,92,93–95
Intrauterine growth restriction
Intrauterine growth restriction is defined as impaired
growth and development of the mammalian embryo/
fetus or its organs during pregnancy.2 In clinics, IUGR
is often diagnosed as birthweight below the 10th per-
centile of the birth-weight-for-gestational-age refer-
ence curve. The risk of IUGR is higher among women
with low pre-pregnancy body mass index (BMI),
low weight gain during pregnancy, short stature,
14 G. Wu et al.
Figure 3. Biochemical mechanisms Maternal Undernutrition
responsible for malnutrition-induced
intrauterine growth restriction (IUGR)
and its transgenerational effects in Deficiencies of
humans. Maternal undernutrition or Glucose
overnutrition during pregnancy can Amino Acids
result in imbalances of nutrients, Fatty Acids
oxidative stress, as well as endocrine and Micronutrients
metabolic disorders. The negative
impacts of these changes include
reductions in placental growth
(including vascular growth) and
utero-placental transfer of nutrients and
oxygen from mother to fetus, thereby
causing IUGR. Fetal growth retardation
increases the risk for birth defects and Birth Defects
other adverse pregnancy outcomes.
Results of recent studies indicate that the
effects of IUGR may be passed onto next
generations via epigenetics in a
sex-dependent manner
(fetal programming).
anaemia, and micronutrient deficiencies (e.g. iron and
zinc).7,46,96–100 IUGR infants represent 11% of all new-
borns in low- and middle-income countries and also a
large number of all newborns in high-income nations,
e.g. approximately 5% in the US.21 Given the large
population of infants in low- and middle-income
nations, IUGR induced by maternal undernutrition is
a major health problem worldwide.
Maternal undernutrition or overnutrition during
gestation reduces fetal growth in both humans and
experimental animals.1,3,13,101–105 Animal studies have
revealed complex biological mechanisms responsible
for IUGR (Figure 3).3 These mechanisms have been
corroborated with clinical observations and include:
(1) reduced placental growth and vascularity; (2)
impaired placental function (including the capacity for
transport of basic, neutral, and acidic amino acids as
well as glucose); (3) oxidative stress in the placenta
and conceptus; (4) reduced concentrations of haemo-
globins (because of iron deficiency) for oxygen trans-
port; and (5) impaired cell signalling for regulation
of protein synthesis in the placenta and fetus.2,3 A
growing body of evidence supports the idea that
NO and polyamines, which are products of arginine
catabolism, play important roles in placental
growth34,106 and, therefore, fetal growth.107–112 During
late (week 33) gestation, daily intravenous infusion of
L-arginine (20 g/day) for 7 days to women with
Imbalances of Maternal Overnutrition
Nutrients
Endocrine and and Excesses of
Growth, Development,
Epigenetics
Health ofDisorders
Metabolic Offspring Carbohydrates
Amino Acids
Fetal Programming Saturated Fats
Oxidative Stress
Calories
Impairment of Placental Growth
Reduced Transfer of Nutrients and Oxygen
from Mother to Fetus
Impairment of Fetal Fetal Programming
Growth and Development
Adverse Health Problems in Children and Adults
Transgenerational Effects
(Both Sex-Dependent and Independent)
unknown causes of IUGR increased birthweight at
term (week 39) by 6.4%.103 Possibly through increasing
NO bioavailability in the vasculature26 and improved
placentation,104 multiple micronutrient supplementa-
tion (vitamins plus minerals) to low-income pregnant
women enhanced fetal growth105,110 and reduced the
proportion of low birthweight infants.105 Similar
results were obtained with dietary supplementation of
folic acid plus iron110 or multiple micronutrients.111 A
meta-analysis of studies in low- and middle-income
country settings also reported that multiple micronu-
trient supplementation during pregnancy provided
some benefits with regards to fetal growth.9
There are concerns that pregnancy may negatively
impact maternal nutritional status because of
an increase in utero-placental blood flow, nutrient
mobilisation, and transfer of nutrients from mother to
fetus. Findings from well-controlled animal studies
indicate that, in mothers who were adequately nour-
ished before conception and then underfed during
pregnancy, maternal nutritional status was well
preserved.107–110,112 This preservation may result from
increased efficiency of metabolic transformations.107–109
It should be noted that limited evidence exists in
humans to support or refute the preservation of
maternal nutritional status during pregnancy. As well,
in resource-poor settings, women commonly enter
pregnancy undernourished. Their nutrition and health
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Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

status may be further compromised by other factors
such as short interpregnancy intervals, early age at
first pregnancy, and infection. Together, these factors
may exacerbate the potential detrimental effects of
undernutrition during pregnancy on maternal nutri-
tional status.
Preterm birth
Preterm birth (<37 weeks) is a leading cause of infant
morbidity and mortality worldwide, and occurs in
approximately 10% of pregnancies globally.113 The inci-
dence of preterm birth is particularly high in certain
countries (e.g. approximately 23% in rural Nepal, 21%
in India, and 17% in Bangladesh). Significant dispari-
ties also exist in prevalence even in the same nation
(e.g. 17–19% for African Americans vs. 7–8% for
whites). Immature infants have numerous complica-
tions, including respiratory distress syndrome, intra-
ventricular haemorrhage, necrotising enterocolitis,
sepsis, hyperammonaemia, and increased risk of
mortality. Preterm labour results from premature
and sustained activation of the uterine myometrium
or placental dysfunction and abruption.114,115 Placental
abruption is a condition in which the placenta
detaches prematurely from the uterine wall. Four
factors can stimulate the contraction of the uterine
myometrium: (1) mechanical stretch of the uterus; (2)
enhanced production of prostaglandin F2a (PGF2a) by
uterus, placenta and fetus; (3) elevated levels of hor-
mones (e.g. cortisol and oxytocin); and (4) reduced
bioavailability of NO.115–120 In response to malnutrition
as a stress factor, high levels of cortisol and oxytocin
are produced by the mother and the fetus. These
hormones trigger a pro-inflammatory response that
increases intracellular calcium, which triggers a cell
signalling cascade resulting in uterine contraction
(Figure 4).119–122 Thus, malnutrition plays a key role in
activating a series of physiological responses, leading
to preterm birth (Figure 4). Improvement of maternal
nutrition during gestation potentially decreases the
risk for preterm birth by two mechanisms: (1) reduc-
ing the circulating levels of cortisol and oxytoxin;
and (2) increasing NO bioavailability through up-
regulation of NO synthesis from arginine and inhibi-
tion of NO oxidation by antioxidative micronutrients.
While there have been inconsistent reports in the
literature regarding effects of maternal nutrition on
gestational length in humans, both maternal undernu-
trition and overnutrition are associated with reduced
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 15
Undernutrition Stress Overnutrition
Hypothalamic–Pituitary–Adrenal Axis
Cortisol Oxytoxin
Foetus, Placenta, and Uterus
PGF2 G-Protein-Coupled
Receptors
Dietary
Supplementation
Phospholipase C
Antioxidant Inositol 1,4,5-trisphosphate
3
Micronutrients
PUFAs
Intracellular Ca2+
(+) (- )
(+)
eNOS ( -)
Arginine NO Preterm Contraction of Uterus
Preterm Birth
Figure 4. Biochemical mechanisms responsible for
malnutrition-induced preterm birth and its amelioration by
dietary supplementation in humans. Maternal undernutrition or
overnutrition represents a stress factor that can stimulate the
release of cortisol and oxytoxin from the adrenal gland and the
posterior pituitary gland, respectively. These hormones enhance
the production of prostaglandin F2a (PGF2a) by the fetus, pla-
centa and uterus. Oxytoxin and (PGF2a) bind their respective
G-protein-coupled receptors, leading to an increase in intracel-
lular concentrations of Ca2+ via the phospholipase C and inositol
1,4,5-trisphosphate pathway. High levels of Ca2+ activate the
preterm contraction of the uterus, thereby stimulating preterm
birth. In contrast, physiological levels of nitric oxide (NO),
which is synthesised from L-arginine by endothelial NO syn-
thase (eNOS), inhibit the preterm contraction of the uterus. The
generation of NO in the vasculature is up-regulated by w3 poly-
unsaturated fatty acids (PUFA). Dietary supplementation with
antioxidant micronutrients, w3 PUFA, and arginine can be ben-
eficial in reducing the risk of preterm delivery in pregnant
women. The signs (+) and (-) denote activation and inhibition,
respectively.
gestational length in well-controlled experimental
animals.3 For example, in adult sheep, severe global
undernutrition during the peri-conceptual period
causes preterm delivery in association of activation
of the hypothalamic–pituitary–adrenal axis for cortisol
synthesis.121 Likewise, in rhesus monkeys, high
protein intake (4 vs. 1 g/kg body weight per day) sub-
stantially reduced gestational length by up to 2 weeks
likely because of endocrine imbalance and adverse
effects of metabolites (e.g. ammonia and H2S) of amino
acid oxidation.123 Human clinical studies also indicated
that increased intake of dietary sugar was associated
with reduced gestational length in pregnant adoles-
16 G. Wu et al.
cents.124 In contrast, higher maternal BMI either in the
first trimester or throughout gestation was associated
with longer gestation in obese women in developed
nations,13 possibly because of impaired contraction of
the uterus. In contrast, excessive gestational weight
gain, but not pre-pregnancy BMI, was positively asso-
ciated with spontaneous preterm delivery.125 The major
component of the excessive maternal weight gain in
these women is likely white adipose tissue, which can
be associated with oxidative stress. In support of this
view, a deficiency of micronutrients in the periconcep-
tional period or throughout gestation is associated
with high incidence of preterm births.104 Similarly,
in a separate study, severely obese women who lost
weight during pregnancy generally had increased risk
for preterm birth,126 possibly as a result of malnutri-
tion, ketosis, and other metabolic disorders.
Low-income women frequently have inadequate
intake of multiple micronutrients127 and many in
developing countries may have short stature because
of chronic malnutrition beginning in early childhood.7
Maternal short stature has been correlated with
reduced gestation length.125 In micronutrient-deficient
women, evidence from some clinical studies suggests
an important role for dietary supplementation with
micronutrients in reducing the risk of preterm births.
For example, a meta-analysis of zinc supplementation
in pregnancy showed a 14% reduction in the risk of
preterm delivery among supplemented women.10,127,128
In another meta-analysis, calcium supplementation
during pregnancy was associated with a 24% reduc-
tion in the risk of preterm delivery.41 Also, one study
involving a prospective cohort of pregnant women
(aged ⱖ16 years) with singleton gestations reported
that women with low intake of dietary vitamin C
(<10th percentile) had twice the risk of preterm birth
because of premature rupture of the membranes.129
Thus, improving the nutritional status of vitamin C is
beneficial for maintaining normal gestational length.
Consistent with this conclusion, results from one trial
indicate that daily supplementation with 100 mg
vitamin C, which was initiated after 20 weeks of gesta-
tion, reduced the incidence of premature rupture
of the chorioamniotic membranes in pregnant women
by 69%.130
Birth defects
Neural tube defects are one of the most severe deve-
lopmental disorders of the fetal brain and spinal
cord.131 These organs arise from specialised cells of
the embryo early in pregnancy (18–28 days).131 The
timing of their development epitomises the impor-
tance of adequate maternal nutrition before gestation
and in the first trimester. The two most common
neural tube defects are spina bifida and anenceph-
aly.132 These birth defects occur commonly worldwide
(e.g. approximately one in 1000 births in the US).132
Compelling evidence suggests that a deficiency
of folate or an excess of homocysteine (a metabolite
of methionine) during pregnancy contributes to
neural tube defects in newborn infants.58 Additionally,
through similar mechanisms as neural tube defects,
folate deficiency is also associated with increased
risk of both cleft lip and palate.133 As noted previ-
ously, folate is required for DNA synthesis in all cell
types, particularly the central nervous system which
develops rapidly during early and mid gestation.
Moreover, homocysteine is an oxidant that damages
macromolecules, including DNA, proteins and lip-
ids.31 In humans who have adequate intake of water-
soluble vitamins, homocysteine is effectively recycled
into methionine through a folate- and vitamin B12-
dependent reaction (methionine synthase) (Figure 1).
Results of clinical studies indicate that dietary
supplementation with folic acid (e.g. 4 mg per day
for pregnant women) can effectively prevent neural
tube defects caused by malnutrition.134 In several
countries (e.g. US, Canada, Chile, and South Africa),
significant reductions in the incidence of neural
tube defects followed the large-scale efforts to fortify
flours with folic acid.134,135 Adequate provision of
B-complex vitamins (particularly folate and vitamin
B12) and the balance of dietary amino acids (especially
sulfur amino acids, glycine, serine, histidine and
arginine) are critical for the prevention of these birth
defects.
Iodine deficiency disorders
Iodine deficiency is a major nutritional problem
around the world, particularly in pregnant
women.136,137 As noted previously, iodine is required
for synthesis of thyroid hormones. When circulat-
ing levels of thyroxine are reduced, the pituitary
gland increases the secretion of thyroid stimulating
hormone (TSH) to enhance iodine trapping by the
thyroid gland as an adaptive response. Persistent
elevation of TSH in response to chronic severe iodine
deficiency results in the enlargement of the thyroid
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Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

gland, and ultimately goiter. Severe iodine deficiency
in pregnant women causes fetal iodine deficiency and
congenital hypothyroidism which may lead to mental
and physical-growth retardation of the offspring,
known as cretinism.46 Less severe iodine deficiency
during pregnancy impairs fetal neurological develop-
ment and the cognition of offspring.138 Accordingly,
supplementing women with iodine before and during
gestation can prevent both goiter and cretinism.139
Prevention of iodine deficiency in iodine-deficient
regions can be effectively achieved through the use of
iodised salt42 although iodine intakes through fortified
salt may not meet the increased needs of pregnant
women.
Effects of malnutrition in pregnancy on maternal
health and survival
Rates of maternal morbidity and mortality remain
unacceptably high in many parts of the world.
Haemorrhage is the leading cause of maternal death
globally, followed by hypertensive disorders of preg-
nancy such as pre-eclampsia and eclampsia.5 Anaemia
and obstructed labour are also substantial contribu-
tors to maternal mortality, especially in Southeast Asia
and Latin America, respectively.140 Numerous studies
report a role for maternal nutrition in these poor
health outcomes.1,132,141 Here we discuss the mecha-
nisms by which malnutrition may contribute to
adverse maternal health.
Hypertensive disorders of pregnancy
Pre-eclampsia is a significant obstetrical complication
that affects 5–7% of pregnancies globally. This compli-
cation is generally diagnosed after 20 weeks of gesta-
tion and is characterised by increased blood pressure
and traces of protein in maternal urine (a condition
called ‘proteinuria’).142 In low-income countries, the
incidence of pre-eclampsia is up to 10% of all preg-
nancies and 2.3% of pre-eclamptic women further
develop eclampsia. Pre-eclampsia is a leading cause
of IUGR, maternal death, and infant morbidity and
mortality associated with preterm birth. Although
the underlying mechanisms remain elusive, recent
studies have provided clinical and biochemical evi-
dence for oxidative stress, reduced bioavailability of
NO in the vasculature, and endothelial cell dysfunc-
tion in pre-eclamptic women.143–145
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Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 17
While pre-eclampsia may have a genetic basis, poor
nutrition may play a key role in its pathogenesis.
Given the potential aetiologies for pre-eclampsia,
numerous studies have tested the effects of supple-
mentation with antioxidants (e.g. arginine, vitamins C
and E, zinc, selenium and glutathione), calcium,
or vitamin D to prevent pre-eclampsia.37,51,146–152 Salt
restriction diets among at risk women151 and arginine
supplementation of pre-eclamptic women have also
been tested for prevention and/or treatment of pre-
eclampsia.146 A recent WHO technical consultation
systematically reviewed and evaluated the evidence
base for some of these interventions to prevent
and/or treat hypertensive disorders of pregnancy.
Of the nutritional interventions included, calcium
supplementation among women with low calcium
intake was strongly recommended to prevent
pre-eclampsia while magnesium sulfate was recom-
mended to treat pre-eclampsia and prevent pro-
gression to eclampsia.152 The Technical Consultation
did not find sufficient evidence to support recom-
mending supplementation with vitamins C, E or D or
dietary salt restriction in the prevention of pre-
eclampsia. However, arginine was not included in
this consultation.152 It is noteworthy that plasma levels
of arginine were reduced in pre-eclamptic compared
with healthy pregnant women,144 thereby impairing
NO generation by endothelial cells.26 Thus, a study
involving women with pre-eclampsia reported that
oral administration of arginine (3 g daily for 4 weeks)
beginning at 29 weeks of gestation reduced blood
pressure, prolonged pregnancy, improved fetal well-
being, and enhanced fetal growth.145 Similar results
were reported for pregnant women with high-risk
pre-eclampsia.146
Calcium deficiency during pregnancy is associated
with increased risk of hypertensive disorders. A
recent systematic review and meta-analysis indicated
that calcium supplementation is associated with a
50% reduction in the risk of gestational hyperten-
sion, pre-eclampsia and preterm delivery.39 Similarly,
daily supplementation with 1.5 g of calcium reduced
the severity of pre-eclampsia and early preterm
labour in nulliparous normotensive women who
had low dietary intake of calcium (<600 mg/day).37
These beneficial outcomes of calcium supple-
mentation may be because of up-regulation of NO
synthesis from arginine by endothelial cells, thereby
enhancing the bioavailability of this vasodilator in the
vasculature.40
18 G. Wu et al.

Maternal haemorrhage can also result in anaemia independent of nutrition

and the relative contributions of each of these factors
Maternal haemorrhage refers to the substantial loss of
to the burden of anaemia is highly context-specific.140
the mother’s blood at delivery and accounts for
Fully integrated approaches that address the nutri-
approximately 60% of all maternal deaths in develop-
tional, infectious and genetic aetiologies of anaemia
ing countries.141 When the placenta is separated from
are needed to develop effective interventions.
the wall of the uterus, the maternal blood vessels
Pregnant women with anaemia have a reduced
that previously supplied blood to the placenta are
capability for: (1) oxygen transport from the heart
sheared, resulting in bleeding. Such bleeding is
to central and peripheral tissues; and (2) impaired
normally stopped by the spontaneous contraction
metabolism of macronutrients and ATP production.
of the uterus and the compression of its vessels.
Thus, these subjects often exhibit pale skin, weakness
However, when uterine contraction is inadequate,
and fatigue. In its severe and acute form (<70 g
bleeding will continue and haemorrhage can occur.
haemoglobin/L), anaemia can lead to rapid cardiac
In developing nutritional means to prevent maternal
decompensation and cardiac failure. Indeed, it is esti-
haemorrhage, it should be recognised that blood clot-
mated that 6.4%, 7.3% and 3.0% of maternal mortality
ting is affected by the amounts of coagulation factors
is attributable to severe anaemia in Africa, Asia and
(proteins that are synthesised from amino acids) and
Latin America, respectively.140 When severe anaemia
their Ca2+- and vitamin K-dependent activities.44 Thus,
is not a primary cause of death, it may be a contrib-
theoretically, in addition to energy (ATP provision),
uting indirect factor, for example, by increasing
nutrients that can beneficially improve uterine con-
the inability of a woman to tolerate blood loss from
traction without inducing premature labour include
haemorrhage or by increasing her risk of infection.156
amino acids (notably arginine and glutamine), miner-
The contribution of less severe anaemia to the burden
als (particularly calcium and iron), long-chain PUFA
of maternal mortality is less well documented, though
(e.g. arachidonic acid and w3-PUFA), and vitamins
recently, Stoltzfus et al.6 estimated that a population
(especially vitamin K and A).140 In support of this
increase in maternal haemoglobin by 1 g/dL could
view, there is evidence that undernutrition and
reduce the risk of maternal mortality by approxi-
overnutrition are associated with increased risk for
mately 25%. With regards to anaemia as an indirect
maternal haemorrhage.136,141 This condition can result
contributor to mortality through increased risk of
in iron deficiency, anaemia, morbidity and maternal
haemorrhage, the epidemiological evidence suffers
death.
from substantial methodological shortcomings and
is largely inconsistent.4,140 However, a recent clinical
study in Zanzibar reported that among women pre-
Maternal anaemia
senting at a clinic with uncomplicated vaginal deliv-
Based on the chemical composition of haemoglobin, eries, those with moderate or severe anaemia lost
a deficiency of amino acids or iron in the maternal significantly more blood during and immediately
diet can cause anaemia.31,46 A deficiency of vitamins after delivery compared with nonanaemic women.157
(vitamin B6, vitamin B12 and folate) and minerals The researchers hypothesised that women with mod-
(cobalt, magnesium, zinc and copper) that participate erate to severe anaemia may have decreased uterine
in one-carbon-unit metabolism and, therefore, DNA blood flow or low uterine muscle strength which con-
synthesis can also indirectly result in anaemia.153–155 tributed to inefficient uterine contractions and greater
Furthermore, insufficient provision of dietary nutri- blood loss.157
ents (e.g. vitamin A, lipids and carbohydrates) that are
essential to the integrity of intestinal epithelial cells,
Implications of IUGR and other poor
the function of enterocytes, and the absorption of
pregnancy outcomes for human health
vitamins and minerals can also increase the risk for
the development of anaemia.156 Thus, a balanced and
Impact of IUGR on infants and children
adequate supply of all nutrients is crucial to prevent
anaemia in humans. However, the causes of anaemia Intrauterine growth restriction is a significant factor
are not solely nutritional. Malaria, parasitic infections, contributing to fetal deaths and preterm births.158,159
and inherited thallasemias and haemoglobinopathies For example, IUGR is responsible for about 50% of

© 2012 Blackwell Publishing Ltd

Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
 Maternal nutrition and healthy pregnancy 19

non-malformed stillbirths in humans. Furthermore, Fetal programming

Heinonen et al.158 reported that different types of
The fetus may survive extreme conditions in utero
IUGR contribute to approximately 40% of preterm
through physiological adaptations that include
births. IUGR infants delivered at preterm gestations
changes in gene expression. Epidemiological studies
have severe perinatal and neonatal medical complica-
show that individuals exposed to the Dutch winter
tions. Of note, the rates of neonatal morbidity and
famine of 1944–1945 in utero had higher rates of insulin
mortality among preterm IUGR infants are much
resistance, vascular disease, morbidity and mortality
higher than those among appropriately grown
in adulthood.162 The intrauterine environment of the
preterm infants with similar gestational age.158 Thus,
conceptus may alter expression of the fetal genome
infants who weigh <2500 g at birth have perinatal
and have lifelong consequences. This phenomenon
mortality rates that are five- to 30-fold greater than
is termed ‘fetal programming’, which has led to the
those of infants who have average birthweights,
theory of fetal origins of adult disease.163 Namely, alter-
while infants that weigh <1500 g have 70- to 100-times
ations in fetal nutrition and endocrine status may
greater mortality rates.159 Compelling evidence shows
result in developmental adaptations that permanently
that surviving infants with IUGR are often at
change the structure, physiology and metabolism
increased risk for neurological, respiratory, intestinal,
of the offspring, thereby predisposing individuals to
immunological and circulatory disorders during the
metabolic, endocrine and cardiovascular diseases in
neonatal period and childhood.159 For girls who suffer
the adult lives of both animals and humans.
from IUGR, short stature can lead to obstructed
Fetal programming may be explained by epigenet-
labour in the future.156
ics, which is defined as stable and inheritable alter-
ations of genes through covalent modifications of
Impact of IUGR on chronic diseases DNA and core histones without changes in DNA
sequences.164 The concept of fetal programming
The adaptation of the IUGR fetus or offspring to in
has now been experimentally tested in a number of
utero or extrauterine environments may confer an evo-
animal models, including rats, mice, cattle and
lutionary advantage for the survival of the species.
sheep,16 and has shown that the effects of changes in
However, when environmental cues during prenatal
nutrition or endocrine status during fetal or neonatal
life inappropriately programme offspring, there are
life can be carried forward to subsequent develop-
adverse consequences, including the increased preva-
mental stages.165 Because DNA methylation, a mecha-
lence of disease in adult life which may result, in part,
nism mediating epigenetic effects, is reversible, it is
from a reduced availability of nutrients to the fetus in
likely that metabolic abnormalities in the offspring
utero.2 Both epidemiological and experimental evi-
can be ameliorated through nutritional interven-
dence indicate that IUGR contributes to a plethora
tions.164 For example, transgenerational exposure of
of metabolic disorders and chronic diseases in
the agouti mice to an ad libitum diet causes obesity-
adults.1,160,161 These problems include: (1) hormonal
associated metabolic syndrome in offspring, which
imbalance (e.g. increased plasma levels of glucocorti-
can be prevented by dietary supplementation with
coids and renin; decreased plasma levels of insulin,
folate.166 While research is still limited, nutrition is
growth hormone, and insulin-like growth factor-I);
expected to play a key role in developmental plasti-
(2) metabolic disorders (e.g. insulin resistance, b-cell
city, potential, and programming.
dysfunction, dyslipidemia, glucose intolerance,
impaired energy homeostasis, obesity, type-II diabe-
tes, oxidative stress, mitochondrial dysfunction, and
Conclusions and perspectives
ageing); (3) organ dysfunction and abnormal develop-
ment (e.g. testes, ovaries, brain, heart, skeletal muscle,
A summary of current knowledge of the field
liver, thymus, and small intestine); and (4) cardiovas-
cular disorders (e.g. coronary heart disease, hyperten- Development of the human conceptus absolutely
sion, stroke, and atherosclerosis).2,3 Hence, infants depends on adequate and balanced supplies of both
who survive the adverse consequences of IUGR macronutrients and micronutrients. During implanta-
through the neonatal period may face an increased tion, the embryo receives nutrients from maternal
risk of poor health in adulthood. uterine secretions, which include water, protein,

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Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
20 G. Wu et al.
amino acids, lipids, and glucose, minerals, and vita-
mins. After placentation, the fetus takes up nutrients
and oxygen from the mother via the umbilical vein.
Maternal undernutrition or overnutrition during
pregnancy can result in IUGR, which, in turn, is a
major factor contributing to reduced neonatal survival,
as well as the impairment of postnatal growth, neuro-
logical function, learning abilities, and health. Folate
deficiency greatly increases the risk of neural tube
defects and orofacial clefts in newborns. In addition,
severe iodine deficiency results in cretinism which is
characterised by impaired neurological development
and permanent growth stunting in offspring.
In addition to IUGR, maternal deficiencies of certain
nutrients are known to negatively impact the health of
mothers. Of particular interest, reduced concentra-
tions of arginine and calcium in the plasma of
pregnant women contribute to the pathogenesis
of pre-eclampsia and preterm labour. A deficiency of
zinc also increases the risk for maternal oxidative
stress and premature labour. Furthermore, dietary
deficiencies of protein or iron can result in maternal
anaemia and may subsequently increase the risk for
maternal haemorrhage. Fortunately, strategies to
increase intakes of these deficient nutrients, including
dietary supplementation, food fortification, dietary
diversification, and nutrition education, can poten-
tially alleviate the burden of, and may even com-
pletely prevent, certain poor health outcomes.
The prenatal growth trajectory of humans is sensi-
tive to direct and indirect effects of nutritional insults
at all stages between oocyte maturation and birth.
However, available evidence shows that placental and
fetal development is most vulnerable to prenatal
nutrition status during the peri-implantation period
and the period of rapid placental development (the
first trimester of gestation). Specifically, a deficiency of
protein and micronutrients during the first trimester
of pregnancy has a greater detrimental effect on fetal
development than during late gestation. In contrast,
energy restriction during mid and late gestation
appears to cause a more profound adverse impact on
the vasculature than during early gestation. Besides
whole-body growth, maternal nutrition influences
development of the fetal immune system and, thus,
health in postnatal life. Adverse effects of IUGR
and other poor pregnancy outcomes can be carried
forward to future generations.
Given the significant problems of IUGR and defi-
ciencies of specific nutrients on neonatal and adult
life, which include high rates of infant morbidity
and mortality as well as adult-onset diabetes and
hypertension, much attention has been directed to
elucidating the biological mechanisms for IUGR, pre-
eclampsia, and birth defects. Compelling evidence
indicates that all types of IUGR are characterised by
impaired transfer of nutrients from mother to fetus
because of placental underdevelopment/dysfunction
and reduced utero-placental blood flow. Optimising
maternal nutrition will not only reduce risk of
maternal/fetal morbidity and mortality, IUGR, and
preterm birth, but will also prevent adverse health
problems in children and adults. Because the largest
detriments appear to occur in early pregnancy when a
woman might not be aware that she is pregnant, cor-
recting malnutrition before a woman conceives is
likely to yield the greatest benefits for her and her
infant.
Directions for future research and perspectives
Much is now known about adverse effects of IUGR
and preterm birth on neonatal survival and adult-onset
metabolic diseases. Effective nutrition strategies that
ameliorate or prevent these problems exist but are
complex and require changes in both individual/
household behaviour and structural changes that
increase women’s access to and acceptability of nutri-
tious food, nutrition supplements, and preventive
health services. While effective postnatal therapies are
required for surviving individuals with IUGR, its pre-
vention should be the best strategy to improve the
health and well-being of infants and adults. One effec-
tive means is to ensure balanced provision of protein
and energy in the diet, which can reduce the risk
of IUGR by 32%.8 Similarly, although medications
are needed to treat preterm labour, its risk may
be substantially reduced by improving maternal
nutrition (particularly arginine145,146 and micronutri-
ents10,127,128,130). Despite the previous research efforts
focusing on mainly individual nutrients or a mix of
multiple micronutrients, there is a paucity of informa-
tion about interactions among nutrients (e.g. between
amino acids and vitamins/minerals or synergism) and
their impact on pregnancy outcomes. In view of the
exciting findings from animal studies,166–171 it is unfor-
tunate that there has been only limited attention to the
use of amino acids to improve pregnancy outcomes in
women carrying IUGR fetuses.146,150,172 Additionally,
little is known about effects of specific nutrients
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

(particularly amino acids, vitamins and minerals) on
epigenetics or fetal programming in mammals.
Future studies with animal models and women
are necessary to develop effective means of nutri-
tional interventions to enhance fetal growth and
development in undernourished, overweight or
obese mothers. Such approaches may include dietary
supplementation with nutrients that play a key role in
regulating utero-placental blow flow and uterine qui-
escence during pregnancy. Because amino acids affect
not only protein synthesis and tissue growth but also
serve as major donors of methyl groups to affect DNA
and histone modifications, designing an ideal mixture
of functional amino acids and micronutrients for
gestating mothers to regulate key metabolic pathways
for nutrient metabolism will be highly desirable in
the field of prenatal and neonatal research. Finally, we
propose that multidisciplinary efforts are required to
develop effective solutions to preventing and treating
IUGR (a complex nutritional and reproductive health
problem), preterm birth, birth defects, and other poor
pregnancy outcomes in humans.
Acknowledgements
Helpful discussions among our colleagues regarding
maternal nutrition and pregnancy outcomes are grate-
fully appreciated.
Conflicts of interest
The authors have not declared any conflicts of interest.
References
1 Abu-Saad K, Fraser D. Maternal nutrition and birth
outcomes. Epidemiological Review 2010; 32:5–25.
2 Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE.
Maternal nutrition and fetal development. Journal of
Nutrition 2004; 134:2169–2172.
3 Wu G, Bazer FW, Wallace JM, Spencer TE. Board-invited
review: intrauterine growth retardation: implications for
the animal sciences. Journal of Animal Science 2006;
84:2316–2337.
4 Rush D. Nutritional and maternal mortality in the
developing world. American Journal of Clinical Nutrition
2000; 72:212S–240S.
5 Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look
PF. WHO analysis of causes of maternal death: a systematic
review. Lancet 2006; 367:1066–1074.
6 Stoltzfus RJ, Mullany L, Black RE. Iron deficiency
anaemic. In: Comparative Quantification of Health Risks:
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 21
Global and Regional Burden of Disease Attributable to
Selected Major Risk Factors, Vol. 1. Editors: Ezzati M,
Lopez AD, Rodgers A, Murray CJL. Geneva: WHO, 2005;
pp. 163–209.
7 United Nations Food and Agriculture Organization.
The State of Food Insecurity in the World 2011. 2011.
http://www.fao.org/publications/sofi/en [Accessed
on November 12, 2011] .
8 Imdad A, Bhutta ZA. Maternal nutrition and birth
outcomes: effect of balanced protein energy
supplementation. Paediatric and Perinatal Epidemiology 2012;
26 (Suppl. 1):178–190.
9 Imdad A, Bhutta ZA. Routine iron/folate supplementation
during pregnancy: effect on maternal anemia and birth
outcomes. Paediatric and Perinatal Epidemiology 2012; 26
(Suppl. 1):168–177.
10 King JC, Chaffee BW. Effect of zinc supplementation on
pregnancy and infant outcomes. Paediatric and Perinatal
Epidemiology 2012; 26 (Suppl. 1):118–137.
11 Zhu BP, Rolfs RT, Nangle BE, Horan JM. Effect of the
interval between pregnancies on perinatal outcomes. New
England Journal of Medicine 1999; 340:589–594.
12 Conde-Agudelo A, Rosas-Bermúdez A, Kafury-Goeta AC.
Birth spacing and risk of adverse perinatal outcomes: a
meta-analysis. Journal of American Medical Association 2006;
295:1809–1823.
13 McKnight JR, Satterfield MC, Li XL, Gao HJ, Wang JJ, Li
DF, et al. Obesity in pregnancy: problems and potential
solutions. Frontiers in Bioscience 2011; E3:442–452.
14 Ovesen P, Rasmussen S, Kesmodel U. Effect of prepreg-
nancy maternal overweight and obesity on pregnancy
outcome. Obstetrics & Gynecology 2011; 118:305–312.
15 Burdge GC, Lillycrop KA. Nutrition, epigenetics, and
developmental plasticity: implications for understanding
human disease. Annual Review of Nutrition 2010;
30:315–339.
16 Satterfield MC, McKnight JR, Li XL, Wu G. Nutrition,
epigenetics, and vascular function. In: Nutrition, Epigenetic
Mechanisms, and Human Disease. Editors: Maulik N, Maulik
G. New York: CRC Press, 2011; pp. 125–139.
17 Fainberg HP, Budge H, Symonds ME. The conflicting
effects of maternal nutrient restriction and early-life
obesity on renal health. Proceedings of Nutrition Society
2011; 70:268–275.
18 Bazer FW, Wu G, Spencer TE, Johnson GA, Burghardt RC,
Bayless K. Novel pathways for implantation and
establishment and maintenance of pregnancy in mammals.
Molecular Human Reproduction 2010; 16:135–152.
19 Kim JY, Burghardt RC, Wu G, Johnson GA, Spencer TE,
Bazer FW. Select nutrients in the ovine uterine lumen: VII.
Effects of arginine, leucine, glutamine, and glucose on
trophectodem cell signaling, proliferation, and migration.
Biology of Reproduction 2011; 84:62–69.
20 Kim JY, Burghardt RC, Wu G, Johnson GA, Spencer TE,
Bazer FW. Select nutrients in the ovine uterine lumen: VIII.
Arginine stimulates proliferation of ovine trophectoderm
cells through mTOR-RPS6K-RPS6 signaling cascade and
synthesis of nitric oxide and polyamines. Biology of
Reproduction 2011; 84:70–78.
22 G. Wu et al.
21 Wu G, Bazer FW, Datta S, Johnson GA, Li P, Satterfield
MC, et al. Proline metabolism in the conceptus:
implications for fetal growth and development. Amino
Acids 2008; 35:691–702.
22 Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G.
Regulatory role for the arginine-nitric oxide pathway in
metabolism of energy substrates. Journal of Nutritional
Biochemistry 2006; 17:571–588.
23 Kalhan SC, D’Angelo LJ, Savin SM, Adam PAJ. Glucose
production in pregnant women at term gestation: sources
of glucose for human fetus. Journal of Clinical Investigation
1979; 63:388–394.
24 Haggarty P. Fatty acid supply to the human fetus. Annual
Review of Nutrition 2010; 30:237–255.
25 Li P, Kim SW, Li XL, Datta S, Pond WG, Wu G. Dietary
supplementation with cholesterol and docosahexaenoic
acid increases the activity of the arginine-nitric oxide
pathway in tissues of young pigs. Nitric Oxide 2008;
19:259–265.
26 Wu G, Meininger CJ. Regulation of nitric oxide synthesis
by dietary factors. Annual Review of Nutrition 2002;
22:61–86.
27 Enke U, Seyfarth L, Schleussner E, Markert UR. Impact of
PUFA on early immune and fetal development. British
Journal of Nutrition 2008; 100:1158–1168.
28 Carlson SE. Docosahexaenoic acid supplementation in
pregnancy and lactation. American Journal of Clinical
Nutrition 2009; 89:678S–684S.
29 Stein AD, Wang M, Martorell R, Neufeld LM, Flores-Ayala
R, Rivera JA, et al. Growth to age 18 months following
prenatal supplementation with docosahexaenoic acid
differs by maternal gravidity in Mexico. Journal of Nutrition
2010; 141:2316–2320.
30 Imhoff-Kunsch B, Stein AD, Martorell R, Parra-Cabrera R,
Romieu I, Ramakrishnan U. Prenatal docosahexaenoic acid
supplementation and infant morbidity: randomized
controlled trial. Pediatrics 2011; 128:e1–e8.
31 Wu G. Amino acids: metabolism, functions, and nutrition.
Amino Acids 2009; 37:1–17.
32 Wu G, Bazer FW, Burghardt RC, Johnson GA, Kim SW,
Knabe DA, et al. Proline and hydroxyproline metabolism:
implications for animal and human nutrition. Amino Acids
2011; 40:1053–1063.
33 Wu G. Functional amino acids in growth, reproduction
and health. Advances in Nutrition 2010; 1:31–37.
34 Wu G, Bazer FW, Davis TA, Kim SW, Li P,
Rhoads JM, et al. Arginine metabolism and nutrition
in growth, health and disease. Amino Acids 2009;
37:153–168.
35 Wu G, Bazer FW, Johnson GA, Knabe DA, Burghardt RC,
Spencer TE, et al. Important roles for L-glutamine in swine
nutrition and production. Journal of Animal Science 2011;
89:2017–2030.
36 Li XL, Rezaei R, Li P, Wu G. Composition of amino acids
in feed ingredients for animal diets. Amino Acids 2011;
40:1159–1168.
37 Villar J, Abdel-Aleem H, Merialdi M, Giordano D, Ba’aqeel
H, Farnot U, et al. World Health Organization randomized
trial of calcium supplementation among low calcium
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
intake pregnant women. American Journal of Obstetrics and
Gynecology 2006; 194:639–649.
38 Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium
supplementation during pregnancy for preventing
hypertensive disorders and related problems. Cochrane
Database of Systematic Reviews 2010; (8):CD001059.
39 Trumbo PR, Ellwood KC. Supplemental calcium and risk
reduction of hypertension, pregnancy-induced
hypertension, and preeclampsia: an evidence-based review
by the U.S. Food and Drug Administration. Nutrition
Review 2007; 65:78–87.
40 Lopez-Jaramillo P. Prevention of preeclampsia with
calcium supplementation and its relation with the
L-arginine:nitric oxide pathway. Brazilian Journal of
Medicine and Biological Research 1996; 29:731–741.
41 Imdad A, Bhutta ZA. Effects of calcium supplementation
during pregnancy on maternal, fetal and birth
outcomes. Paediatric and Perinatal Epidemiology 2012;
26 (Suppl. 1):138–152.
42 Vanderpas J. Nutritional epidemiology and thyroid
hormone metabolism. Annual Review of Nutrition 2006;
26:293–322.
43 Zimmermann MB. The effects of iodine deficiency in
pregnancy and infancy. Paediatric and Perinatal Epidemiology
2012; 26 (Suppl. 1):108–117.
44 Institute of Medicine. Dietary Reference Intakes (DRIs):
Recommended Intakes for Individuals. Washington, DC: Food
and Nutrition Board, Institute of Medicine, National
Academies, 2004.
45 Winzerling JJ, Law JH. Comparative nutrition of
iron and copper. Annual Review of Nutrition 1997;
17:501–526.
46 Zimmermann MB. The influence of iron status on iodine
utilization and thyroid function. Annual Review of Nutrition
2006; 26:367–389.
47 Stolzfus RJ. Iron interventions for women and children in
low-income countries. Journal of Nutrition 2011;
141:756S–762S.
48 Romani AM. Cellular magnesium homeostasis. Archives of
Biochemistry and Biophysics 2011; 512:1–23.
49 Mercer BM, Merlino AA, Society for Maternal-Fetal
Medicine. Magnesium sulfate for preterm labor and
preterm birth. Obstetrics & Gynecology 2009; 114:650–668.
50 Murakami M, Hirano T. Intracellular zinc homeostasis and
zinc signaling. Cancer Science 2008; 99:1515–1522.
51 Yin JD, Li XL, Li DF, Yue T, Fang Q, Ni JJ, et al. Dietary
supplementation with zinc oxide stimulates ghrelin
secretion from the stomach of young pigs. J Nutr Biochem
2009; 20:783–790.
52 Merialdi M, Caulfield L, Zavaleta N, Figueroa A, Costigan
K, Dominici F, et al. Randomized controlled trial of zinc
supplementation and fetal bone growth. American Journal of
Clinical Nutrition 2004; 79:826–830.
53 Merrill AH Jr, Henderson JM. Diseases associated with
defects in vitamin B6 metabolism or utilization. Annual
Review of Nutrition 1987; 7:137–156.
54 Koury MJ, Ponka P. New insights into erythropoiesis: the
roles of folate, vitamin B12, and iron. Annual Review of
Nutrition 2004; 24:105–131.
© 2012 Blackwell Publishing Ltd

55 Allen LH. Vitamin B12 metabolism and status during
pregnancy, lactation and infancy. Advances in Experimental
Medicine and Biology 1994; 352:173–186.
56 Niebyl JR. Clinical practice. Nausea and vomiting in
pregnancy. New England Journal of Medicine 2010;
363:1544–1550.
57 Shane B, Stokstad EL. Vitamin B12-folate interrelationships.
Annual Review of Nutrition 1985; 5:115–141.
58 De-Regil LM, Fernández-Gaxiola AC, Dowswell T,
Peña-Rosas JP. Effects and safety of periconceptional folate
supplementation for preventing birth defects. Cochrane
Database of Systematic Reviews 2010; (10):CD007950.
59 Ross AC, Cifelli CJ, Zolfaghari R, Li NQ. Multiple
cytochrome P-450 genes are concomitantly regulated by
vitamin A under steady-state conditions and by retinoic
acid during hepatic first-pass metabolism. Physiological
Genomics 2011; 43:57–67.
60 Mora JR, Iwata M, von Andrian UH. Vitamin effects on the
immune system: vitamins A and D take centre stage.
Nature Review in Immunology 2008; 8:685–698.
61 Clagett-Dame M, DeLuca HF. The role of vitamin A in
mammalian reproduction and embryonic development.
Annual Review of Nutrition 2002; 22:347–381.
62 Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino
S, Milunsky A. Teratogenicity of high vitamin A intake.
New England Journal of Medicine 1995; 333:1369–1373.
63 Strobel M, Tinz J, Biesalski HK. The importance of
beta-carotene as a source of vitamin A with special regard
to pregnant and breastfeeding women. European Journal of
Nutrition 2007; 46 (Suppl 1):11–20.
64 DeLuca HF. Overview of general physiologic features and
functions of vitamin D. American Journal of Clinical
Nutrition 2004; 80:1689S–1696S.
65 Christakos S, DeLuca HF. Vitamin D: is there a role in
extraskeletal health? Endocrinology 2011; 152:2930–2936.
66 Zehnder D, Evans KN, Kilby MD, Bulmer JN, Innes BA,
Stewart PM, et al. The ontogeny of 25-hydroxyvitamin D(3)
1a-hydroxylase expression in human placenta and
decidua. American Journal of Pathology 2002; 161:105–114.
67 Evans KN, Nguyen L, Chan J, Innes BA, Bulmer JN, Kilby
MD, et al. Effects of 25-hydroxyvitamin D3 and
1,25-dihydroxyvitamin D3 on cytokine production by
human decidual cells. Biology of Reproduction 2006;
75:816–822.
68 Liu N, Kaplan AT, Low J, Nguyen L, Liu GY, Equils O,
et al. Vitamin D induces innate antibacterial responses in
human trophoblasts via an intracrine pathway. Biology of
Reproduction 2009; 80:398–406.
69 Stein AD, Zybert PA, van de Bor M, Lumey LH.
Intrauterine famine exposure and body proportions at
birth: the Dutch Hunger Winter. International Journal of
Epidemiology 2004; 33:831–836.
70 Pond WG, Strachan DN, Sinha YN, Walker EF Jr, Dunn JA,
Barnes RH. Effect of protein deprivation of swine during
all or part of gestation on birth weight, postnatal growth
rate and nucleic acid content of brain and muscle of
progeny. Journal of Nutrition 1969; 99:61–67.
71 Fowden AL, Ralph MM, Silver M. Nutritional regulation of
uteroplacental prostaglandin production and metabolism
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 23
in pregnant ewes and mares during late gestation.
Experimental and Clinical Endocrinology 1994; 102:212–221.
72 Fall CHD, Yajnik CS, Rao S, Davie AA, Brown N, Farrant
HJW. Micronutrients and fetal growth. Journal of Nutrition
2003; 133:1747S–1756S.
73 Redmer DA, Wallace JM, Reynolds LP. Effect of nutrient
intake during pregnancy on fetal and placental growth and
vascular development. Domestic Animal Endocrinology 2004;
27:199–217.
74 Krishnaveni GV, Hill JC, Veena SR, Bhat DS, Wills AK,
Karat CLS, et al. Low plasma vitamin B-12 in pregnancy is
associated with gestational ‘diabesity’ and later diabetes.
Diabetologia 2009; 52:2350–2358.
75 Mellor DJ. Nutritional and placental determinants
of fetal growth rate in sheep and consequences for
the newborn lamb. British Veterinary Journal 1983;
139:307–324.
76 Kwon H, Ford SP, Bazer FW, Spencer TE, Nathanielsz PW,
Nijland MJ, et al. Maternal undernutrition reduces
concentrations of amino acids and polyamines in ovine
maternal and fetal plasma and fetal fluids. Biolology of
Reproduction 2004; 71:901–908.
77 Jobgen WS, Ford SP, Jobgen SC, Feng CP, Hess BW,
Nathanielsz PW, et al. Baggs ewes adapt to maternal
undernutrition and maintain conceptus growth by
maintaining fetal plasma concentrations of amino acids.
Journal of Animal Science 2008; 86:820–826.
78 Wallace JM, Luther JS, Milne JS, Aitken RP, Redmer DA,
Reynolds LP, et al. Nutritional modulation of adolescent
pregnancy outcome – a review. Placenta 2006; 27:
S61–S68.
79 Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S,
Fisher DJ, et al. Vitamin B-12 and folate concentrations
during pregnancy and insulin resistance in the offspring:
the Pune Maternal Nutrition Study. Diabetologia 2008;
51:29–38.
80 Kalra P, Das V, Agarwal A, Kumar M, Ramesh V, Bhatia E,
et al. Effect of vitamin D supplementation during
pregnancy on neonatal mineral homeostasis and
anthropometry of the newborn and infant. British Journal of
Nutrition 2012; 3:1–7. [Epub ahead of print].
81 Ashworth CJ, Antipatis C. Micronutrient programming of
development throughout gestation. Reproduction 2001;
122:527–535.
82 Dror DK, Allen LH. Vitamin D inadequacy in pregnancy:
biology, outcomes, and interventions. Nutrition Review
2010; 68:465–477.
83 Roseboom T, de Rooij S, Painter R. The Dutch famine and
its long-term consequences for adult health. Early Human
Development 2006; 82:485–491.
84 Sloan NL, Lederman SA, Leighton J, Himes JH, Rush D.
The effect of prenatal dietary intake on birth weight.
Nutrition Research 2001; 21:129–139.
85 Zimmermann MB. Iodine deficiency in pregnancy and the
effects of maternal iodine supplementation on the
offspring: a review. American Journal of Clinical Nutrition
2009; 89:668S–672S.
86 Zosky GR, Berry LJ, Elliot JG, James AL, Gorman S, Hart
PH. Vitamin D deficiency causes deficits in lung function
24 G. Wu et al.
and alters lung structure. American Journal of Respiratory
and Critical Care Medicine 2011; 183:1336–1343.
87 Jou MY, Philipps AF, Lönnerdal B. Maternal zinc
deficiency in rats affects growth and glucose metabolism in
the offspring by inducing insulin resistance postnatally.
Journal of Nutrition 2010; 140:1621–1627.
88 Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer
BA, Cole PM, et al. Prenatal micronutrient supplementation
and intellectual and motor function in early school-aged
children in Nepal. JAMA 2010; 304:2716–2723.
89 Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C,
Frick JS, Frokiaer H, et al. Early nutrition and immunity –
progress and perspectives. British Journal of Nutrition 2006;
96:774–790.
90 McDade TW, Beck MA, Kuzawa C, Adair LS. Prenatal
undernutrition, postnatal environments, and antibody
response to vaccination in adolescence. American Journal of
Clinical Nutrition 2001; 74:543–548.
91 Shah D, Sachdev HP. Zinc deficiency in pregnancy and
fetal outcome. Nutrition Review 2006; 64:15–30.
92 Calder PC, Yaqoob P. The level of protein and type
of fat in the diet of pregnant rats both affect lymphocyte
function in the offspring. Nutrition Research 2000;
20:995–1005.
93 Li P, Yin YL, Li DF, Kim SW, Wu G. Amino acids and
immune function. British Journal of Nutrition 2007;
98:237–252.
94 Wintergerst ES, Maggini S, Hornig DH. Contribution of
selected vitamins and trace elements to immune
function. Annals of Nutrition and Metabolism 2007;
51:301–323.
95 Uriu-Adams JY, Scherr RE, Lanoue L, Keen CL. Influence
of copper on early development: prenatal and postnatal
considerations. Biofactors 2010; 36:136–152.
96 Christian P. Micronutrients, birthweight, and survival.
Annual Review of Nutrition 2010; 30:83–104.
97 Maggini S, Wintergerst ES, Beveridge S, Hornig DH.
Selected vitamins and trace elements support immune
function by strengthening epithelial barriers and cellular
and humoral immune responses. British Journal of Nutrition
2007; 98:S29–S35.
98 Jacob RA, Sotoudeh G. Vitamin C function and
status in chronic disease. Nutrition in Clinical Care 2002;
5:66–74.
99 Singh U, Devaraj S, Jialal I. Vitamin E, oxidative stress,
and inflammation. Annual Review of Nutrition 2005;
25:151–174.
100 King JC. The risk of maternal nutritional depletion
and poor outcomes increases in early or closely
spaced pregnancies. Journal of Nutrition 2003;
133:1732S–1736S.
101 Wallace JM, Aitken RP, Milne JS, Hay WW Jr. Nutritionally
mediated placental growth restriction in the growing
adolescent: consequences for the fetus. Biology of
Reproduction 2004; 71:1055–1062.
102 Gao KG, Jiang ZY, Lin YC, Zheng CT, Zhou GL, Chen F,
et al. Dietary L-arginine supplementation enhances
placental growth and reproductive performance in sows.
Amino Acids 2011. doi: 10.1007/s00726-011-0960-9.
103 Xiao XM, Li LP. L-arginine treatment for asymmetric fetal
growth restriction. International Journal of Gynecology and
Obstetrics 2005; 88:15–18.
104 Cetin I, Berti C, Calabrese S. Role of micronutrients in the
periconceptional period. Human Reproduction Update 2010;
16:80–95.
105 Osrin D, Vaidya A, Shrestha Y, Baniya RB, Manandhar DS,
Adhikari RK, et al. Effects of antenatal multiple
micronutrient supplementation on birthweight and
gestational duration in Nepal: double-blind, randomised
controlled trial. Lancet 2005; 365:955–962.
106 Tan BE, Yin YL, Kong XF, Li P, Li XL, Gao HJ, et al.
L-Arginine stimulates proliferation and prevents
endotoxin-induced death of intestinal cells. Amino Acids
2010; 38:1227–1235.
107 Mateo RD, Wu G, Bazer FW, Park JC, Shinzato I, Kim SW.
Dietary L-arginine supplementation enhances the
reproductive performance of gilts. Journal of Nutrition 2007;
137:652–656.
108 Wu G, Bazer FW, Burghardt RC, Johnson GA, Kim SW, Li
XL, et al. Impacts of amino acid nutrition on pregnancy
outcome in pigs: mechanisms and implications for swine
production. Journal of Animal Science 2010; 88:E195–E204.
109 Satterfield MC, Bazer FW, Spencer TE, Wu G. Sildenafil
citrate treatment enhances amino acid availability in the
conceptus and fetal growth in an ovine model of
intrauterine growth restriction. Journal of Nutrition 2010;
140:251–258.
110 Zeng LX, Dibley MJ, Cheng Y, Dang SN, Chang SY, Kong
LZ, et al. Impact of micronutrient supplementation during
pregnancy on birth weight, duration of gestation, and
perinatal mortality in rural western China: double blind
cluster randomised controlled trial. BMJ (Clinical Research
Ed) 2008; 337:a2001.
111 Shrimpton R, Huffman SL, Zehner ER, Darnton-Hill I,
Dalmiya N. Multiple micronutrient supplementation
during pregnancy in developing-country settings:
policy and program implications of the results of a
meta-analysis. Food and Nutrition Bulletin 2009;
30 (4 Suppl):S556–S573.
112 Lassala A, Bazer FW, Cudd TA, Datta S, Keisler DH,
Satterfield MC, et al. Parenteral administration of
L-arginine prevents fetal growth restriction in
undernourished ewes. Journal of Nutrition 2010;
140:1242–1248.
113 Beck S, Wojdyla D, Say L, Betran AP, Merialdi M,
Requejo JH, et al. The worldwide incidence of preterm
birth: a systematic review of maternal mortality and
morbidity. Bulletin of the World Health Organization 2010;
88:31–38.
114 Challis JRG, Matthews SG, Gibb W, Lye SJ. Endocrine and
paracrine regulation of birth at term and preterm.
Endocrine Review 2000; 21:514–550.
115 Petraglia F, Imperatore A, Challis JRG. Neuroendocrine
mechanisms in pregnancy and parturition. Endocrine
Review 2010; 31:783–816.
116 Dole N, Savitz DA, Hertz-Picciotto I, Siega-Riz AM,
McMahon MJ, Buekens P. Maternal stress and preterm
birth. American Journal of Epidemiology 2003; 157:14–24.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26

117 Ahamed M, Mehrotra PK, Kumar P, Siddiqui MKJ.
Placental lead-induced oxidative stress and preterm
delivery. Environmental Toxicology and Pharmacology 2009;
27:70–74.
118 Dong YL, Dai BS, Singh P, Yallampalli C. Involvement of
nitric oxide pathway in prostaglandin F2 alpha-induced
preterm labor in rats. American Journal of Obstetrics and
Gynecology 1997; 177:907–917.
119 Phillippe M, Saunders T, Basa A. Intracellular mechanisms
underlying prostaglandin F2a-stimulated phasic myometrial
contractions. American Journal of Physiology Endocrinology
and Metabolism 1997; 273:E665–E673.
120 Molnár M, Hertelendy F. Signal transduction in rat
myometrial cells: comparison of the actions of
endothelin-1, oxytocin and prostaglandin F2a. European
Journal of Endocrinology 1995; 133:467–474.
121 Fowden AL, Forhead AJ. Endocrine mechanisms of
intrauterine programming. Reproduction 2004; 127:515–526.
122 Neumann ID. Involvement of the brain oxytocin system in
stress coping: interactions with the
hypothalamo-pituitary-adrenal axis. Progress in Brain
Research 2002; 139:147–162.
123 Riopelle AJ, Hale PN. Nutritional and environmental
factors affecting gestation length in rhesus monkeys.
American Journal of Clinical Nutrition 1975; 28:
1170–1176.
124 Lenders CM, Hediger ML, Scholl TO, Khoo CS, Slap GB,
Stallings VA. Gestational age and infant size at birth are
associated with dietary sugar intake among pregnant
adolescents. Journal of Nutrition 1997; 127:1113–1117.
125 Kramer MS, McLean FH, Eason EL, Usher RH. Maternal
nutrition and spontaneous preterm birth. American Journal
of Epidemiology 1992; 136:574–583.
126 Bodnar LM, Siega-Riz AM, Simhan HN, Himes KP,
Abrams B. Severe obesity, gestational weight gain, and
adverse birth outcomes. American Journal of Clinical
Nutrition 2010; 91:1642–1648.
127 Torheim LE, Ferguson EL, Penrose K, Arimond M. Women
in resource-poor settings are at risk of inadequate intakes
of multiple micronutrients. Journal of Nutrition 2010;
140:2051S–2058S.
128 Mahomed K, Bhutta Z, Middleton P. Zinc supplementation
for improving pregnancy and infant outcome. Cochrane
Database of Systematic Reviews 2007; CD000230.
129 Siega-Riz AM, Promislow JHE, Savitz DA, Thorp JM,
McDonald T. Vitamin C intake and the risk of preterm
delivery. American Journal of Obstetrics and Gynecology 2003;
189:519–525.
130 Casanueva E, Ripoll C, Tolentino M, Morales RM, Pfeffer
F, Vilchis P, et al. Vitamin C supplementation to prevent
premature rupture of the chorioamniotic membranes: a
randomized trial. American Journal of Clinical Nutrition
2005; 81:859–863.
131 Detrait ER, George TM, Etchevers HC, Gilbert JR,
Vekemans M, Speer MC. Human neural tube defects:
developmental biology, epidemiology, and genetics.
Neurotoxicology and Teratology 2005; 27:515–524.
132 Christian P. Maternal nutrition, health, and survival.
Nutrition Review 2002; 60:S59–S63.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26
Maternal nutrition and healthy pregnancy 25
133 Wehby G, Murray JC. Folic acid and orofacial clefts: a
review of the evidence. Oral Disease 2010; 16:11–19.
134 De Wals P, Tairou F, Van Allen MI, Lowry RB, Evans JA,
Van den Hof MC, et al. Spina bifida before and after folic
acid fortification in Canada. Birth Defects Research A Clinical
and Molecular Teratology 2008; 82:622–626.
135 Williams LJ, Rasmussen SA, Flores A, Kirby RS, Edmonds
LD. Decline in the prevalence of spina bifida and
anencephaly by race/ethnicity: 1995–2002. Pediatrics 2005;
116:580–586.
136 Chandra RK. Interactions between early nutrition and the
immune system. Ciba Foundation Symposium 1991;
156:77–89.
137 Andersson M, de Benoist B, Rogers L. Epidemiology of
iodine deficiency: salt iodisation and iodine status. Best
Practice in Research and Clinical Endocrinology and
Metabolism 2010; 24:1–11.
138 Zimmermann MB. Iodine deficiency. Endocrine Review
2009; 30:376–408.
139 Zimmermann MB. Research on iodine deficiency and
goiter in the 19th and early 20th centuries. Journal of
Nutrition 2008; 138:2060–2063.
140 Brabin BJ, Hakimi M, Pelletier D. An analysis of anemia
and pregnancy related maternal mortality. Journal of
Nutrition 2001; 131 (2 Suppl 2):604S–614S.
141 Main EK. Maternal mortality: new strategies for
measurement and prevention. Current Opinion in Obstetrics
and Genecology 2010; 22:511–516.
142 NIH (Washington, DC). High blood pressure in pregnancy.
2011. http://www.nhlbi.nih.gov/hbp/issues/preg/
preg.htm [Last accessed on October 12, 2011].
143 Roberts JM. Objective evidence of endothelial dysfunction
in preeclampsia. American Journal of Kidney Disease 1999;
33:992–997.
144 Kim YJ, Parks HS, Lee HY, Ha EH, Suh SH, Oh SK, et al.
Reduced L-arginine level and decreased placental eNOS
activity in preeclampsia. Placenta 2006; 27:438–444.
145 Rytlewski K, Olszanecki R, Lauterbach R, Grzyb A, Basta
A. Effects of oral L-arginine on the foetal condition and
neonatal outcome in preeclampsia: a preliminary report.
Basic Clinical Pharmacology and Toxicology 2006; 99:146–152.
146 Vadillo-Ortega F, Perichart-Perera O, Espino S,
Avila-Vergara MA, Ibarra I, Ahued R, et al. Effect of
supplementation during pregnancy with arginine and
antioxidant vitamins in medical food on pre-eclampsia in
high risk populations: randomized controlled trial. BMJ
(Clinical Research Ed) 2011; 342:d2901.
147 Erkkola M, Nwaru BI, Viljakainen HT. Maternal vitamin D
during pregnancy and its relation to immune-mediated
diseases in the offspring. Vitamins and Hormornes 2011;
86:239–260.
148 Nassar N, Halligan GH, Roberts CL, Morris JM, Ashton
AW. Systematic review of first-trimester vitamin D
normative levels and outcomes of pregnancy. American
Journal of Obstetrics and Gynecology 2011; 205:208.e1–208.e7.
149 Weiss ST, Litonjua AA. The in utero effects of maternal
vitamin D deficiency: how it results in asthma and other
chronic diseases. American Journal of Respiratory and Critical
Care Medicine 2011; 15:1286–1287.
26 G. Wu et al.
150 Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ,
et al. Effect of antioxidants on the occurrence of
pre-eclampsia in women at increased risk: a randomised
trial. Lancet 1999; 354:810–816.
151 Duley L, Henderson-Smart DJ, Meher S. Altered dietary
salt for preventing pre-eclampsia, and its complications.
Cochrane Database of Systematic Reviews 2005; (4):CD005548.
152 World Health Organization. WHO Recommendations for
Prevention and Treatment of Pre-Eclampsia and Eclampsia.
WHO/RHR/11.30. Geneva: Food and Agricultural
Organization of the United Nations. [Accessed on
November 10, 2011].
153 Said HM. Intestinal absorption of water-soluble vitamins in
health and disease. Biochemical Journal 2011; 437:357–372.
154 McNulty H, Scott JM. Intake and status of folate and
related B-vitamins: considerations and challenges in
achieving optimal state. British Journal of Nutrition 2008; 99
(Suppl 3):S48–S54.
155 Haider BA, Yakoob MY, Bhutta ZA. Effect of multiple
micronutrient supplementation during pregnancy on
maternal and birth outcomes. BMC Public Health 2011; 11
(Suppl 3):S19.
156 Lee AI, Okam MM. Anemia in pregnancy. Hematology and
Oncology Clinics in North America 2011; 25:241–259.
157 Kavle JA, Stolzfus RJ, Witter F, Tielsch JM, Khalfan SS,
Caulfield LE. Association between anemia during
pregnancy and blood loss at and after delivery among
women with vaginal births in Pemba Island. Journal of
Health, Population and Nutrition 2008; 26:232–240.
158 Heinonen K, Matilainen R, Koski H, Launiala K.
Intrauterine growth retardation in pre-term infants. Journal
of Perinatal Medicine 1985; 13:171–178.
159 Gardosi J. Intrauterine growth restriction: new standards
for assessing adverse outcome. Best Practice in Research and
Clinical Obstetrics and Gynecology 2009; 23:741–749.
160 Barker DJP. Growth and living conditions in childhood
and hypertension in adult life: a longitudinal study. Journal
of Hypertension 2002; 20:1951–1956.
161 Kajantie E, Osmond C, Barker DJP, Forsen T, Phillips DIW,
Eriksson JG. Size at birth as a predictor of mortality in
adulthood: a follow-up of 350 000 person-years.
International Journal of Epidemiology 2005; 34:655–663.
162 Lumey LH. Reproductive outcome in women prenatally
exposed to undernutrition: a review of findings from the
Dutch famine birth cohort. Proceedings of Nutrition Society
1998; 57:129–135.
163 Barker DJP, Clark PM. Fetal undernutrition and disease in
later life. Review of Reproduction 1997; 2:105–112.
164 Wang JJ, Wu ZL, Li DF, Li N, Dindot SV, Satterfield MC,
et al. Nutrition, epigenetics, and metabolic syndrome.
Antioxidants and Redox Signaling 2012. doi: 10.1089/
ars.2011.4381.
165 Youngson NA, Whitelaw E. Transgenerational epigenetic
effects. Annual Review of Genomics and Human Genetics
2008; 9:233–257.
166 Waterland RA, Travisano M, Tahiliani KG, Rached MT,
Mirza S. Methyl donor supplementation prevents
transgenerational amplification of obesity. International
Journal of Obesity 2008; 32:1373–1379.
167 McKnight JR, Satterfield MC, Jobgen WS, Smith SB,
Spencer TE, Meininger CJ, et al. Beneficial effects of
L-arginine on reducing obesity: potential mechanisms and
important implications for human health. Amino Acids
2010; 39:349–357.
168 Wu G, Jaeger LA, Bazer FW, Rhoads JM. Arginine
deficiency in premature infants: biochemical mechanisms
and nutritional implications. Journal of Nutritional
Biochemistry 2004; 15:442–451.
169 Reynolds LP, Caton JS, Redmer DA, Grazul-Bilska AT,
Vonnahme KA, Borowicz PB, et al. Evidence for altered
placental blood flow and vascularity in compromised
pregnancies. Journal of Physiology 2006; 572:51–58.
170 Wu X, Ruan Z, Gao YL, Yin YL, Zhou XH, Wang L, et al.
Dietary supplementation with L-arginine or
N-carbamylglutamate enhances intestinal growth and heat
shock protein-70 expression in weanling pigs fed a corn-
and soybean meal-based diet. Amino Acids 2010;
39:831–839.
171 Li FN, Yin YL, Tan BE, Kong XF, Wu G. Leucine nutrition
in animals and humans: mTOR signaling and beyond.
Amino Acids 2011; 41:1185–1193.
172 Brown LD, Green AS, Limesand SW, Rozance PJ. Maternal
amino acid supplementation for intrauterine growth
restriction. Frontiers in Bioscience 2011; S3:428–444.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 4–26