Guoyao Wu, Rm. 212, Kleberg Center, Texas A&M University, 2471 TAMU, College Station, TX 77843-2471, USA. E-mail: email@example.com
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 hypertensive 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 disorders). 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.
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, intrauterine growth restriction (IUGR), and preterm birth are well-known adverse outcomes of general and specific nutrient deficiencies in human pregnancy.1 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 deficiency 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 Agriculture 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 nutritional problems in poor regions of the world.8–10 Fetal undernutrition can occur in adolescent pregnancies 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 intervals (<18 months) which are associated with miscarriage, 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 overnutrition 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 overweight 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 epidemiological studies have linked both over- and undernutrition 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 highlights 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.
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 β-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.
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 pathways 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 homeostasis cannot be served by any other nutrient. Fetal glucose is primarily derived from the uptake of maternal glucose by the placenta.23 The fetal liver and kidney synthesise only a small amount of glucose from gluconeogenic 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 undernutrition, pregnant women mobilise glucose from (1) glycogen stores in the liver and muscle; (2) glycerol from lipolysis in adipose tissue; and (3) amino acids released by skeletal muscle.22 However, sole dependence of these mechanisms to provide glucose in the maternal circulation will cause maternal wasting.
Table 1. Needs of macronutrients for maternal health and fetal growth and development
Uptake by the fetus
Action on fetal growth and development
Consequences of insufficiency in pregnancy
Complex carbohydrates for enteral nutrition (starch, glycogen and fibre) and simple carbohydrate for parenteral nutrition (glucose).
PUFA that cannot be synthesised de novo by mother and fetus are linoleic acid (18:2ω6) and α-linolenic acid (18:3ω3); PUFA that cannot be adequately synthesised by mother and fetus from preformed precursors include arachidonic acid (20:4ω6), eicosapentaenoic acid (20:5ω3), and docosahexaenoic acid (20:6ω3); MUFA that can be adequately synthesised by mother and fetus include palmitoleic acid (16:1ω7), cis-vaccenic acid (18:1ω7), and oleic acid (18:1ω9); 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.
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
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.
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.
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.
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.
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.
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.
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).
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.
The human placenta is permeable to LCFA and transfers them to the fetus for metabolic utilisation.24 Liver, skeletal muscle, and heart in the mother and the fetus depend on LCFA as major metabolic fuels. Conversely, short-chain fatty acids are the primary energy sources for colonocytes. Prior to 25 weeks of gestation, the human fetus accumulates only a small amount of lipids. After 25 weeks of pregnancy, the fetus exponentially accumulates a relatively large amount of lipids.24 Placental and fetal tissues are able to synthesise the ω9 (oleic acid) family of unsaturated fatty acids. However, humans cannot synthesise the ω6 or ω3 fatty acids, linoleic acid and α-linolenic acid. Therefore, these two unsaturated fatty acids must be provided in the diet to synthesise the long-chain ω-6 and ω-3 polyunsaturated fatty acids (PUFA; Table 1). Physiologically and nutritionally important long-chain ω-6 and ω-3 PUFA include arachidonic acid (20:4ω6), eicosapentaenoic acid (EPA 20:5ω3), and docosahexaenoic acid (DHA 20:6ω3) (Table 1). Beyond serving as an energy source, long-chain PUFA play an important role in maintaining the fluidity, permeability and conformation of cell membranes. They are also precursors for the synthesis of bioactive lipid molecules, including prostaglandins, thromboxanes and leukotrienes.24 Additionally, some long-chain PUFA (e.g. DHA) are regulators of eicosanoid metabolism and the synthesis of nitric oxide (NO), a signalling molecule and a neurotransmitter in multiple tissues, including the brain).25,26 Among PUFA, DHA has received the most attention over the past decade for its role in development. DHA modulates appropriate neuronal sheath mylenation and differentiation of neural stem cells to neurons and promotes the development of the brain, nerves, retinal photoreceptors, and the immune system in the fetus.27–30 However, rates of the synthesis of DHA from α-linolenic acid in the human placenta and fetal brain are low relative to the needs of DHA by the rapidly growing fetus.24
Amino acids serve not only as building blocks for proteins but also as essential precursors for the synthesis of a variety of physiologically important molecules, including hormones, neurotransmitters, NO, creatine, glutathione, carnitine and polyamines.31,32 Additionally, through multiple cell signalling pathways, amino acids regulate key metabolic pathways that are vital to human health, growth, development and reproduction.33 Based on nitrogen balance and growth, amino acids are traditionally classified as either nutritionally essential or nonessential (Table 1). However, the classification of nutritionally nonessential amino acids (NEAA) has conceptual limitations because there is no compelling evidence that certain NEAA (e.g. arginine and glutamine) can be adequately synthesised by the mother or fetus to support optimal fetal growth and development.33–35 The synthesis of fetal proteins depends on the balanced provision of all the constituent amino acids, namely both nutritionally essential amino acids (EAA) and NEAA. To meet the needs for amino acids by the developing fetus, pregnant women should consume diets containing adequate amounts of high-quality proteins. Because most staple grains are deficient in several EAA (e.g. lysine, methionine, threonine and tryptophan), the consumption of animal source foods is recommended.36 Vegetarian and vegan women must carefully balance their intakes of grains, legumes, and other sources of protein to ensure they meet their EAA requirements; when this is not possible, supplements with specific amino acids will be needed to ensure adequate EAA intakes.
Nutritionally significant micro-minerals cannot be synthesised by the body and, therefore, must be provided in the diet (Table 2). These inorganic nutrients are the backbone of the skeleton system, serve as second messengers in cell signalling, and maintain the polarity of the plasma membrane. Minerals also regulate extracellular and intracellular osmolality, which is important for maintaining cell and blood volume as well as cell viability and shape. Most minerals are either cofactors for enzymes or components of metallo proteins, and also participate in electron transport and redox reactions. The metabolic functions of the minerals are summarised in Table 2. We review those most commonly implicated in fetal and maternal health outcomes.
Table 2. Nutritional needs of minerals for maternal health and fetal growth and development
Rich dietary sources
Special importance during pregnancy
Consequences of insufficiency in pregnancy
ATP, adenosine triphosphate; ETS, electron transport system; IUGR, intrauterine growth restriction; PIH, pregnancy-induced hypertension; SOD, superoxide dismutase.
Component of the bone; second messenger that regulates numerous biochemical pathways.
Cell-to-cell adhesion; implantation; and placentation
PIH, pre-eclampsia, eclampsia; preterm delivery
Meat, dairy foods, salt
Principal anion in the extracellular fluid; required for production of gastric acid; maintain a hydrated state of the mucus on epithelial cells
Maintenance of osmolality in blood protein digestion
Disturbance of whole-body homeostasis; embryonic and fetal death
Potentiate insulin sensitivity
Glucose transport; toxic at high intake
Contributes to insulin resistance
A component of vitamin B12
One-carbon-unit metabolism; toxic at high intake
Anaemia, neurological disorders
Function of mitochondrial ETS; cofactor of cytosolic Cu/Zn-SOD; regulation of iron and molybdenum absorption by the small intestine
ATP production in mitochondria; toxic at high intake and contribute to iron-deficiency anaemia and impairment of zinc absorption
Weakness, fatigue, impaired fetal growth and development
A component of teeth
Strength of teeth; toxic at high levels
Reduced fertility (animal studies)
Sea vegetables, seafood, iodised salt
Production of thyroid hormones
Important for the proper development of central nervous system in fetuses
Iodine deficient disorders, including cretinism
Meat, legumes, fortified foods
Oxygen binding, transport and storage; metabolism, generation of ATP
Strain on maternal iron supply in pregnancy to meet maternal haemo-expansion; toxic at high intake
Iron deficiency anaemia can increase risk of maternal haemorrhage; maternal mortality; preterm birth; IUGR
Required for glucose and protein metabolism
ATP production by red blood cells; cofactor for some ATP-dependent enzymes
Pre-eclampsia and preterm birth
Required by Mn-dependent enzymes (including arginase and mitochondrial Mn-SOD)
Ammonia detoxification by liver anti-oxidative reactions
Neurological damage, oxidative stress, and death
Component of molybdopterin, sulfite oxidase, and xanthine oxidoreductase; regulation of copper and iron absorption
Toxic at high levels and contribution to iron-deficiency anaemia; prevention of copper toxicity
Increase of risk for copper toxicity; impaired metabolism of purines
Cofactor for microbial enzymes (e.g. urease, glyoxylase, and Ni-SOD); required for microbial metabolism in the lumen of the intestine
Normal microbial activity in the intestine; toxic at high levels
Maintenance of the normal microbiota in the intestine
Meat, dairy products
ATP production, cell signalling, component of the bone
Embryonic survival; fetal growth and development energy metabolism
Weakness; fatigue; embryonic and fetal death; IUGR
Meat, dairy products, vegetables
Most abundant cation in intracellular fluid
Maintenance of intracellular osmolality; function of the nerve and muscle; fetal growth and development
Cardiac arrest; weakness; fatigue; IUGR
Cofactor for antioxidant enzymes
Protect mother and fetus from oxidative stress; toxic at high levels
Cardiac dysfunction; oxidative stress
Mediate association between cells and macromolecules (e.g. osteonectin); required for cartilage calcification
Required for the growth of connective tissue and bones; toxic at high intake
Abnormal joint structure; soft-bone syndrome;
Meat, dairy products; salt
Principal cation in extracellular fluid; sodium pump; nutrient transport
Maintenance of extracellular osmolality; function of the nerve and muscle; fetal growth and development
Malnutrition; multiple organ dysfunction; IUGR
Meat, milk, egg
Component of sulfur-containing amino acids metabolism of intestinal bacteria
Inorganic sulfur cannot be used by mother or fetus; toxic at high levels
Oxidative stress; IUGR
React with H2O2 to form a pervanadate to stimulate phosphorylation of receptor proteins; potentiate insulin sensitivity
Cell signalling; glucose transport
Contribute to insulin resistance
Gene expression; cofactor of cytosolic Zn/Cu-SOD; immune function; cell signalling
Fetal growth and development; regulation of food intake; impairment of copper absorption at high levels
Malnutrition; potential detrimental effect on immune function; IUGR
Calcium is a major component of the skeleton, cytoskeleton and teeth.37 Calcium-activated enzymes and calcium-binding proteins include pancreatic α-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 digestion 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 messenger and in this role regulates uterine contraction. By maintaining the uterus in a quiescent state through an NO-dependent mechanism,40 calcium supplementation may modulate the risk of preterm labour.41
Iodine is an essential component of the thyroid hormones (triiodothyronine and thyroxine). Thyroid hormones 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 µg/day to 220 µg/day during pregnancy.44
Iron is the most abundant trace element in the body.45 It is a component of haeme and haeme proteins, including haemoglobin, myoglobin, and cytochromes. 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) mitochondrial electron transport and ATP production; (4) DNA synthesis; (5) immunity; and (6) antioxidative reactions. A deficiency of iron can result in anaemia, hypoxia, increased risk for maternal mortality, as well as preterm birth and IUGR.46 Iron requirements 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 pregnancy; however, the amounts that can be absorbed 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 especially 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 α-ketoacid decarboxylation.48 This mineral regulates nutrient metabolism, 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, phospholipase 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, immunity, growth and development.51,52
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 synthesised in human cells. The functions of all vitamins are summarised in Table 3. Deficiencies of vitamins generally result in metabolic disorders and diseases with characteristic syndromes. In this section, we review those vitamins whose deficiencies in pregnancy are most commonly associated with poor maternal and fetal outcomes, namely vitamins A, B6, B12, D, and folate.
Table 3. Nutritional needs of vitamins for maternal health and fetal growth and development
Embryonic and fetal survival life-span of red blood cells
Maternal and fetal anaemia; muscle weakness
Vegetables; animal products; intestinal synthesis by bacteria
Generation of biologically active clotting factors
Stop bleeding when a blood vessel is cut.
Risk for maternal haemorrhage
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 conversion of homocysteine into methionine, neurological and immunological function, growth and development, and the formation of red blood cells.53–55 Additionally, vitamin B6 is required for the synthesis of neurotransmitters, polyamines and histamine, as well as the removal of ammonia from the body.53 Of particular 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 the conversion of N5-methyl-tetrahydrofolate into 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, vegetarians, 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 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 development 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 integrity 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 deficiency, is associated with maternal and neonatal mortality 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. β-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 metabolism and, therefore, bone accretion and mineralisation.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) stimulating the growth of osteoclasts; and (3) enhancing calcium resorption by the kidney. Additional regulatory 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 hypothesised that the immunosuppressive effects of calcitrol dampen the immune response against the early conceptus 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 classified as malnutrition because these two extremes of nutrition are commonly characterised by (1) imbalances 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 malnutrition 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 birthweight, 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 undernutrition on fetal development.70–81 Results from these studies indicate that deficiencies of energy or macronutrients during the first trimester of pregnancy have a greater detrimental effect on fetal development 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 pregnancies.73,78 Regarding specific nutrients, the animal studies suggest that the embryo/fetus is most vulnerable 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 deficiency 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 undernutrition, overnutrition in pregnancy has distinct metabolic 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 characterised by elevated levels of glucose, hyperinsulinaemia, 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 detrimental 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: (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 micronutrients) 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 hypoglycaemia, 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) systems.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 infection 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 availability of macro and micro nutrients.27,90,91 Epidemiological 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 percentile of the birth-weight-for-gestational-age reference curve. The risk of IUGR is higher among women with low pre-pregnancy body mass index (BMI), low weight gain during pregnancy, short stature, anaemia, and micronutrient deficiencies (e.g. iron and zinc).7,46,96–100 IUGR infants represent 11% of all newborns 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 haemoglobins (because of iron deficiency) for oxygen transport; 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 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 supplementation (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 micronutrient 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 nourished 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 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 nutritional status.
Preterm birth (<37 weeks) is a leading cause of infant morbidity and mortality worldwide, and occurs in approximately 10% of pregnancies globally.113 The incidence of preterm birth is particularly high in certain countries (e.g. approximately 23% in rural Nepal, 21% in India, and 17% in Bangladesh). Significant disparities 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 complications, including respiratory distress syndrome, intraventricular 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 F2α (PGF2α) by uterus, placenta and fetus; (3) elevated levels of hormones (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) reducing the circulating levels of cortisol and oxytoxin; and (2) increasing NO bioavailability through up-regulation of NO synthesis from arginine and inhibition 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 undernutrition and overnutrition are associated with reduced 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) substantially 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 adolescents.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 associated 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 periconceptional 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 malnutrition, 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% reduction in the risk of preterm delivery.41 Also, one study involving a prospective cohort of pregnant women (aged ≥16 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 gestation, reduced the incidence of premature rupture of the chorioamniotic membranes in pregnant women by 69%.130
Neural tube defects are one of the most severe developmental 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 importance of adequate maternal nutrition before gestation and in the first trimester. The two most common neural tube defects are spina bifida and anencephaly.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 previously, 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 lipids.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 circulating 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 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 development 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 pregnancy such as pre-eclampsia and eclampsia.5 Anaemia and obstructed labour are also substantial contributors 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 mechanisms 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 complication is generally diagnosed after 20 weeks of gestation 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 pregnancies 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 evidence for oxidative stress, reduced bioavailability of NO in the vasculature, and endothelial cell dysfunction in pre-eclamptic women.143–145
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 supplementation 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 recommended to treat pre-eclampsia and prevent progression to eclampsia.152 The Technical Consultation did not find sufficient evidence to support recommending 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 hypertension, 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 supplementation 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
Maternal haemorrhage refers to the substantial loss of the mother's blood at delivery and accounts for approximately 60% of all maternal deaths in developing countries.141 When the placenta is separated from the wall of the uterus, the maternal blood vessels that previously supplied blood to the placenta are sheared, resulting in bleeding. Such bleeding is normally stopped by the spontaneous contraction of the uterus and the compression of its vessels. However, when uterine contraction is inadequate, bleeding will continue and haemorrhage can occur. In developing nutritional means to prevent maternal haemorrhage, it should be recognised that blood clotting is affected by the amounts of coagulation factors (proteins that are synthesised from amino acids) and their Ca2+- and vitamin K-dependent activities.44 Thus, theoretically, in addition to energy (ATP provision), nutrients that can beneficially improve uterine contraction without inducing premature labour include amino acids (notably arginine and glutamine), minerals (particularly calcium and iron), long-chain PUFA (e.g. arachidonic acid and ω3-PUFA), and vitamins (especially vitamin K and A).140 In support of this view, there is evidence that undernutrition and overnutrition are associated with increased risk for maternal haemorrhage.136,141 This condition can result in iron deficiency, anaemia, morbidity and maternal death.
Based on the chemical composition of haemoglobin, a deficiency of amino acids or iron in the maternal diet can cause anaemia.31,46 A deficiency of vitamins (vitamin B6, vitamin B12 and folate) and minerals (cobalt, magnesium, zinc and copper) that participate in one-carbon-unit metabolism and, therefore, DNA synthesis can also indirectly result in anaemia.153–155 Furthermore, insufficient provision of dietary nutrients (e.g. vitamin A, lipids and carbohydrates) that are essential to the integrity of intestinal epithelial cells, the function of enterocytes, and the absorption of vitamins and minerals can also increase the risk for the development of anaemia.156 Thus, a balanced and adequate supply of all nutrients is crucial to prevent anaemia in humans. However, the causes of anaemia are not solely nutritional. Malaria, parasitic infections, and inherited thallasemias and haemoglobinopathies can also result in anaemia independent of nutrition and the relative contributions of each of these factors to the burden of anaemia is highly context-specific.140 Fully integrated approaches that address the nutritional, infectious and genetic aetiologies of anaemia are needed to develop effective interventions.
Pregnant women with anaemia have a reduced capability for: (1) oxygen transport from the heart to central and peripheral tissues; and (2) impaired metabolism of macronutrients and ATP production. Thus, these subjects often exhibit pale skin, weakness and fatigue. In its severe and acute form (<70 g haemoglobin/L), anaemia can lead to rapid cardiac decompensation and cardiac failure. Indeed, it is estimated that 6.4%, 7.3% and 3.0% of maternal mortality is attributable to severe anaemia in Africa, Asia and Latin America, respectively.140 When severe anaemia is not a primary cause of death, it may be a contributing indirect factor, for example, by increasing the inability of a woman to tolerate blood loss from haemorrhage or by increasing her risk of infection.156 The contribution of less severe anaemia to the burden of maternal mortality is less well documented, though recently, Stoltzfus et al.6 estimated that a population increase in maternal haemoglobin by 1 g/dL could reduce the risk of maternal mortality by approximately 25%. With regards to anaemia as an indirect contributor to mortality through increased risk of haemorrhage, the epidemiological evidence suffers from substantial methodological shortcomings and is largely inconsistent.4,140 However, a recent clinical study in Zanzibar reported that among women presenting at a clinic with uncomplicated vaginal deliveries, those with moderate or severe anaemia lost significantly more blood during and immediately after delivery compared with nonanaemic women.157 The researchers hypothesised that women with moderate to severe anaemia may have decreased uterine blood flow or low uterine muscle strength which contributed to inefficient uterine contractions and greater blood loss.157
Implications of IUGR and other poor pregnancy outcomes for human health
Impact of IUGR on infants and children
Intrauterine growth restriction is a significant factor contributing to fetal deaths and preterm births.158,159 For example, IUGR is responsible for about 50% of non-malformed stillbirths in humans. Furthermore, Heinonen et al.158 reported that different types of IUGR contribute to approximately 40% of preterm births. IUGR infants delivered at preterm gestations have severe perinatal and neonatal medical complications. Of note, the rates of neonatal morbidity and mortality among preterm IUGR infants are much higher than those among appropriately grown preterm infants with similar gestational age.158 Thus, infants who weigh <2500 g at birth have perinatal mortality rates that are five- to 30-fold greater than those of infants who have average birthweights, while infants that weigh <1500 g have 70- to 100-times greater mortality rates.159 Compelling evidence shows that surviving infants with IUGR are often at increased risk for neurological, respiratory, intestinal, immunological and circulatory disorders during the neonatal period and childhood.159 For girls who suffer from IUGR, short stature can lead to obstructed labour in the future.156
Impact of IUGR on chronic diseases
The adaptation of the IUGR fetus or offspring to in utero or extrauterine environments may confer an evolutionary advantage for the survival of the species. However, when environmental cues during prenatal life inappropriately programme offspring, there are adverse consequences, including the increased prevalence of disease in adult life which may result, in part, from a reduced availability of nutrients to the fetus in utero.2 Both epidemiological and experimental evidence indicate that IUGR contributes to a plethora of metabolic disorders and chronic diseases in adults.1,160,161 These problems include: (1) hormonal imbalance (e.g. increased plasma levels of glucocorticoids and renin; decreased plasma levels of insulin, growth hormone, and insulin-like growth factor-I); (2) metabolic disorders (e.g. insulin resistance, β-cell dysfunction, dyslipidemia, glucose intolerance, impaired energy homeostasis, obesity, type-II diabetes, oxidative stress, mitochondrial dysfunction, and ageing); (3) organ dysfunction and abnormal development (e.g. testes, ovaries, brain, heart, skeletal muscle, liver, thymus, and small intestine); and (4) cardiovascular disorders (e.g. coronary heart disease, hypertension, stroke, and atherosclerosis).2,3 Hence, infants who survive the adverse consequences of IUGR through the neonatal period may face an increased risk of poor health in adulthood.
The fetus may survive extreme conditions in utero through physiological adaptations that include changes in gene expression. Epidemiological studies show that individuals exposed to the Dutch winter famine of 1944–1945 in utero had higher rates of insulin resistance, vascular disease, morbidity and mortality in adulthood.162 The intrauterine environment of the conceptus may alter expression of the fetal genome and have lifelong consequences. This phenomenon is termed ‘fetal programming’, which has led to the theory of fetal origins of adult disease.163 Namely, alterations in fetal nutrition and endocrine status may result in developmental adaptations that permanently change the structure, physiology and metabolism of the offspring, thereby predisposing individuals to metabolic, endocrine and cardiovascular diseases in the adult lives of both animals and humans.
Fetal programming may be explained by epigenetics, which is defined as stable and inheritable alterations of genes through covalent modifications of DNA and core histones without changes in DNA sequences.164 The concept of fetal programming has now been experimentally tested in a number of animal models, including rats, mice, cattle and sheep,16 and has shown that the effects of changes in nutrition or endocrine status during fetal or neonatal life can be carried forward to subsequent developmental stages.165 Because DNA methylation, a mechanism mediating epigenetic effects, is reversible, it is likely that metabolic abnormalities in the offspring can be ameliorated through nutritional interventions.164 For example, transgenerational exposure of the agouti mice to an ad libitum diet causes obesity-associated metabolic syndrome in offspring, which can be prevented by dietary supplementation with folate.166 While research is still limited, nutrition is expected to play a key role in developmental plasticity, potential, and programming.
Conclusions and perspectives
A summary of current knowledge of the field
Development of the human conceptus absolutely depends on adequate and balanced supplies of both macronutrients and micronutrients. During implantation, the embryo receives nutrients from maternal uterine secretions, which include water, protein, amino acids, lipids, and glucose, minerals, and vitamins. 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, neurological 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 concentrations 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 potentially alleviate the burden of, and may even completely prevent, certain poor health outcomes.
The prenatal growth trajectory of humans is sensitive 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 deficiencies 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, correcting 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 nutritious food, nutrition supplements, and preventive health services. While effective postnatal therapies are required for surviving individuals with IUGR, its prevention should be the best strategy to improve the health and well-being of infants and adults. One effective 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 micronutrients10,127,128,130). Despite the previous research efforts focusing on mainly individual nutrients or a mix of multiple micronutrients, there is a paucity of information 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 unfortunate 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 (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 nutritional 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 quiescence 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.
Helpful discussions among our colleagues regarding maternal nutrition and pregnancy outcomes are gratefully appreciated.
Conflicts of interest
The authors have not declared any conflicts of interest.