1 Introduction

Vitamin and mineral deficiencies are a worldwide problem, but seem to occur only in low-income countries. The FAO and WHO estimate that more than a billion people suffer from iron deficiency, 0.5–1 billion from zinc deficiency, and 200 million from vitamin A deficiency. Most of these are women and children. In high-income countries, by contrast, vitamin and mineral deficiencies are widely thought to be no longer present due to the increasing availability of a varied and well-balanced diet.

Food security exists when all people, at all times, have physical and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life.

World Food Summit, 1996

Consequently, food security as defined by FAO/WHO has been achieved in high-income countries, and any concern regarding adequate intake of essential micronutrients is apparently allayed. With food plentiful, varied and accessible, it seems unimaginable that the diet might not deliver all the important nutrients necessary for a healthy life. However, some individuals might not have access to an adequate diet due to low income, others due to their inadequate knowledge of nutrition essentials, and others again might have a diet which is not as nutritious as it should be in view of their body’s increased need for essential micronutrients during a particular stage in their lives. Access to a diet that is quantitatively sufficient and diverse does not of itself guarantee adequate nutritional status. Depending on age and lifestyle, individuals may have need of higher levels of certain micronutrients. Moreover, inadequate supply might have harmful health effects above and beyond the signs of pure micronutrient deficiency.

2 Inadequate Supply: The Problem and Consequences of Hidden Hunger

Hidden hunger can be defined as an inadequate intake beyond deficiency or without typical clinical signs and symptoms.

Figure 10.1 is a schematic representation of hidden hunger. Supply of a micronutrient declines from left top to right bottom. As long as the supply of a micronutrient is not near zero, specific clinical signs will not develop (e.g. scurvy in the case of vitamin C deficiency, night blindness or blindness in the case of vitamin A deficiency). However, long before such signs appear, the inadequate supply results in more or less unspecific symptoms such as increased risk of infectious diseases (in the case of vitamin A and iron inadequacy) or chronic diarrhea (in the case of zinc deficiency).

Fig. 10.1
figure 1

A schematic representation of hidden hunger

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There is ample evidence that inadequate micronutrient supply might have negative consequences for health and development. Especially in situations where demand increases—e.g. in cases of sudden or chronic disease, pregnancy or lactation—hidden hunger will significantly compromise reactivity of the immune system or the energy metabolism.

3 Is Hidden Hunger a Problem in European Countries?

In a recent Europe-wide study [1], the percentage of healthy people below the EAR (Estimated Average Requirement) was extracted from the various national surveys (Tables 10.1 and 10.2). However, below EAR means being at increased risk of deficiency. The EAR is the daily intake value that is estimated to meet the requirement in half of the apparently healthy individuals in a life stage or gender group. The other half by definition would not have its nutritional needs met.

Table 10.1 Vitamins
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Table 10.2 Minerals
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Inadequate intake of calcium and vitamin D will have a strong impact on bone mineral density and subsequently on the development of early osteoporosis, with a significant impact on quality of life. However, a more serious condition is an inadequate intake of one or more micronutrients during pregnancy.

Data depicted in Table 10.3 show that iron, iodine, vitamin A, and zinc deficiencies in pregnant women and children below the age of five are present not only in low-income countries, but also to an extent in Europe, which is not a peripheral matter with respect to childhood development [2]. In some cases, the prevalence of a deficiency is similar between low- and high-income countries. A deficiency might result in different consequences of various severities; however, its cause is always the same. We need to understand that poor dietary quality and poor dietary diversity are some of the major reasons for micronutrient inadequacy. Iron deficiency or vitamin A inadequacy signal a diet that is low in food containing iron or vitamin A, or even both (e.g., meat, liver, eggs). A detected micronutrient deficiency can thus be taken as a biomarker for an inadequate diet that might result in more deficiencies than those in iron or vitamin A alone. Consequently, increasing diet diversity will close the known and unknown micronutrient gaps.

Table 10.3 Vitamin A deficiency
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4 Pregnancy

A balanced diet with adequate energy intake usually provides an adequate supply of the essential micronutrients. Although a balanced diet is accessible for the European population as a whole, specific population groups are at risk of inadequate vitamin and mineral intakes, especially with regard to iron, folic acid, vitamin D and vitamin B12. Micronutrient malnutrition represents an important challenge for public health worldwide, particularly in vulnerable population groups such as pregnant women. For example, a study in Hackney, London—the region with the highest incidence of low birth weight (LBW) infants in England and Wales [3]—showed that 78% of mothers had an inadequate diet that met fewer than four of 16 dietary reference intake values. On follow-up at nine months post-partum, over half of the unsupplemented, inadequate-diet group remained severely deficient in folate and had low serum ferritin levels. The risk of giving birth to a child with low birth weight for gestational age was fourfold for this group.

During the childbearing period, females are often not sufficiently supplied with all the water-soluble vitamins, especially folate. In both women of child-bearing age and pregnant women, micronutrient deficiencies or suboptimal/inadequate intakes may be associated with significantly elevated reproductive risks, ranging from infertility to fetal structural defects and long-term diseases (reviewed in Cetin et al. [4] and Berti et al. [5]). The reasons for inadequate intake are manifold: poor knowledge regarding adequate nutrition; special diets aimed at avoiding excessive weight gain; ‘healthy’ vegetarian or even vegan diets; problems with eating (nausea, vomiting); and misinformation regarding specific nutrients (e.g. vitamin A).

The adequacy of micronutrient intake during pregnancy seems to be influenced also by environmental, cultural and demographic variables, such as maternal age, clothing, geography, socioeconomic status (SES). The impact of SES on nutrient supply is discussed in Chaps. 1 and 3.

4.1 Critical Micronutrients During Pregnancy

Inadequate supply of several micronutrients has an impact on fetal development (Table 10.4).

Table 10.4 Critical micronutrients during pregnancy
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Malnutrition during pregnancy, and in particular poor micronutrient intake, is a general risk for a small-for-gestational age (SGA) newborn.

The prevalence and consequences of inadequate micronutrient supply have been reviewed recently [6].

4.2 Folic Acid and Vitamin B12

There is consistent scientific evidence that folic acid is of critical importance both pre- and periconceptionally in protecting against neural tube defects (NTDs) in the developing fetus [7]. Estimated folate requirements increase by 50% to 600 µg during pregnancy. Even though a small number of vegetables seem to be good sources of folate, the poor bioavailability of folate limits an adequate supply. Moreover, in most countries, females do not reach even the recommendations for non-pregnant women. For this reason, internationally, periconceptional supplementation of 400 µg/day of folic acid is recommended for the prevention of NTDs. A near 100% reduction of NTDs in addition to significant reductions of congenital heart defects was achieved by periconceptional supplementation of 800 µg/day of folic acid combined with multivitamins [8]. Women with a low folate supply in combination with low vitamin B12 blood levels have a drastically increased risk of NTDs through the combined deficiency. These findings suggest that the most effective periconceptional prophylaxis to prevent NTDs may be the provision of both folic acid and vitamin B12. Even though the relevance of periconceptional folic acid supplementation for the prevention of NTDs has been widely acknowledged and supported by expert bodies and governmental recommendations throughout the world, its practical application is still very inadequate.

4.3 Vitamin A

Vitamin A is obtained from the diet either as pre-formed vitamin A in the form of retinol or retinyl-esters, or as provitamin A-carotenoids. The highest content of preformed vitamin A is found in liver and liver oils of marine animals. Yellow and green leafy vegetables provide significant amounts of provitamin A-carotenoids [9]. However, high doses (<6 mg/day) of provitamin A are needed to substitute preformed retinol [10].

Fetal and neonatal vitamin A status depends on maternal vitamin A status. The fetal/neonatal synthesis of the retinol-binding protein is not sufficient to ensure continuous supply from stores in the liver. Therefore maternal vitamin A supply is of essential importance for adequate fetal supply, growth and development. An inadequate supply to the fetus during pregnancy is associated with malformations, preterm birth, low birth weight and low neonatal liver stores. Low vitamin A status of the newborn appears to contribute to the risk of bronchopulmonary dysplasia (lung disease in preterm).

The American Pediatrics Association [11] cites vitamin A as one of the most critical vitamins during pregnancy and the breastfeeding period, especially in terms of lung function and maturation. If the vitamin A supply of the mother is inadequate, her supply to the fetus will also be inadequate, as will later be her milk. These inadequacies cannot be compensated for by postnatal supplementation. Despite the fact that food rich in vitamin A and beta-carotene is generally available, risk groups for low vitamin A supply do exist in the western world.

4.4 Vitamin D

Over the past decade, interest in vitamin D status has been growing because of its potential links with a number of diseases and conditions. In fact, observational studies in non-pregnant individuals have associated low 25-OH-vitamin D levels in plasma with the risk of a wide range of common chronic diseases such as colon, breast and prostate cancer, metabolic syndrome, hypertension, multiple sclerosis, type I diabetes, and inflammatory bowel disease [12]. Given the evolving concept of vitamin D sufficiency, it is currently believed that sufficiency may be defined as serum 25(OH)D levels >75 nmol/L. The actual prevalence of vitamin D insufficiency during pregnancy is therefore not known with certainty, but it could be as high as 70% in western countries if insufficiency is defined as 25(OH)D concentrations below 75–80 nmol/L [13]. In light of the high incidence of non-sufficient vitamin D status in women of child-bearing age, the public health implications of these findings warrant attention.

With regard to fetal and infant outcomes, maternal vitamin D deficiency predisposes newborns to neonatal hypocalcemia, and subsequently to rickets. Observational studies also suggest that the bone mass of the newborn is related to the vitamin D status of the mother [14]. Low vitamin D concentrations during prenatal or early life development were proposed to affect functional characteristics of various body tissues, leading to a greater later risk of multiple sclerosis, cancer, insulin-dependent diabetes mellitus, and schizophrenia [15]. There is growing evidence that vitamin D deficiency during pregnancy disrupts brain development in the offspring and leads to changes which are persistent in the adult brain [16]. A recent meta-analysis shows that the risk of type 1 diabetes is significantly reduced in infants who were supplemented with vitamin D compared to those who were not supplemented, suggesting that vitamin D supplementation in early childhood may offer protection against the development of type 1 diabetes [2].

The data available to date suggest that vitamin D deficiency during pregnancy is not only linked to maternal skeletal preservation and fetal skeletal formation but may also affect maternal outcomes and fetal imprinting [17]. However, most of these findings are observational associations, and further evidence from controlled trials is required.

4.5 Iron

Neonates at term birth have a total body store of about 1 g of iron, and all this has been provided by the mother. The mother will, however, have to provide about 400 mg from her own hepatic stores. Extra iron is required for the growing fetus and for the formation of the placenta, as well as expansion of maternal red cell mass and blood loss during delivery [18]. Women often become pregnant without adequate iron reserves or are already iron-deficient. The most severe consequence of iron depletion is maternal iron deficiency anemia (IDA). IDA may be aggravated during pregnancy, as fetal iron metabolism depends completely on maternal metabolism [19]. Iron status seems to be implicated in some pregnancy disorders affecting mother and fetus such as preeclampsia and inappropriate catch-up growth [20, 21].

Iron deficiency anemia should be prevented and treated. Selective prophylaxis seems to be the most effective and appropriate approach: Screening of ferritin levels in early pregnancy may identify women who may benefit from iron supplementation. The increased iron absorption during pregnancy, coupled with the mobilization of iron stores, may be sufficient in women with high iron stores, who may not need iron supplements.

4.6 Iodine

Approximately half the European population still suffers from an inadequate iodine supply. Low urinary iodine excretion is especially common among pregnant women and school children. WHO recently increased its recommendation for iodine intake during pregnancy and lactation from 200 to 250 µg/day and suggested that a median urinary iodine concentration (UIC) of 150–250 µg/L indicates adequate iodine intake [22]. WHO recommends iodine supplementation in pregnancy only in countries where less than 90% of households use iodized salt or where the median UIC in schoolchildren is below 100 µg/L. However, different national surveys in the USA and Europe document that even when iodized salt is consumed, this might not be enough to cope with the increased iodine demand during pregnancy. Iodine supplementation (150 μg/day) has been recommended in the case of pregnancy [23].

Iodine is involved in nerve development, as well as thyroid follicle growth and the synthesis of thyroid hormones (THs), which are of essential importance for the development of the fetal central nervous system [24]. Pregnant women with UICs during the third trimester below 50 μg/L were significantly more likely to have an SGA infant, and mean birthweight was lower than among women, with the UICs between 100 and 149 µg/L. Higher TSH levels were also associated with a higher risk of having an SGA baby or a LBW newborn. The later mean intelligence quotient (IQ) of children born to women an UIC below 50 µ/L was found to be significantly lower compared to controls with adequate iodine supplementation [25]. Recent cross-sectional studies performed in several European countries revealed a median UIC in pregnant women in the range of 95–130 µg/L [22, 26]. Half the women were below 100 and about a quarter below 50 µg/L, indicating a maternal iodine status associated with moderate or severe iodine deficiency, respectively, in the offspring (see Chap. 14 for further discussion of this topic).

5 The First 1,000 Days: A Developmental Window Which Might Be Irreversibly Closed

During the first 1,000 days of a human life from conception until the end of the second year of life, the most important developmental steps occur. The nutrition status of the mother at the moment of conception is a critical condition influencing the development of the embryo.

Malnutrition during pregnancy and early childhood has a negative impact on physical growth and cognitive development. The magnitude depends on the severity of the malnutrition and on the micronutrients involved.

Malnutrition during pregnancy may result in Intra Uterine Growth Restriction (IUGR). The birth weight of the children is too low for gestational age. However, not only physical growth is restricted but also the growth and development of various internal organs—in particular, the kidneys, pancreas, and lungs. This increases the risk of IUGR children contracting non-communicable diseases such as obesity, high blood pressure, and diabetes (for review, see [27]).

There are two types of IUGR: symmetrical IUGR, in which all organs are affected by improper growth, and asymmetrical IUGR, in which the head and brain are normal. IUGR occurs as a result of lifestyle (alcohol, smoking, stress or malnutrition) during pregnancy.

The risk of low birth weight and preterm birth also increases with malnutrition. The most critical period for the development of the child is the 1,000-day window.

The phenotype of IUGR is low birth weight of the newborn. Newborns with low birth weight at term (<2.500 g) are four times more likely to die during their first 28 days of life than those weighing 2.500–2.999 g, and 10 times more likely to die than newborns weighing 3.000–3.499 g [28]. If malnutrition persists after birth, the children may not develop appropriately—a condition known as stunting. Stunting is defined as 2 Standard Deviations below the 95% percentile of height for age. This is independent of body weight. Improving the diet during childhood development after the 1,000 days of linear growth will in many cases not compensate, and the children remain stunted. The consequence is reduced physical strength.

Low birth weight is also the phenotype of intrauterine stunting and consequently also a visible marker for potentially impaired brain development. Indeed, it was documented that the effect of stunting on short-term memory was equivalent to the difference in short-term memory between children in US families that had experienced poverty for 13 years and children in families with incomes at least three times higher than the poverty levels [29]. Malnutrition is a frequent companion of poverty, not only in developing countries, and has a powerful impact on brain development.

6 Brain Development and Poverty: A Fateful Relationship

The human brain develops in different steps during embryogenesis. Interneuron connections develop during weeks 8–16 within the so-called cortical plate and are replaced by cortical neurons from week 24 until the perinatal period. The brain growth spurt begins in the last trimester of pregnancy and continues for the first two years after birth. During this time, the majority of dendritic growth, synaptogenesis and glial cell proliferation occurs [30, 31]. During the first two years of life—by the age of two, the brain has 80–90% of its future adult weight—this period is highly sensitive to micronutrient deficiencies [32, 33].

The structure of the brain at any time is a product of interactions between genetic, epigenetic and environmental factors [34]. Environmental factors include outside events and the internal physiological milieu. Consequently, poor nutrition or stress will have an impact on the brain structure and ultimately on its function. The connection between stress and poor nutrition is poverty. The developmental cognitive neuroscience dealing with poverty and social gradients is a new field of research which has only recently emerged. It has been shown that pregnancy and growing up with a low socio-economic-status (SES) will have neural and cognitive consequences [35, 36].

Children living in poverty have impaired cognitive outcome and school performance. Poor SES is related to reduced levels of attention, literacy and numeracy, which, together with other factors, may explain the poor educational level of children living in poverty [37]. Language and memory functions are related to brain regions sensitive to environmental and nutritional influences. Research in both animals and humans suggests that the experience of stress has important negative effects on the hippocampus and the amygdala, which are highly susceptible during the late fetal and early neonatal period.

The amygdala and hippocampus subserve emotion, language, and memory—functions that change markedly between the ages of four and 18 years. The volume of the amygdala and hippocampus increase with age. Both are involved in stress regulation and emotion processing and sensitive to environmental stimuli, including nutrition. Different studies report lower hippocampal volume in children and adolescents (age 5–17) from lower-income backgrounds compared to the same age group from higher SES [36,37,,39,40].

Poor nutrition as a result of poor income is not the only reason for developmental changes of the brain. Poverty is strongly associated with other factors that have an impact on brain development, such as unsupportive parenting, poor education, lack of education of caregivers, and a high level of stressful events. In particular the income-to-need ratio, for example to ensure daily nutrition for others, might become a stressful event which influences brain development [41]. Income-to-need ratio—but not parental education—was positively associated with hippocampal size [19, 20]. Stressors more directly related to income, such as limited access to material resources (e.g., a variety of food), may have greater influence on hippocampal size than parental education related to cognitive stimulation and parenting style.

A study with healthy children from France showed a positive correlation between SES reading and verbal abilities and literacy [21]. The neural correlate was a significant correlation of SES and local gray matter volumes of bilateral hippocampi. Similar results were obtained from a study with US households, documenting a significant positive relationship between income and hippocampus gray matter volume. The authors suggest that differences in the hippocampus, perhaps due to stress tied to growing up in poverty, might partially explain differences in long-term memory, learning, control of neuroendocrine function, and modulation of emotional behavior. Lower family income may cause limited access to material resources, including food, which may be more important for predicting hippocampal size [42].

Two independent studies which might have used part of the same group of children in Brandenburg, Germany documented an impact of SES on physical and cognitive outcome. The first study [43] investigated children at admission into primary school (aged six years in the year 2000) and documented an impairment of literacy in 18.2% of the children from low SES compared to 8.2% mean SES and 4.3% in high SES, and an impairment of cognitive development of 13.2% versus 2.8% versus 0.9%.

In another study using anthropometric data from children living in Brandenburg, the effect of unemployment on childhood development was investigated [44].

Data from 253,050 preschool children during the period 1994–2006 were used and the authors stated that: “After an initial substantial height increase of school starters in the Eastern German Land [federal state] of Brandenburg between the re-unification of 1990 and 1995, the upward trend stopped suddenly and even developed into a downturn in children’s heights between 1997 and 2000. Since 2000, heights have been stagnating at a low level. This is all the more remarkable, as heights have never declined over longer time spans in Eastern German Laender [federal states] since 1880 – except for the most recent period 1997–2006.”

The authors further conclude: “The interaction terms of unemployment and additional children are remarkably large. Above, it was already shown that households with four and more children fall behind smaller households with regard to children’s height, the former’s children being significantly shorter (−1.8 cm). The unemployment variable subtracts another height coefficient of −0.3 cm, in addition to the ‘normal’ sibling effect! In addition, if the parents are unemployed, the detriment is even larger.”

The height difference is around 1SD from the 95% percentile of the children within that area, so it cannot be defined as stunting, but it must be taken seriously. Together with the data from the other Brandenburg study showing a massive impact of SES on cognitive development in one of the richest countries of the world, the data are alarming because this has consequences for the later hopes of the children achieving a better education and income in order to escape from poverty. Accordingly, it was very recently reported in an analysis of 10 European countries that the economic conditions at the time of birth significantly influence cognitive function in later life [45]. The authors argue that birth during a time of recession may lead to a low quality and/or quantity of food, which impacts development during that time, with consequences for later life.

Poor nutrition is not only documented in low-income countries but also in families living in poverty in high-income countries [46]. Diet quality is affected not only by age, traditions and personal preferences but also by education, living conditions and income—important indices of SES and social class. If the income-to-need ratio is not sufficient to ensure an adequate food pattern, either other needs (e.g., education, medicine) are reduced or else the diet becomes poorer and poorer in quality. If food costs rise, food selection narrows to those items that provide the most energy at the lowest cost. When these conditions persist, essential nutrients disappear from the diet and malnutrition develops [47, 48]. Indeed, a recent study into the effect of poverty on children’s living conditions showed that beside lack of cognitive stimulation, food insecurity also has a strong association with income [49]. There is clear evidence that SES has a strong impact on dietary quality because diet costs are positively related to food of higher quality [50].

The individual driving force for food selection is emphatically to reduce hunger with an appropriate quantity of food. Food quality is then the second choice. Indeed, when indicators of well-being in children living in poverty were compared in the US [51], the most obvious difference was related to the category “Experienced hunger (food insecurity) at least once in past year.” This applied to 15.9% of poor children compared to 1.6% of non-poor—a nearly 10-fold difference—followed by child abuse and neglect (6.8-fold), lead poisoning (3.5-fold), and violent crimes, days of hospital stays, stunting, grade repetition or high school drop-out (all 2-fold).

Poverty and low income are often associated with poor dietary quality and consequently with more or less expressed malnutrition. Even when other factors (e.g., parental care, education) are involved, the impact of inadequate supply with essential nutrients on physical and in particular cerebral development should not be underestimated.

7 Micronutrients and Brain Development

We have scientific evidence that certain micronutrients—in particular iron, iodine, zinc, folate, vitamin A and vitamin D—are critically involved in pre- and postnatal brain development. These micronutrients are the major missing sources, whether isolated or in combination, in the diet of one-third of the world’s population. Further micronutrients, protein and energy and n−3 fatty acids may also have an impact on brain development.

Table 10.4 summarizes the specific brain-related micronutrients and their impact on brain development during the late fetal and neonatal period. The magnitude of any impairment of brain development and at least effect on brain function depends on the severity of the micronutrient deficiency. In many cases, deficiencies do not exist in isolated form. Other micronutrients may also be involved, depending on the food pattern, and protein-energy malnutrition might be also present. The latter has also a negative impact on brain development [52], but will not be discussed further in this chapter.

Table 10.5 Impact of selected nutrients on brain development
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Even though further vitamins are discussed as playing a role in brain development, studies investigating the effect within the 1,000-day window are not available. Studies (n = 6) investigating the effect of consuming fish containing n–3 fatty acids during pregnancy on cognitive outcome showed that higher intakes of fish in pregnant women are linked to higher scores on tests of cognitive function in their children at ages between 18 months and 14 years [53]. The n–3 fatty acids are not further discussed in this chapter, because they cannot be really attributed to hidden hunger.

A review discussing 14 different studies found associations between iron deficiency anemia and poor cognitive and motor development and behavioral problems in all studies. Longitudinal studies consistently indicate that children anemic in infancy continue to have poorer cognition, school achievement, and more behavior problems into middle childhood [54].

Severe zinc deficiency is rare, but moderate deficiency or inadequate supply affects up to 40% of the world’s population [55]. Diets low in animal-derived food (the best source of zinc) or high in starchy food (which makes for low bioavailability of zinc) promote deficiency. Indeed, zinc deficiency during pregnancy as a consequence of a diet high in starchy food with high phytate (which lowers the bioavailability of zinc and iron) has been reported to be associated with lower scores on the psychomotor index of infants [56].

Various studies on zinc supplementation during pregnancy revealed controversial results on cognitive development. Zinc supplementation alone may unbalance the availability of other nutrients, or zinc deficiency may not occur on its own. Indeed, it has been documented that a combination of zinc and iron showed an improvement in cognition [57].

WHO considers iodine deficiency to be “the single most important preventable cause of brain damage” worldwide. Approximately one-third of the world’s population is estimated to have insufficient iodine intake, in particular in Southeast Asia and Europe [58]. Adequate maternal iodine stores within the thyroid are important for normal fetal and infant neurodevelopment. Adequate thyroid iodine stores (in iodine-sufficient regions) ensure the increased demand for iodine during pregnancy if optimal intake is maintained. In iodine-deficient regions however, the potentially inadequate iodine stores are rapidly depleted during pregnancy, putting the fetus at risk of developmental impairment, especially of the brain.

The effect of mild to moderate iodine deficiency on fetal brain development is less clear, however. Observational studies from different countries in Europe and the USA document a significant association between mild maternal iodine deficiency and cognitive impairment in children. Depending on the severity and onset of iodine deficiency during pregnancy, the clinical signs are expressed to a greater or lesser extent. In particular the severity of cognitive impairment seems to be associated with the degree of iodine deficiency [59]. In early childhood, iodine deficiency impairs cognition, but in contrast to fetal iodine deficiency there is evidence of improvement with iodine treatment. Children from iodine-deficient areas had more cognitive impairments compared with children from areas with sufficient iodine [60]. Several European studies showed that isolated iodine deficiency during pregnancy is associated with impaired cognitive development in children (reviewed in [52]).

In a recent observational trial in the UK, the effect of inadequate iodine status in 14,551 pregnant women on the cognitive outcome of their children (13,988) was evaluated. The data support the hypothesis that inadequate iodine status during early pregnancy is adversely associated with child cognitive development. Low maternal iodine status was associated with an increased risk of suboptimum scores for verbal IQ at age eight, and reading accuracy, comprehension, and reading score at age nine. The authors have shown that risk of suboptimum cognitive scores in children is not confined to mothers with very low iodine status (i.e. <50 μg/g), but that iodine-to-creatinine ratios of 50–150 μg/g (which would suggest a more mild-to-moderate deficiency) are also associated with heightened risk [61].

Based on different intervention studies in children at different ages, it is argued that the developmental effects of iodine deficiency during early gestation are irreversible by later iodine repletion. Supplementation of pregnant women however, showed a clear benefit on cognitive outcome of the children. In iodine-insufficient areas of Spain, the effect of a supplementation during pregnancy on cognitive development of the offspring (aged three months to three years) was clearly documented in three out of four studies [62].

By contrast, supplementation after birth has no clear impact on cognitive development (reviewed in [63]). This underlines the importance of adequate nutrition of females, in particular at the onset of and during pregnancy [64, 65]. In addition, it has to be considered that the newborn depends on iodine from breast milk during lactation. In areas with inadequate iodine supply, breast milk iodine concentration is not sufficient to meet the needs of infants, even when their mothers were supplemented with 150 μg daily iodine during the first six months post-partum [66].

Vitamin D deficiency (VDD) is a worldwide problem with various health consequences in childhood and in adults. VDD is observed in 60% of Caucasian women and also in women with dark skin, where the rate is estimated to be even higher [67].

Maternal VDD during pregnancy has frequently been described as associated with adverse health outcome of the offspring, including intrauterine growth restriction and impaired bone mass. Vitamin D deficiency is also related to various cognitive and behavioral dysfunctions, e.g., schizophrenia [68]. Infants born to mothers with VDD had significantly lower birth weights and an increased risk of being too small for gestational age compared with infants born to mothers with adequate plasma levels as a sign of vitamin D sufficiency [69]. Low maternal serum vitamin D levels during pregnancy of 743 Caucasian women in Australia are significantly associated with offspring language impairment at five and 10 years of age [70]. Besides its well-known actions on bone and the immune system, vitamin D seems also important in the developing brain, controlling the gene expression of so-called neurotrophins, which are important for neurogenesis [62].

8 A Sustainable Approach to Improve Pregnancy Outcomes

Based on increasing data indicating that malnutrition during pregnancy also occurs in high-income countries, various meta-analyses have been performed to study the effect of supplementation on pregnancy and birth outcomes.

In a recent meta-analysis, the impact of a multivitamin/mineral supplement (MVM) on pregnancy outcome was evaluated.

Meta-analysis [71]

Malformation

Risk reduction

 

(OR/95% CI)a

MVM supplement

Study type

NTD

0.67 (0.58–0.77)

Case control

0.52 (0.39–0.69)

Cohort and RCT

Cardiovascular

0.78 (0.67–0.92)

Case control

0.61 (0.40–0.92)

Cohort and RCT

Limb

0.48 (0.30–0.76)

Case control

0.57 (0.38–0.85)

Cohort and RCT

Cleft palate

0.76 (0.62–0.93)

Case Control

0.42 (0.06–2.84)

Cohort and RCT

Cleft lip

0.63 (0.54–0.73)

Case control

0.58 (0.28–1.19)

Cohort and RCT

Urogenital

0.48 (0.30–0.76)

Case control

0.68 (0.35–1.31)

Cohort and RCT

Hydrocephalus

0.37 (0.24–0.56)

Case control

1.54 (0.53–4.50)

Cohort and RCT

  1. a p < 0.01

Prenatal supplementation with an MVM does indeed reduce malformations. It also increases birth weight and reduces the incidence of low for gestational age newborns [72]. Based on these findings, the Canadian Society of Gynaecology and Obstetrics makes the following recommendations:

  • In cases of planned pregnancy, healthy females should take a folate-containing (0.4–1.0 mg) MVM on a daily basis.

  • Females with specific risks (BMI > 35, diabetes, history of a child with NTDs) are advised to take folate (5.0 mg) together with an MVM 2–3 months prior to conception and up to 12 weeks after delivery.

9 Safety of MVM and Pregnancy

The rationale for MVM supplementation during pregnancy is the co-existence of multiple micronutrient deficiencies in pregnant women, especially in resource-poor settings [73]. Resources, however, are not only a question of availability but also of education and knowledge.

Trials of MVMs in pregnant women for primary prevention are carried out to improve either maternal health or birth outcome. Most trials did not specifically address AEs. Nevertheless, differences in birth outcome can be taken as harmful or as AEs. In a double-blind randomized, controlled trial (RCT) [74], the effect of MVM versus folic acid (400 µg) alone versus folic acid + iron (IFA) (30 mg) was tested in 18,775 nulliparous pregnant women. Prenatal MVM and IFA did not affect perinatal mortality (primary outcome) or preterm delivery, birth weight, birth length, or gestational duration (secondary outcomes). In a double-blind cluster-randomized trial, MVM (n = 15,804) or IFA (30 mg/400 µg) (n = 15,486) supplementation were used to study effect on early infant mortality (primary outcome) or neonatal mortality, fetal loss, or low birth weight (secondary outcomes) [75]. Compared with IFA supplementation, MVM reduced early infant mortality by a significant 18%. In addition, all secondary outcomes were significantly improved in the MVM group. Specific AEs were not reported. In different studies from the same group [76], the effect of MVM on pregnancy outcome was evaluated. MVM decreased the incidence of neural tube defects and other cleft formations. AEs were not reported. MVM versus IFA (60 mg/400 µg) during pregnancy showed a significant increase in birth weight in the MVM group. AEs were not reported.

A Danish cohort study [77] documented that regular use of MVM around the time of conception was associated with a decreased risk of preterm birth and small-for-gestational-age birth. Any AEs were not reported, but the authors concluded that “multivitamin use around the time of conception could be a safe and simple strategy.” In an RCT with either MVM (n = 600) or IFA (n = 600) from 12 weeks gestation until delivery [78], morbidity during pregnancy was taken as an AE measure. Typical antenatal problems frequently occurring during pregnancy, such as nausea, dyspepsia, and abdominal pain, occurred in both groups without any significant difference. MVM supplementation was associated with increased birth weight when compared with IFA supplementation. In this study dealing with females from Nepal, nutrition status was not assessed, but might not have been optimal. In another study from Nepal [79], undernourished women were selected for MVM supplementation (n = 99) or placebo (n = 101). Both groups received IFA (60 mg/500 µg). AEs of supplementation (nausea, vomiting, diarrhea, abdominal pain, and anorexia) were documented in seven subjects receiving MVM and in 13 in the IFA control group. In a randomized double-blind RCT, the effect of MVM use (n = 55) versus placebo (n = 59) on subjective health and well-being was elucidated [30]. Those who supplemented with MVM experienced an increased energy level (P = 0.022) and enhanced mood (P = 0.027), both significant versus placebo. One participant in the MVM group reported minor gastrointestinal symptoms (nausea).

Taken together, in controlled clinical trials with MVM supplementation before and during pregnancy, AEs were not reported. The safety and improvement of pregnancy outcomes justify the recommendation to supplement MVM from early conception until delivery. The Genetics Committee of the Society of Obstetricians and Gynecologists of Canada made clear recommendations: Women in the reproductive age group should be advised of the benefits of folic acid in addition to a multivitamin supplement during wellness visits, especially if pregnancy is contemplated [80]. This recommendation is based on an extensive review of articles published between 1985 and 2007 and related to MVM supplementation and its impact on birth defects. Supplementation with MVMs including iron and folate significantly reduced congenital anomalies (anencephaly, myelomeningocele, meningocele, oral facial cleft, structural heart disease, limb defect, urinary tract anomaly, and hydrocephalus).

9.1 Conclusion

MVM supplements show clear benefits on pregnancy outcome and no harm. Recommendation of supplementation is indeed a sustainable approach and covers all inadequacy gaps due to new dietary behaviors or economic problems, achieving a sufficient dietary diversity and meeting the increased needs within the 1,000-day window.

Furthermore, an adequate micronutrient supply within the 1,000-day window will have a curbing impact on diseases in later life.

10 Impact of Maternal Malnutrition on Outcome of the Child in Later Life

It has long been speculated that a poor diet during pregnancy has an impact on diseases in later life. This so-called Barker Hypothesis (also known as intrauterine programming) is also related to poor intake of certain micronutrients during pregnancy. Figure 10.2 summarizes the present state of knowledge regarding the impact of micronutrient deficiencies on later disease development.

Fig. 10.2
figure 2

The relation between inadequate micronutrient supply and risk of disease in later life (reproduced with permission from [81])

Full size image

Inadequate micronutrient supply affects fetal development in different ways depending on the micronutrients in low supply. Hormonal adaptation may impact the growth hormone axis, low supply of methyl-donors will influence epigenetic changes, and inadequate vitamin A and D will influence the innate and acquired immune system and maturation of the lung.

Hormonal adaptations due to low supply of iron or zinc may have a long-term consequence on the growth hormone axis, including appetite regulation and at least body weight [82]. By contrast, prenatal zinc deficiency seems to reduce appetite [83]. Impact of deficiencies on kidney development may increase salt sensitivity and subsequent risk of hypertension. Cardiovascular function, including blood vessel formation and endothelial function, is critically dependent on several micronutrients (vitamin A, folate, iron, zinc) [84]. The impact of vitamins D and A on the development of the immune system might explain the high incidence of type I diabetes in cases of low vitamin D levels during pregnancy. Indeed, a recent meta-analysis documented that vitamin D supplementation during early childhood significantly reduced type 1 diabetes compared to non-supplemented children [85].

10.1 Conclusion

Preventing nutrient gaps during pregnancy and early childhood may reduce the risk of diseases in later life. The major issue during pregnancy is sustainability of the micronutrient supply, because organ systems and hormonal axes develop and react differently from mother to child and within the fetus at different stages of gestation. In addition, the demand will vary in accordance with development and is controlled via supply from maternal or fetal stores. In many cases, micronutrient gaps are not detected and the consequences may occur years later and will not be correlated to a specific gap, which might have produced a ‘genetic’ imprinting on hormonal axis or organ function. To avoid effects of ‘silent’ micronutrient gaps, it is necessary to ensure a sufficient diet with adequate nutrients, as proposed in the FAO/WHO statement on food security.

11 Summary: Key Messages

  • The problem of micronutrient deficiency (hidden hunger) is not confined to the developing world.

  • Significant sections of the population of Europe have been documented in a number of recent studies as being deficient in key micronutrients.

  • Women of child-bearing age and especially women who are pregnant have heightened needs for key micronutrients.

  • Micronutrient provision via the diet is a key factor in brain development, and an adequate micronutrient supply during the first 1,000 days of life is essential for long-term health and wellbeing.

  • Supplementation with multivitamin/mineral supplements during pregnancy is a safe approach to improving birth outcomes and reducing the risk of a range of diseases in later life.

  • To avoid effects of ‘silent’ micronutrient gaps, it is necessary to ensure a sufficient diet with adequate nutrients, as proposed in the FAO/WHO statement on food security.