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Abstract

The prenatal period encompasses a critical window for future health and functioning of mother and child. Attention previously focused on undernutrition risk (i.e., in developing countries and famine conditions) shifted to mismatch between prenatal ‘programming’ by undernutrition and postnatal overconsumption (i.e., low birthweight vs rapid postnatal growth), now to overconsumption/overweight throughout the reproductive cycle and short- and long-term health risks, including obesity, diabetes, dyslipidemia and cardiovascular disease. Moreover, overconsumption/overweight do not guarantee adequacy of critical nutrients (i.e., against birth defects or for brain development). Multinutrient supplementation – including zinc, iodine, choline and long-chain polyunsaturated fatty acids, especially n-3 – may have advantages over single-nutrient supplements, for example, iron or folate. Future nutritional care for healthy in utero programming may necessitate individual assessment and follow-up, including preconception nutritional preparation, appropriate weight gain, metabolic balance and food-based regimens enhanced by key nutrient fortification and/or supplementation, warranting further research into nutritional optimization of pregnancy outcomes.

Keywords

birthweight brain development maternal nutrition multivitamin supplementation pregnancy

Growing evidence from scientific and epidemiological research continue to support proper nutritional status of women before and during pregnancy as key to maintaining maternal health, supporting optimal fetal growth and brain development [1] and the early prevention of adverse pregnancy outcomes, birth defects [2] and chronic disease throughout the lifespan [3 –9]. Since pregnancy creates special metabolic demands for intensive production of the placenta, fetal tissue, blood volume and peak brain development, nutritional imbalance could significantly impact the future health and functioning of the mother and child [5,6]. The intrauterine and early postnatal months are well known to be particularly critical for future health and brain development, as identified in population-based cohorts [10,11]. Optimal maternal nutrition is an essential component for fetal and infant development, closely linked with maternal supply of essential nutrients, including vitamins and minerals [12]. The periconceptional period was also found to be a critical period for nutritional effects on the ability of the fetus to respond to acute and chronic stressors, for timing of parturition and for fetal, postnatal and adult cardiovascular and metabolic health outcomes [13] Beyond the direct implications to growth and development, it is increasingly suggested that the periconception period constitutes a critical time for nutritional effect on gene expression [14].

Traditional understanding of prenatal nutritional deficiency has been based on conditions in economically disadvantaged populations, resulting in maternal depletion, low birthweight (LBW) and impaired postnatal growth [15]. The now classic study of World War II famine in Holland [16] suggested long-term effects of prenatal deficiency on adult health of offspring, with surprising correlations between LBW and increased incidence later in life of obesity, glucose intolerance, atherogenic lipid profile and coronary heart disease (CHD). Although additional risks may have been at play, the hypothesis of prenatal undernutrition as the origin of adult disease continues to accrue support by research findings [17], recently attributing it to the ‘mismatch’ between in utero conditioning for metabolic efficiency in states of undernutrition (i.e., LBW) versus rapid postnatal catch-up growth and exposure to a modern Western diet and overconsumption ( Figure 1 ) [18,19]. Recently, the focus has shifted to postnatal risks associated with prenatal maternal overconsumption and overweight, including related diseases such as high blood pressure, cardiovascular disease (CVD), diabetes mellitus and metabolic syndrome (MetS) [3,4].

Figure 1.

The developmental programming hypothesis.

The new challenge of prenatal nutrition involves managing the risks of preconception and early pregnancy overweight, gestational weight gain, overconsumption and high caloric density, which has been found in dietary surveys to be further associated with nutritional inadequacy, especially with regard to micronutrients [20].

New evidence regarding critical impact of the Western diet on pregnancy course, outcomes and future health and development, including information for the brain during its peak development time, is addressed here, with implications for future approaches to optimizing prenatal nutrition.

in utero nutritional programming

During pregnancy, changes in key reproductive hormones are responsible for the dramatic adjustments in maternal metabolism that maintain the flow of nutrients to the fetus, stimulate uterine growth and promote mammary development, among many other functions. These changes are supported by increases in absorption of nutrients, specifically, of iron and calcium, as well as in blood volume [7].

The original hypothesis of the ‘developmental origins of adult health and disease’ assumed that undernutrition in utero conditions the body's structure, function and metabolism to be permanently more efficient in storing fat and utilizing energy, which may lead to risk of obesity, CVD, diabetes mellitus and MetS in adult life [3,4]. This effect was initially dubbed ‘programming’ and related to ‘epigenetic’ or ‘imprinting’, which is related to quantitative aspects of organ growth and function, later found to be associated with alterations in gene structure and expression, which impact endocrinological and metabolic mechanisms [21]. There is a growing body of evidence from studies of in vitro embryo cultures that elements within the genome may be epigenetically labile to early nutrition – as early as the periconceptual phase [22] – that may result in subsequent alterations in gene expression, modulating health throughout the life cycle [9,19,23] and yielding transgenerational nutritional affects [8].

The association between LBW and adult CHD has been confirmed in longitudinal studies of men and women around the world [4] and across economic conditions [18], and is supported by comprehensive evaluations lending greater differentiation between factors, such as body composition, biomarkers and other key measurements, including endothelium-dependent vasodilation [23 –25]. Although there appears to be a range of tolerance to nutritional imbalances and related adaptive responses, they may be sensitive to the degree of mismatch between the in utero and postnatal nutritional environments [26]. Epidemiological and animal studies have further shown that programmed effects may be exacerbated by postnatal dietary insufficiency and/or overconsumption, socioeconomic stressors, additional illness and classic lifestyle risk factors such as smoking, alcohol use and lack of exercise [27].

However, with increasing awareness of Western nutritional risk factors, including maternal over-consumption and excess BMI, it is important to note that animal models demonstrated exposure to these factors in fetal life to result in a series of central and peripheral neuroendocrine responses that, in turn, program the development of the fat cell and central appetite regulatory system. This may result in precursors to chronic disease emerging already in childhood and adolescence [23,28]. In an observational human cohort, infants of mothers who were overweight and obese during pregnancy had lower resting energy expenditure and increased BMI and body fat during the first 3–6 months postnatally compared with infants of lean women [29]. Furthermore, early maternal overweight has been found in longitudinal cohorts to be a strong determinant of offspring MetS at ages 6–11 years [30], as well as overweight at 18 years of age [31].

Better understanding of these correlations could lead to the development of novel diagnostic and preventive measures, and by the early detection of at-risk individuals, including monitoring of blood pressure, weight and renal function in children, it might be possible to reduce the risk of CVD and renal disease in later life [22]. At present, the better management of pregnancy will have long-term, wide-scale effects on our society's health [27].

Nutritional programming & early biomarkers for chronic disease

Potential etiological mechanisms for in utero programming of disease have further led to consideration of surrogate markers, specifically, those known to be characteristic of subclinical inflammation, as novel components of the high-risk intrauterine environment. In rodent models, intrauterine growth-restricted offspring – particularly those from food-restricted, undernourished dams – develop hypertension, with enzymatic assays revealing alterations in the renin–antiogensin system and elevations in angiotensin-converting enzymes, correlating to adult hypertension, impaired renal morphology, as well as elevated plasma Ang II and aldosterone [32,33]. In humans, testing of cord blood in offspring of women with diabetes has shown elevations in plasma insulin, 32–33 split proinsulin, proinsulin, leptin, insulin growth factor-1, IL-6, C-reactive protein, intracellular adhesion molecule-1, plasma total cholesterol, triglyceride, nonesterified fatty acids, very low-density lipoproteins and low-density lipoproteins (LDLs) and reductions in adiponectin high-density lipoproteins (HDLs) – the same markers associated with risk in adults – and correlated to measures of fetal adiposity and maternal glycemia in humans [34].

Prenatal nutritional risks

Undernutrition

Micronutrient deficiencies during pregnancy are associated with adverse pregnancy outcomes, including reduced birthweight. LBW has in turn been associated with increased risk of infant mortality and growth failure in randomized, controlled human research [35]. Furthermore, maternal deficiencies have been shown to impair breast milk composition [13].

Early gestation appears to be a particularly vulnerable period [16]. During the first trimester of pregnancy, the embryo and placenta undergo a process of rapid cell differentiation and division and are particularly sensitive to excesses and deficiencies in micro-nutrients that may lead to faulty reprogramming – modification of previously established genotype – and, thus, predispose the infant to chronic illnesses in adulthood [2]. Early–mid gestational undernutrition has been found to impact the fetal and adult adipocyte as well as renal and brain function, which together act to increase the risk of postnatal development of hypertension [36]. LBW, especially when followed by accelerated growth in childhood and greater central adiposity in adulthood, has been found to be a risk factor for a range of common diseases, including CVD and Type 2 diabetes mellitus [19,37]. In animal models, this relationship has been somewhat inconsistent, and may depend on the timing and status of other nutrients, specifically, iron deficiency, which has been linked to characteristics consistent with MetS development in animals with or without catch-up growth [38]. In humans, an association was found in a longitudinal survey between maternal nutritional stress – even prior to pregnancy – and patterns of LDL-cholesterol in children, especially in cases of greater catch-up growth potential, extending to adolescence in boys [39].

Generally, prenatal nutrient requirements are easily met in women having a balanced diet, with noted exceptions identified in surveillance studies of elemental iron [6], iodine [40], folic acid (folate) [41] and n-3 polyunsaturated fatty acids (PUFAs) [42]. Consequently, deficiency states are considered to be rare in developed countries, and supplementation should be made on an individual basis, especially since nutritional deficiencies during pregnancy can be difficult to detect.

Epidemiological studies from developing countries, where micronutrient malnutrition is common during pregnancy, provide strong evidence that supplementation of certain trace elements and minerals could prevent some of the most severe adverse pregnancy outcomes, and conclusions from monitoring status of such minerals as iodine and iron and vitamins, such as folic acid, have supported a need for ongoing supplementation with a focus on pregnancy and early childhood for prevention of neurological consequences [43], with supplementation lending an advantage even in the USA [41] and Western and Central European countries [38,44,45]. This is because over 13% of pregnant women may suffer from iron deficiency, even in populations with average or higher social status or food availability [46,47], probably due to inadequately increased dietary intake during pregnancy [48].

The developing brain is particularly vulnerable to nutrient insufficiency between 24 and 42 weeks of gestation because of the rapid course of several neurologic processes, including synapse formation and myelination. Key nutrients include protein, iron, zinc, selenium, iodine, folic acid, vitamin A, choline and long-chain PUFAs (LCPUFAs). Studies in animal models have demonstrated early nutritional insults to have a greater effect on cell proliferation, thereby affecting cell number, while postnatal nutritional insults affect differentiation, including size, complexity and, in the case of neurons, synaptogenesis and dendritic arborization. Since they fundamentally affect neuroanatomy, neurochemistry and neurophysiology [49], even temporary insufficiencies of key nutrients may delay and reduce brain development, as observed in animal and human cohorts [50 –55]. In reviews of human outcomes, prenatal maternal iodine deficiency has been linked to preventable mental retardation in children, even in apparently iodine-sufficient areas, and often goes unnoticed [52].

Unfortunately, many children are born under conditions of inadequacy, with gestational outcomes and child development threatened by wide-ranging nutritional deficiencies, including minerals (i.e., iron, zinc and iodine), vitamins (B6, B12, choline, folic acid, C and D) and LCPUFAs, as noted in prospective interventional and observational studies [56,57]. Maternal supplies of various nutrients are highly expended during pregnancy, and high parity may cause progressive depletion that could compromise maternal wellbeing, limit nutrient availability to the fetus and infant, and hinder gestational outcomes. Therefore, maternal dietary repletion may be as critical as infant nutrition for the developmental support and stimulation, and maintenance of a nurturing environment [5,58].

Overconsumption

Western-type disease risks tend to be associated with dietary overconsumption, and include obesity, diabetes mellitus, hypercholesterolemia and hypertension. These carry special significance during pregnancy, as they have been shown to impact the postnatal health of mother and child alike. Although most undernutrition research models may mimic the challenge faced in developing nations, or in the underprivileged members of Western societies, they may have little in common with the dietary intake of the majority of Western societies. Ironically, prenatal obesity does not guarantee nutritional adequacy, as a recent survey of women in the USA found pregravid obesity to be associated with 76% increased odds of falling into the lowest diet quality tertile compared with underweight women, with regard to adequacy of folic acid and iron [20] and vitamin D [59].

Obesity

The overweight and obesity epidemic in the Western world – 30% of the US population [60] – appears to significantly affect pregnancy. In a recent large-scale retrospective analysis, 43% of women were found to gain more weight during pregnancy than is recommended, 37% had appropriate gain and 20% had less than recommended gain [61]. Overweight and obese women are at greater risk for pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM), require induced labor and cesarean sections more frequently, have more difficulty initiating breastfeeding and are more likely to retain the excess pregnancy weight [7,37]. Maternal obesity also increases the risk of adverse pregnancy outcomes [62], preterm delivery, fetal mortality and neural tube defects in the child independent of folic acid intake, and has been linked to macrosomia, low Apgar scores [63,64] and an intergenerational cycle of obesity [23] in observational studies. Maternal obesity at conception, which may lead to corresponding fetal programming of offspring, has been linked to obesity in later life in large animal models [65].

Diabetes mellitus

Gestational diabetes mellitus is the prenatal onset of maternal carbohydrate intolerance that generally appears in the latter half of pregnancy (after 24 weeks) and increases the risk of macrosomia and other obesity-associated pregnancy complications, including morbidity for both mother and fetus [66,67]. Up to 70% of affected women will manifest Type 2 diabetes mellitus within 10 years thereafter, although balancing maternal glucose levels through diet and lifestyle can ameliorate it [68]. Even borderline high blood glucose levels increase risk of infants being large for gestational age (LGA), earlier adiposity rebound and higher prevalence of MetS, especially if they themselves become obese [69]. Children who are LGA at birth and exposed to an intrauterine environment of either diabetes or maternal obesity may be at increased risk of developing elevated blood pressure and BMI, as well as MetS [30]. Infants of mothers with diabetes may also be at risk for depleted stores of iron [70]. The association between subdiabetic elevations in maternal glucose levels with increased birthweight and increased cord blood serum C-peptide levels was recently supported by findings from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [71].

To reduce the risks of GDM, achieving levels of hemoglobin A1C less than 1% above normal range is desirable. In obese women (BMI > 30), appropriate caloric intake (25 kcal/kg body), medical nutrition therapy and moderate exercise, can often control GDM, but insulin may be recommended in women with poor glycemic control. Guidance for managing GDM has been published by the American Diabetes Association [66].

Hypercholesterolemia

Hypercholesterolemia may lead to excessive lipid peroxidation that, if coexistent with diminution in antioxidant activity, may lead to oxidative stress, elevated atherogenicity index (AI) and atherogenicity in pre-eclampsia, which places the mother at risk for postgestational cardiovascular sequelae [72]. Maternal inflammation and hypercholesterolemia have been demonstrated in animal models to affect the programming of offspring atherosclerosis development; even if only temporary, maternal hypercholesterolemia in pregnancy may be associated with increased fatty-streak formation in human fetal arteries and accelerated progression of atherosclerosis in normocholesterolemic children [73]. Conversely, animal models have demonstrated the use of anti-oxidant, lipid-lowering and other innovative therapies to counteract the impact of these intrauterine risk factors for CVD [74]. This suggests that prevention of LDL oxidation may inhibit the progression of atherosclerosis in the offspring of hypercholesterolemic mothers [73]. The susceptibility to formation of neointima – a new and usually thickened layer of smooth muscle cells that occurs in response to vascular injury – in morphologically normal adult arteries is already imprinted during prenatal development, and may manifest itself in the presence of additional atherogenic risk factors in adult life [75].

Hypertension: pregnancy-induced hypertension & pre-eclampsia

Approximately 8–10% of pregnant primiparous women may develop PIH after 20–32 weeks of pregnancy or 6–8 weeks postpartum. More severe forms include pre-eclampsia, eclampsia and/or toxemia. Predisposing factors include obesity, primaparity, multiple pregnancy, older maternal age (>35 years), maternal obesity history and chronic hypertension [64] It may be associated with decreased uterine blood flow and supply of nutrients and increased blood pressure, and may raise the risk for poorer pregnancy outcomes, such as preterm delivery, intrauterine growth restriction, neonatal death and maternal morbidity and mortality [76]. Inflammatory cytokines are thought to link placental ischemia with cardiovascular and renal dysfunction [77], which may imply that a nutritional anti-inflammatory approach is warranted.

Epidemiologic studies have also demonstrated a relationship between pre-eclampsia and an increased risk of future maternal CHD [72]. A combination of increased oxidative stress, total cholesterol and AI with decreased HDL, anti-oxidant activity and albumin levels has been observed in pre-eclamptic compared with nor-motensive pregnant women, suggesting that oxidative stress and elevated AI may contribute to the associated atherogenicity [72].

Low prenatal intakes of calcium [78], vitamin D [59] and selenium [79,80] were suggested as nutritional risk factors based on animal as well as human case–control and prospective cross-sectional studies.

Nutritional goals & guidance during pregnancy

The primary aims of nutrition during pregnancy are to foster a healthy uterine environment for optimal fetal metabolism and development, and to support sound maternal health. A balanced diet should limit overconsumption for the mother and prevent under-nutrition for the fetus. Several consensus reports of expert opinions under the auspices of the American Dietetic Association [64], US Department of Health and Human Services [81], US Department of Agriculture, Institute of Medicine of the National Academy of Sciences (IOM) [2] and Health Canada [82] have concluded that this may be attained by a balance of healthy meals and snacks, and selected foods from the following: lean nutrient-dense protein sources, such as fish, eggs, beef, poultry and dried legumes paired with brown rice; complex carbohydrates that are sources of vitamin A, C and B vitamins (including folic acid), such as fruit, vegetables and whole grains (cereals and breads); low-fat dairy products that are sources of protein, calcium, magnesium, phosphorus and vitamins A, B12 and D, such as fortified milk, yoghurt and cheese; and sources of n-3 LCPUFA, such as fatty fish, taking care to avoid higher sources of mercury contamination as recommended based on data from observational cohort studies [81,83–85]. Pregnant women need 8–12 cups of fluids a day for adequate hydration, including from water, milk, juice and liquids contained in fruits and vegetables [64]. Women who eliminate certain foods or food groups should take care to compensate for omitted nutrients through evaluation and professional guidance. Beyond nutritional adequacy and traditional protective components, prevention of metabolic disorders preferably incorporates limitation of high glycemic foods, including white flour and baked goods, quick-cooking rice, oatmeal or other instant grains, and simple carbohydrates, including refined starch, sugar, soda and sweets.

MyPyramid nutritional plan for pregnancy

The USDA recently introduced the MyPyramid Plan for Moms, an interactive and ultimately personalized dietary framework that replaces the traditional USDA Food Guide Pyramid for Pregnancy (see example in Figure 2 ).

Figure 2.

MyPyramid Plan for Moms: example of individualized dietary recommendations (October 27, 2007).

Guidance for energy balance

According to guidelines set forth by the IOM, additional energy needs during the second and third trimesters of pregnancy are approximately 340 and 452 kcal/day, respectively (500 kcal/day in young adolescents [<14 years]). Although a total ranging between 2708 and 2855 kcal/day has been estimated for general guideline purposes, maternal BMI, age, rate of weight gain, physiological appetite and activity level must be considered in tailoring this recommendation to the individual [81]. Normal and overweight women in developed countries may require less than the extra 300 kcal/day usually recommended, especially if sedentary.

Regular physical activity confers benefits of weight management and reduced risk of chronic disease, and serves to balance excessive energy intake. Some evidence suggests that women who engage in recreational physical activity have a 50% lower risk for GDM and 40% less for pre-eclampsia [86]. Since some obstetric and medical conditions may preclude or limit perinatal activity, each sport or activity should be examined for potential risk.

Bodyweight as a nutritional indicator

Maternal weight gain must support an increase in blood volume to nourish the fetus, as well as the products of conception – the placenta, amniotic fluid and fetus itself [7]. Appropriate weight gain is a better indicator of energy sufficiency than the amount of daily calories consumed. Initial maternal weight and gestational gain have been found in community-based longitudinal studies to be good predictors of infant birthweight [87]. In turn, pre-pregnancy weight affects the additional caloric requirement recommended during pregnancy [88].

Healthy prenatal weight gain ranges that were recommended by IOM in 1990, primarily based on pre-pregnancy weight [89], remain the standard for single pregnancies, referenced in recently updated guidance published by both the American Dietetic Association [64] and the American College of Obstetricians and Gynecologists [90] For multiple pregnancies (twin and triplet), additional recommendations were recently published based on retrospective observational analyses [91,92]. In these cases, higher weight gains before 20–24 weeks may be beneficial, with total gain depending on pre-pregnancy weight ( Table 1 ): underweight, normal weight, overweight and obese [89,91–94].

Table 1.

Recommended guidelines for weight gain during pregnancy.

	Recommended total weight gain	Weight gain per week after 12 weeks
First 12 weeks [89]	0.9–1.8 kg (2–4 lb)
After 12 weeks [89]
BMI < 19.8	12.5–18 kg (28–40 lb)	0.5 kg (~1 lb)
BMI = 19.8–26.0	11.5–16 kg (25–35 lb)	0.4 kg (~1 lb)
BMI > 26.0–29.0	7–11.5 kg (15–25 lb)	0.3 kg (0.7 lb)
BMI > 29.0	7–11.4 kg (15–25 lb)
Multiple pregnancy [89,91,92]
BMI < 19.8	22.7–28.1 kg (50–62 lb)
BMI = 19.8–26.0	18.1–24.5 kg (40–54 lb)
BMI > 26.0–29.0	17.2–21.3 kg (38–47 lb)
BMI > 29.0	13.2–17.2 kg (29–38 lb)
Twin pregnancy	15.9–20.4 kg (34–45 lb)	0.7 kg (3 lb)
Triplet pregnancy	>16.2 kg at 24 weeks [92] 22.7 kg (50 lb) overall
Adolescent pregnancy [94]
≤16 years old	Upper end of recommendations	Upper end of recommendations
>16–19 years old	Similar to adult women	Similar to adult women

Significant deviation from IOM recommendations has been associated with undesirable gestational outcomes in retrospective analyses of community cohorts [95,96]. Underweight women (BMI < 19.8) are at high risk of delivering a LBW infant if their prenatal weight gain is inadequate, and those who lose weight or gain less than 6 kg are more likely to deliver a small-for-gestational-age infant. Overweight women (BMI > 29.0) should gain at least 7 kg, but not exceed 11.4 kg, in order to reduce risk of postpartum weight retention; excessive weight gain in overweight women (BMI > 26.0) places the child at risk of being LGA and having excess body fat during childhood. Specific ranges of pregravid weight status for good pregnancy outcomes may differ across ethnic groups, owing to differences in maternal anthropometry. At all maternal weight levels, excessive gain (above the upper limit of the IOM range) contributes to postpartum weight retention [64,97].

Nutrient intake guidance

Depending on food quality, increased consumption to meet increased energy needs during pregnancy – especially given increased absorption and utilization – would be generally adequate to meet the nutritional needs for most nutrients ( Table 2 ).

Table 2.

Dietary reference intakes: recommended intakes for pregnant women.

Nutrient	Adult woman	Pregnancy	Lactation (0–6 months)
Energy (kcal)	2403	2743*, 2855‡	2698
Protein (g/kg/day)	0.8	1.1	1.1
Carbohydrate (g/day)	130	175	210
Total fiber (g/day)	25	28	29
Linoleic acid (g/day)	12	13	13
Linoleic acid (g/day)	12	13	13
Vitamin A (μg; retinol activity equivalents)	700	770	1300
Vitamin D (μg)	5	5	5
Vitamin E (mg α-tocopherol)	15	15	19
Vitamin K (μg)	90	90	90
Vitamin C (mg)	75	85	120
Thiamin (mg)	1.1	1.4	1.4
Riboflavin (mg)	1.1	1.4	1.6
Vitamin B-6 (mg)	1.3	1.9	2.0
Niacin (mg; niacin equivalents)	14	18	17
Folate (μg; dietary folate equivalents)	400	600	500
Vitamin B-12 (μg)	2.4	2.6	2.8
Pantothenic acid (mg)	5	6	7
Biotin (μg)	30	30	35
Choline (mg)	425	450	550
Calcium (mg)	1000	1000	1000
Phosphorus (mg)	700	700	700
Magnesium (mg)	320	350	310
Iron (mg)	8	27	9
Zinc (mg)	8	11	12
Iodine (μg)	150	220	290
Selenium (μg)	55	60	70
Fluoride (mg)	3	3	3
Manganese (mg)	1.8	2.0	2.6
Molybdenum (μg)	45	50	50
Chromium (μg)	25	30	45
Copper (μg)	900	1000	1300
Sodium (mg)	2300	2300	2300
Potassium (mg)	4700	4700	5100

Values are recommended dietary allowances except for energy (estimated energy requirement) and total fiber, linoleic acid, α-linoleic acid, vitamin D, vitamin K, pantothenic acid, biotin, choline, calcium, manganses, chromium, sodium and potassium (adequate intakes).

Second trimester for women aged 19–50 years.

‡

Third trimester for women aged 19–50 years.

Data taken with permission from [141].

However, supplementation (without exceeding upper limits) may be appropriate or even required for some nutrients ( Box 1 ) [98 –119 201], especially for women who are underweight or have inadequate dietary intake, whether owing to economic reasons, illness, food avoidances, ongoing attempts at weight loss or other inappropriate food patterns. Common pregnancy conditions such as digestive complaints, including heartburns, nausea, vomiting, morning sickness and pica, may also compromise adequate nutritional intakes, often specifically impacting the intake of carbohydrate, animal proteins, heme iron and zinc [120]

Nutrient-deficit combinations often exist and, even if subclinical, could lead to significant consequences. Studies conducted in developing countries have demonstrated that improving micronutrient intake in deficient women can reduce maternal morbidity and mortality [6], and may reduce risk of LBW [6,35]. While maternal supplementation has generally been limited to iron and folic acid, the added advantage of multiple micronutrients on gestational outcomes has been confirmed in two recent randomized, interventional trials, especially emphasized in undernourished women in economically disadvantaged populations [35,121]. They also may play an important role for women who have inappropriate dietary patterns or food avoidances, for example, those who are underweight or constantly trying to lose weight, consume no or small amounts of animal food sources (including strict vegetarians) and in pregnant women infected with HIV as revealed in community surveillance [122,123]. Recent epidemiological and research evaluations further support the combination of folic acid plus multivitamins in prenatal dietary supplementation in decreasing risk for several congenital anomalies, beyond neural tube defects [82,98]. Moreover, a meta-analysis examining the potential protective effect of prenatal multivitamins on several pediatric cancers found an inverse relationship between multinutrient supplementation and leukemia, pediatric brain tumors and neuroblastoma, although it was not established which constituent(s) among them conferred this effect [124]

Nutrition in specific situations

Pregnancy in adolescence

Adolescent pregnancy is associated with significant medical, nutritional, social and economic risk for mothers and their infants. This is often related to the fact that many teenaged females have been found in observational studies and retrospective analyses to have poor nutritional status [125], including nutrient deficiencies [126], even in developed countries [127], probably owing to economic difficulties as well as to dieting and Western food trends, which affect this age group more than others. Intakes may be below the dietary reference intake for energy, iron, folate, calcium, vitamin E and magnesium [127]. Many pregnant adolescents gain more weight than is recommended by the IOM, and may be misclassified when current IOM adult BMI categories are used, especially in those of lower age or smaller size [128].

Targeted preconception nutritional conditioning is impossible for unplanned pregnancies. Risks have been observed in retrospective analyses to be particularly acute in girls still growing at time of conception [129], with nutritional compensation presenting a special challenge; while overconsumption may impair growth of both placenta and fetus [125,129] and excessive adolescent weight gain may contribute to long-term overweight and obesity as in adults [94], negative fetal effects of dietary restriction may be particularly severe [129]. Complexities involved in this age group indicate a need for detailed perinatal nutritional care.

Multiple pregnancies

Greater reliance on fertility treatments with delayed pregnancies has increased the incidence of multiple pregnancies by more than threefold since 1980, which may present special concerns, including nutritional adequacy, birthweight and prevention of preterm births [91]. Maternal nutrient depletion is accelerated in multiple pregnancies, particularly exaggerated during the second half of gestation. Attention to dietary macronutrient distribution and general nutritional density, as well as supplementation with micronutrients, may carry even greater importance in reducing complications and improving postnatal health [91,92,95].

Box 1.

Roles of selected micronutrients frequently emphasized prenatally

Folic acid

Folic acid supplements taken before (at least 1 month) and during pregnancy (in much greater amounts in women at high risk) can reduce the risk of birth defects and congenital anomalies. In a meta-analysis of 41 studies from around the world spanning from 1966 to 2005, folic acid-fortified multivitamin supplementation in expectant women was demonstrated to provide consistent protection against neural tube, cardiovascular and limb defects, and some protection against fore cleft palate, urinary tract anomalies and congenital hydrocephalus [98]. Folic acid is routinely recommended for prenatal supplementation.

Vitamin B12

Vitamin B12 is an independent risk factor for neural tube defects in humans [99], with low concentrations associated in retrospective analyses with an approximately two- to three-fold increased risk, even where median serum folate concentrations were similar between affected and nonaffected cases [100]. Strict vegetarians, specifically vegans, are routinely advised to take a supplement of vitamin B12, as animal foods are an almost exclusive source.

Choline

Choline is important for the composition and repair of normal cellular membranes, and for normal brain and cardiovascular function. Adequate choline during pregnancy has been associated with healthy fetal brain development in both animal models and humans, with long-lasting positive effects on cognitive function, including memory [101], and has thus been receiving increasing attention for prenatal use. Many prenatal multivitamin supplements provide a minute amount of choline, generally 10–25 mg per dose (vs dietary reference intake of 450 mg/day). An NIH-sponsored placebo-controlled clinical trial is currently underway to evaluate the effects on infant development of taking high-dose choline supplements (900 mg/day, 200% dietary reference intake) during pregnancy [102].

Calcium

Although the fetus uses a relatively large amount of calcium during development, overall requirements during pregnancy are similar to those in the nonpregnant state, owing to the increased efficiency of calcium absorption. Calcium supplementation appears to reduce the risk of pre-eclampsia [103,104]. Pregnant adolescents and women at risk of pregnancy-induced hypertension might benefit from higher intakes of calcium. A meta-analysis of 17 randomized, controlled studies demonstrated that calcium supplementation may significantly reduce the risk of pre-eclampsia, especially in severe cases [103]. Maternal skeletal calcium release may play a major role in calcium homeostasis during pregnancy, especially in cases of dietary inadequacy; thus increased intake may contribute to a decrease in subsequent risk of osteoporosis, as suggested in a observational cohort [105].

Vitamin D

Vitamin D is required for calcium absorption and utilization, and low maternal status has been suggested to be a nutritional risk factor in gestational bone resorption and pregnancy-induced hypertension [106]. A relatively low maternal blood level of 50 nmol/l of 25-hydroxy-vitamin D was associated with a 2.4-fold increase of pre-eclampsia [65]. Women who do not consume fish or whole or fortified milk products may require supplementation, especially in northern locations during the winter, where low exposure to ultraviolet light has been found in randomized, controlled trials to limit internal synthesis [107,108]. Vitamin D is routinely recommended prenatally, generally in combination with calcium.

Iron

Iron requirements of pregnant women are approximately double that of nonpregnant women because of increased blood volume, increased needs of the fetus and blood losses that occur during delivery. Iron-deficiency anemia may increase the risk of low birthweight, preterm delivery and perinatal mortality, where iron supplementation may increase birthweight by over 200 g [108]. Since many women have difficulty maintaining iron stores during pregnancy, the US CDC recommend routine iron supplementation (30 mg/day) for all pregnant women, and an increased dose (60 mg/day) for anemic women. As iron repletion during pregnancy may be difficult, pre-pregnancy iron supplementation may be advised, especially where the interval between multiple pregnancies is short [109].

Zinc

Zinc deficiency is associated with intrauterine growth retardation, congenital malformations and low birthweight in both animal models and humans. Low serum zinc levels may be associated with suboptimal outcomes of pregnancy, such as prolonged labor, atonic postpartum hemorrhage, pregnancy-induced hypertension, preterm labor, post-term pregnancies and impaired neuropsychologic function. A meta-analysis of 11 randomized, controlled trials of zinc supplementation in pregnancy involving over 4941 women and their babies demonstrated an inverse correlation with both preterm birth and low birthweight [110]. High-dose iron supplements (>30 mg/day) may reduce zinc (and copper) absorption, implying a need for supplementation in such cases; an additional 15 mg of zinc and 2 mg of copper have been recommended; however, a recent observational study demonstrated that a 100 mg/day iron supplement did not interfere with zinc metabolism [111], suggesting a need for individual assessment and intervention.

Iodine

An inadequate supply of iodine during gestation results in damage to the fetal brain that is irreversible by mid-pregnancy. Animal studies have demonstrated that even mild-to-moderate maternal hypothyroxinemia may result in suboptimal neurodevelopment, and increase the risk for neurological disabilities in offspring [112]. Based on epidemiological evidence, iodine is routinely advised for prenatal supplementation in order to prevent neurological consequences [43], and is routinely fortified in the USA and Western and Central European countries [44].

Long-chain polyunsaturated fatty acids

Long-chain polyunsaturated fatty acids (LCPUFAs) are involved in various aspects of early development, including immunological, neurological and optical systems, motor skills and cognition, and supplements have been evaluated prospectively in randomized, controlled trials carried out in humans for their potential role in the prevention of related dysfunction, including long term [112 –114]. Developmental and visual acuity scores for infants of women with docosahexaenoic acid (DHA) intakes above requirements have been shown to be higher than for those with a typical Western diet [112,113]. Where research suggests that LCPUFAs may be responsible for the nutritional advantage of breast milk in ensuring development of proper visual acuity [116], maternal supplies of n-3 LCPUFAs – especially DHA – are highly expended during pregnancy [5,58]. High n-3 LCPUFA consumption during pregnancy [116] and lactation [117] is suggested to reduce general allergy risk in infants based on observational cohorts [118]. Improved prenatal LCPUFA status has been associated with a reduction in neonatal oxidative stress, and inflammatory leukotriene B4 and altered T-cell function [115] has been more strongly linked to neurodevelopmental and anti-allergy outcomes than has postnatal infant diet supplementation in humans [115,119], Currently, the principal dietary source of n-3 LCPUFAs is fatty fish, which tends to be limited in many diets owing to geographic or economic factors and/or environmental contamination risk, and is cautioned in pregnancy owing to effects on infant development [84,85]. The European Commission sponsored a 2007 consensus statement, which recommends a minimum of 200 mg/day of DHA supplements for pregnant and lactating women [120].

Future strategies for pregnancy nutrition

Prenatal conditioning

To prepare the body for optimal nutritional status in pregnancy and to support the physiological challenges of pregnancy through adequate nutrition, three dietary strategies are key:

Consumption of a variety of natural nutritionally dense (including animal foods) rather than simply calorie-dense foods (including ‘empty’ calories);

Consumption of specially fortified foods, that is, with n-3 PUFAs and folic acid;

Supplements of specific nutrients found to be critical in pregnancy, but which may be inadequate in the maternal diet.

Additional lifestyle considerations include maintaining a routine of adequate and safe physical activity, as well as prevention of dietary hazards, specifically, from dietary contaminants (as in marine fish), alcohol, excess caffeine and artificial sweeteners.

Mediterranean model

The Mediterranean diet, considered a gold standard for protection against cardiovascular and related metabolic diseases [130], may be a relevant dietary model for a food-based approach to perinatal nutrition, particularly in preventing CVD, hypertension, diabetes mellitus and MetS. The diet features most of the recommended nutritional protection factors – including relatively high amounts of vegetables, fruits, fish, low-fat dairy products, probiotic yogurt, fiber and olive oil, while being low in meat and sodium, similar to the DASH diet – which may explain its beneficial effect on inflammation and endothelium dysfunction associated with Western diseases [131]. Beyond the potential of reducing pregnancy-related risks, maternal consumption of the Mediterranean diet during pregnancy has been shown to protect against asthma and allergies in offspring, compared with a diet relatively high in red meat [117]. This may possibly be related to a high intake of n-3 LCPUFAs and probiotics that are thought to contribute to infant immunity [132,133].

Food fortification

Where past fortification efforts have focused on compensation for processing losses in foods, such as in refined grains, newer understanding promotes a high-quality food base as a vehicle best tailored for targeted perinatal nutritional support, to optimize nutrient absorption and yield high concentrations with minimal calories and cost. A key example is the egg, which has been successfully fortified [134] and may be further modified to support peak brain development [135].

Moreover, phytochemicals in a variety of whole plants and well-fed animals are also valuable for health protection, especially in the high-risk perinatal period, and may yield advantages over use of isolated phytochemical supplements.

Nutritional supplementation

Multiple nutrient supplementation is particularly relevant in pregnancy, as multiple deficiencies are likely to occur in a period of accelerated growth and development. Furthermore, increased needs are often compounded by a low intake of whole foods, resulting in low levels of bioavailable iron and zinc, calcium, retinol, LCPUFAs and vitamins A (including β-carotene), several Bs and C.

Cost versus benefit evaluation

Cost–benefit evaluations of nutrition intervention have long emphasized the high cost–effectiveness of individual prenatal nutrition counseling for improving outcomes even in Western countries. In US studies, women receiving intensive counseling on appropriate weight and nutrient intake were found in a targeted program to have fewer LBW infants, with their infants weighing up to 300 g more at birth, and concurrent cost–benefit ratio of 1:4–5 in preventing intensive neonatal care [136,137]. Programs channeling such results into existing frameworks include the US government's Women, Infants and Children (WIC) program and the Virginia Expanded Food and Nutrition Education Program (EFNEP), which continue to conclude that benefits and monetary savings exceed costs [138].

Executive summary

Introduction

Growing evidence supports the understanding that proper nutritional status before and during pregnancy is key to maintaining maternal and offspring lifelong health.

The perinatal period constitutes a critical time for the nutritional effect on gene expression.

Developmental origins of adult disease model describes the connection between early nutrition and later health, based initially on in utero deficiencies alone or with later catch-up growth and the resulting mismatch, and now focuses on short- and long-term risks associated with pre- and post-natal overconsumption.

In utero nutritional programming

Elements within the genome may be epigenetically labile to early nutrition – as early as the periconceptual phase – resulting in subsequent alterations in gene expression, modulating health and transgenerational effects.

Despite the range of tolerance to nutritional imbalances and related adaptive responses, offspring may be sensitive to a high degree of mismatch between the in utero and postnatal nutritional environments.

Early programmed effects may be exacerbated by postnatal dietary insufficiency and/or overconsumption.

Nutritional programming & early biomarkers for chronic disease

Food restriction during pregnancy (in animal models) has been demonstrated to induce biomarkers in offspring that are very similar to the adult risk factors, thus indicating the close association with later dyslipidemia, hypertension and cardiovascular disease.

Prenatal nutritional risks

Undernutrition

– – – – – – – – – In addition to inadequate fetal weight gain, maternal micronutrient deficiencies are associated with adverse pregnancy outcomes, both short- and long-term.

– – – – – – – – – Each stage of gestation has a specific vulnerability to nutritional inadequacy, specifically, initially for DNA and differentiation; then for adiposity, renal function, hypertension and brain development; and later for growth and development.

– – – – – – – – – Where prenatal nutritional requirements are easily met by a balanced diet in Western nations, expectant mothers in developing countries are often dependent upon supplementation of nutrients critical to pregnancy outcomes.

– – – – – – – – – The developing brain is particularly vulnerable during late pregnancy through early childhood.

Overconsumption

– Maternal overconsumption has been linked to increased chronic disease risk in offspring.

– Overweight and obesity do not guarantee nutritional adequacy, and pregravid obesity in the USA has been found to be accompanied by a low-quality diet.

Diabetes mellitus

– Gestational diabetes mellitus has increased with overconsumption and overweight, negatively affecting pregnancy outcomes and future health of mother and child. Maternal weight and dietary control are key to prevention and management.

Hypercholesterolemia

– Hypercholesterolemia in pregnancy may be associated with increased oxidative stress, which affects the embryonic vasculature. A preventive maternal diet has been found to reduce prenatal atherogenic risk.

Hypertension

– Pregnancy-induced hypertension may lead to negative pregnancy outcomes, including preterm delivery and restricted growth and blood flow. The risk is increased significantly by overweight and inadequate dietary calcium, magnesium, vitamin D and selenium.

Bodyweight as a nutritional indicator

– As appropriate maternal weight is a highly relevant measure of caloric balance and predictor of risks for pregnancy and future health, close weight follow-up is critical in pregnancy management.

Nutrient intake guidance

A food-based approach for meeting increased requirements during pregnancy necessitates a variety of whole foods innately rich in nutrients or fortified foods, avoiding processed foods with high caloric density.

As specific dietary habits may be associated with insufficiencies during pregnancy, compensatory supplementation should be considered.

Several studies have demonstrated that the use of multiple nutrient compared with single (i.e., folate and iron) supplements has been associated with advantages in managing dietary inadequacy and preventing congenital defects and other negative pregnancy outcomes. This is consistent with the multiple requirements for fetal development and growth.

Nutrition in specific situations

Pregnancy in adolescence

– Nutritional requirements for pregnant adolescents are uniquely high owing to compounded demands by maternal body growth, and complicated by low-quality diet and socioeconomic challenges, requiring intensive nutritional support and follow-up.

Multiple pregnancy

– Pregnancies of twins, triplets and more carry with them increased requirements for weight, calories and nutrients that are carefully calculated to meet the needs of both mother and children, without leading to overconsumption and excessive gain.

– Use of fertility treatments not only increases the chances of multiple pregnancy, but may also affect the metabolic state.

Future strategies for pregnancy nutrition

Three main nutritional strategies are proposed to meet requirements for a healthy pregnancy: consumption of a variety of foods, naturally rich in key nutrients, food fortification and nutrient supplementation.

The Mediterranean diet represents a nutritionally dense and balanced diet, associated with prevention of chronic western diseases and, thus, is highly relevant to prenatal nutrition.

Cost versus benefit evaluation

– Populations of low economic status in Western countries tend to eat low-cost, calorically dense rather than nutritionally dense foods. Close monitoring throughout their pregnancy, together with nutritional support is highly recommended.

– Large-scale studies are now being conducted to demonstrate the cost-effectiveness and developmental benefits of early nutrition intervention, starting prenatally.

Conclusion

New understanding of nutritional mechanisms affecting the reproductive cycle should increase the commitment toward nutritional intervention at the personal and professional level, starting from the prenatal and even preconception periods.

The modern Western diet, with its typical calorie-dense foods, may cause a combination of nutrient insufficiencies and overweight, negatively impacting pregnancy outcomes and future health.

Efforts toward dietary improvement may include nutritional counseling and follow-up, use of fortified foods, and/or multinutrient supplementation

While such analyses have thus far predominantly addressed undernutrition issues, future efforts will undoubtedly address more comprehensive perinatal and lifespan health issues. The Early Nutrition Programming – Long-Term Efficacy and Safety Trials and Integrated Epidemiological, Genetic, Animal, Consumer and Economic Research (EARNEST) consortium has brought together a multidisciplinary team of scientists from European research institutions in a program of work that includes multiple large-scale, prospective, randomized, controlled trials in human subjects testing early nutritional programming of disease and reprogramming of risk, measuring diet and nutritional interventions in pregnancy and early life, to be followed by disease markers in childhood and early adulthood and evaluation of associations between early nutrition and later outcomes. These studies are complemented by evaluation of the social and economic importance of programming, while encouraging integration, communication, training and wealth-creation of populations. Running from the year 2005 to 2010, the project aims to help identify interventions to prevent and reverse adverse early nutritional programming, and has the potential to develop new food products with recommended composition and nutritional value through industrial partnerships [139].

Conclusion

Where pregnancy has generally been approached as a maternal stage with temporal additional nutritional requirements, evidence in the post-genome medical arena increasingly suggests that the prenatal period may constitute a critical time for postgestational short- and long-term maternal health and wellbeing, and that nutrition provides essential design factors for the lifelong health and functioning of mother and child. The modern Western diet, with increasingly calorie-dense foods, challenges pregnancy with simultaneous risks associated with overconsumption and undernutrition – as caloric density does not necessarily translate to adequate nutrition – affecting short- and long-term pregnancy outcomes. A pre-pregnancy ‘preparation’ period may be beneficial in ensuring healthy initial weight and adequate stores of critical nutrients for structuring the uterine environment and supporting the highly intensive stage of cell growth and proliferation by affecting gene expression and metabolic programming. Continuous nutritional assessment – incorporating weight, rate of weight gain, metabolic biomarkers and dietary composition – together with the monitoring of fetal growth, may support early prevention of pregnancy-associated metabolic risks and reduction of future negative impact. Further research may be warranted to explore new nutritional biomarkers specific to pregnancy outcomes and future health. Guided dietary design, together with food fortification and fetal nutrient supplementation, could serve to optimize prenatal conditions for beneficial effects on short- and long-term health and performance.

Footnotes

Acknowledgement

The author thanks Ossie Sharon, MSc, RD for her assistance in this paper.

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Prenatal Nutrition: a Critical Window of Opportunity for Mother and Child

Abstract

Keywords

in utero nutritional programming

Nutritional programming & early biomarkers for chronic disease

Prenatal nutritional risks

Undernutrition

Overconsumption

Obesity

Diabetes mellitus

Hypercholesterolemia

Hypertension: pregnancy-induced hypertension & pre-eclampsia

Nutritional goals & guidance during pregnancy

MyPyramid nutritional plan for pregnancy

Guidance for energy balance

Bodyweight as a nutritional indicator

Nutrient intake guidance

Nutrition in specific situations

Pregnancy in adolescence

Multiple pregnancies

Future strategies for pregnancy nutrition

Prenatal conditioning

Mediterranean model

Food fortification

Nutritional supplementation

Cost versus benefit evaluation

Conclusion

Footnotes

Acknowledgement

References