Micronutrient Deficiencies and Cognitive Functioning

Abstract

The relationship between four micronutrient deficiencies (iodine, iron, zinc and vitamin B-12) and children’s cognitive functioning is reviewed. Iodine deficiency during pregnancy has negative and irreversible effects on the developing fetus. Although there is some evidence that postnatal iodine deficiency is associated with cognitive deficits, the findings are controversial. Iron deficiency is widespread and has been associated to cognitive deficits, but the results of prevention trials are inconsistent. Zinc deficiency has been linked with low activity and depressed motor development among the most vulnerable children. Associations with cognitive development are less clear and may be limited to specific neuropsychological processes. Vitamin B-12 deficiency has been associated with cognitive problems among the elderly, but little is known about its effect on children’s cognitive functioning. Rates of vitamin B-12 deficiency are likely to be high because animal products are the only source of vitamin B-12. Although micronutrient deficiencies often co-occur in the context of poverty, little is known about the impact of multiple micronutrient deficiencies on cognitive development. J. Nutr. 133: 3927S–3931S, 2003.

Recent evidence suggests that micronutrient deficiencies may play a role in children’s development. Micronutrient deficiencies are a critical concern among children throughout the world. Approximately 30% of the world’s population live in iodine-deficient areas and 25% of the world’s children under age 3 y have iron-deficiency anemia, with higher rates in developing countries (1). When iron deficiency without anemia is considered, rates are even higher (2). Less is known about the prevalence of zinc and vitamin B-12 deficiency. Based on the dietary intakes of children from developing countries, there is a high rate of zinc deficiency among infants and toddlers (3), and recent data suggest that inadequate zinc intakes may be common among middle-class infants and toddlers in America (4). Because animal products are the only source of vitamin B-12, rates of vitamin B-12 deficiency are likely to be high among children who consume little or no meat or milk.

The relationship between micronutrient deficiency and early cognitive development has captured recent attention because micronutrients are related to specific physiological processes (5). Therefore, programs designed to prevent or treat micronutrient deficiencies can be targeted toward specific recommendations. At least four micronutrients have been linked to cognitive processes in infants and young children and are the focus of this review: iodine, iron, zinc and vitamin B-12.

The research examining the effects of micronutrient deficiencies on children’s cognitive and motor development suffers from many of the same methodological problems that have hindered research examining the effect of protein-energy malnutrition. Micronutrient deficiencies often occur in the context of poverty and among families who are beset by multiple stressors that may interfere with the healthy development of their children. In addition, micronutrient deficiencies often co-occur, particularly if the micronutrients are derived from the same source. For example, meat, fish and poultry are important sources of iron, zinc and vitamin B-12. If children are deficient in multiple micronutrients, it can be difficult to interpret the effects of single micronutrient supplementation trials.

Observational studies have compared children with and without micronutrient deficiencies. Although these studies can yield useful information about micronutrients and differences in development, they lack the rigor of randomized trials because there are often factors that differ between separating the groups that may influence children’s development, such as care-giving practices (6). Randomized trials can often clarify differences related to the effects of micronutrients, but they are expensive and must also control for confounding factors that may influence children’s development, such as the quality of the care-giving environment. In addition, as the evidence demonstrating the detrimental effects of specific micronutrient deficiencies on children’s development is clarified (e.g., the effect of iodine deficiency), it becomes unethical to identify micronutrient-deficient children and then not to offer treatment.

Iodine deficiency

The link between prenatal iodine deficiency and cognitive development is direct, but can be prevented through public health methods, making iodine deficiency the most preventable cause of mental retardation in the world (7). Iodine deficiency is a major problem that affects children in areas where iodine is depleted from the soil, primarily mountainous regions, such as the Himalayas and the Andes, and in flood plains (8). A 1993 World Health Organization report estimates that 1.6 billion people or 30% of the world’s population live in iodine-deficient areas and are therefore at risk for iodine deficiency (1). Public health methods, such as iodized salt, injections of iodinated oil or oral iodine, have been effective in preventing congenital hypothyroidism and the associated mental retardation (7).

Iodine is an essential component of at least two thyroid hormones that are necessary for skeletal growth and neurological development (8). When iodine is deficient, hypothyroidism occurs, resulting in increased production of thyroid stimulating hormones and goiter (8).

When iodine deficiency occurs in utero, it leads to fetal hypothyroidism and irreversible neurological and cognitive deficits manifested as cretinism. Neurological cretinism includes mental retardation, primitive reflexes, visual problems, facial deformities, stunted growth and diplegia (9). In addition to cognitive delays, primitive reflexes and pyramidal signs, myxodematous cretinism includes severe growth retardation, dry skin and electrocardiogram abnormalities. Randomized iodine supplementation trials from iodine-deficient areas of Asia, Africa and South America have shown that children whose mothers were supplemented before conception or early in pregnancy have better developmental outcomes than those whose mothers are not supplemented (10).

When iodine deficiency occurs postnatally, the child may experience thyroid failure that can lead to hypothyroidism. Observational studies that have compared children with and without goiter have had mixed results; some have reported cognitive deficits among children with goiters and others have not. One explanation for the lack of clarity may be that differing levels of hypothyroidism can lead to a goiter (9). In a metaanalysis of 18 observational studies that compared children based on whether they lived in an iodine-deficient area or not, children who lived in iodine-deficient areas had deficits in cognitive functioning (11). In a well-controlled observational study in Bangladesh, investigators found that children with mild hypothyroidism had deficits in spelling and reading compared to healthy controls (12). Although evidence from these studies is compelling, families who live in iodine-deficient areas are often more impoverished than families in areas where iodine status is adequate.

Several randomized trials have been conducted to examine the impact of iodine supplementation on the cognitive performance of children in iodine-deficient areas. However, results have not been consistent. In a recent longitudinal follow-up of school-age children, all of whom received iodine, those who received iodine in utero before the third trimester had better scores on a measure of psychomotor performance than children who received iodine later in pregnancy or at age 2 y (13). There was a similar trend when measures of cognitive performance were considered; however, the differences did not reach statistical significance. Thus, the effects of postnatal iodine deficiency on children’s cognitive performance are less clear than the effects of prenatal iodine deficiency. In addition, many of the studies have had methodological problems that interfere with interpretation.

Universal salt iodization is a public health priority for women of childbearing age to protect their unborn children from the severe consequences of hypothyroidism. In cases where iodine deficiency is common, but iodized salt is either not consumed or unavailable, iodized oil can be used. Although iodine supplementation will reduce the incidence of goiter in children, the impact on their cognitive development requires further investigation.

Iron deficiency

Iron deficiency is the most common nutritional deficiency in the world. WHO estimates that worldwide there are 2 billion individuals with anemia and up to 5 billion who are iron deficient (2). The highest risk of iron deficiency occurs during times of rapid growth and nutritional demand, especially age 6–24 mo, adolescence and pregnancy. Iron is necessary for hemoglobin synthesis. Iron deficiency leads to reduced oxygen carrying capacity and can impact immunity, growth and development. Only 50% of anemia is caused by iron deficiency. The remainder is caused by vitamin A deficiency, deficiencies of vitamin B-12 and folate, malaria, HIV, other infectious diseases, sickle cell disease, or other inherited anemias (14).

A number of observational studies have found that children who experienced anemia early in life continued to demonstrate lower academic performance during their school-age years, even after the anemia had been treated. For example, Hurtado and colleagues examined the records of children who enrolled in the Special Supplemental Nutrition Program for Women, Infants and Children before age 5 y (15). Those who were anemic were more likely to experience academic problems at 10 y of age, compared to children who were not anemic on enrollment. Concurrent iron status is also related to academic performance, as demonstrated in a recent investigation using data from 5398 children aged 6–16 y from the NHANES III survey in the United States (16). When standardized mathematics test scores were examined controlling for background variables, children with iron deficiency, with and without anemia, had lower scores than children with normal iron status. These findings suggest that iron deficiency, even without anemia, may place children at risk for cognitive delays.

Treatment for anemic children

A Cochrane Review in 2001 focused on randomized placebo-controlled trials that had been conducted to examine the impact of iron therapy on development among children under age 3 y with iron deficiency anemia (17). Among the five trials of short-term treatment, involving 180 children, iron therapy resulted in no differences in the children’s mental or motor performance. There were two trials of longer-term therapy (over 30 d), involving 160 children. One study tested children 2 mo after iron treatment, using a screening test (the Denver Test), and found no difference in performance (18). The other study, conducted in Indonesia, found that 4 mo of iron treatment produced 18-point improvements in both mental and motor scores on a standardized assessment (Bayley Scales of Infant Development) (19). Although the evidence from the Indonesia trial regarding long-term treatment is very encouraging, more randomized trials are needed. There have been other randomized trials of iron treatment that showed no treatment effect on cognitive performance; however, most investigators have relied on nonanemic control groups to avoid the ethical dilemma of denying iron therapy to anemic children.

Prevention trials

There are at least seven published randomized control prevention trials that have been conducted among children under 3 y of age. Three found no effect of iron supplementation on cognitive performance (20–22), but four found beneficial effects of iron supplementation on varying aspects of children’s behavior and development (23–26). In a trial conducted in Papua, New Guinea, findings may have been blunted due to confounding with malaria (20). Four of the investigators used the Bayley Scales to measure mental and motor development (21–24). Only one found effects—iron supplemented infants had better motor development at 9- and 12- mo of age, but not at 15 mo (23). In a trial that used the Griffiths Scale to measure development, children who received iron experienced less decline in developmental skills over the first year of life (25). In a recent trial from Zanzibar that used maternal report of developmental skills, children who received iron for 1 y had better language scores (26). Children who had low hemoglobin initially also had better motor scores after iron therapy (26). Lozoff et al. found beneficial effects of iron on visual perceptual skills (24). Infants with iron-deficient anemia have been described as wary and irritable (27,28). Iron-supplemented children have been described as less wary and hesitant than those who were not supplemented (28); behavioral differences continued into childhood even after the children’s iron status had been corrected. Taken together, these findings illustrate the complexity of using general cognitive assessments and suggest that iron deficiency may be related to specific processes, especially when it occurs early in life. Additional iron supplementation trials are needed, especially in younger children.

Iron has multiple roles in neurotransmitter systems and may affect behavior through its effects on dopamine metabolism. Dopamine clearance has strong effects on attention, perception, memory, motivation and motor control (29).

Zinc deficiency

Low zinc intake appears to be a major public health problem (30). However, biological measures of zinc status, such as plasma and hair zinc, are imperfect indicators of functional impairment due to zinc deficiency, and response to randomized trials of zinc supplementation conducted in zinc-deficient populations has been an important means to examine the consequences of zinc deficiency (31). Supplementation trials among nutritionally deficient infants have demonstrated beneficial effects of zinc on growth (32), diarrhea and pneumonia morbidity (33) and on mortality (34).

An early observational study from Egypt demonstrated a link between maternal micronutrient intake and infants’ developmental skills (35). Several supplementation trials among pregnant women, infants and toddlers have shown increased activity and motor development among zinc-supplemented groups (36–40). However, a recent trial among women who received zinc supplementation during pregnancy found no differences in their children’s mental and motor performance at age 5 y (41).

Trials that have examined changes in cognitive functioning have found either no differences related to zinc supplementation (36,40,42) or, as in two recent studies from Bangladesh, found lower scores among zinc-supplemented infants (43,44). In one trial, zinc supplementation was delivered to infants (43) and, in the other, it was delivered to their mothers during pregnancy (44). Both trials reported that at 12 mo, zinc-supplemented infants achieved lower scores on a measure of cognitive development than control infants.

When behavior changes related to zinc supplementation were considered, in Brazil zinc-supplemented infants were more responsive than control group infants (42). Although the evidence from the supplementation trials among vulnerable infants and toddlers suggests that zinc deficiency may compromise children’s early motor development, the evidence linking zinc deficiency to cognitive development is not conclusive (45).

There have been at least three randomized trials of zinc supplementation measuring cognitive development among school-age children. A trial in Canada found no differences when children were tested with subscales from the Detroit Test of Learning Abilities (46). However trials in China and Mexican-American children from Texas have found that zinc-supplemented children demonstrated superior neuropsychological performance, particularly reasoning, when compared with controls (47–49). The evidence for improved neuropsychological performance among zinc-supplemented children is increasing, but more work is needed to replicate existing studies and clarify the effect on academic performance.

Vitamin B-12 deficiency

Because animal products are the only source of vitamin B-12, infants breastfed by mothers with low intakes of these products, and children who do not consume them, are at risk for vitamin B-12 deficiency. Research from rural Kenya presented by Siekmann et al. in this supplement indicates that over two thirds of the school-age children are experiencing vitamin B-12 deficiency (50). The worldwide prevalence of vitamin B-12 deficiency may be very high.

Vitamin B-12 deficiency is a recognized problem among geriatric populations even in wealthier countries, often related to their diminished ability to absorb the vitamin. Consequently, most of the research linking vitamin B-12 deficiency to cognitive functioning has been conducted in the elderly, where it has been associated with dementia and neurobehavioral deficits (51).

Most of the research on the relationship between vitamin B-12 deficiency and cognitive functioning in children is limited to case studies of infants of mothers with pernicious anemia (who are unable to absorb vitamin B-12) or vegan mothers (52). These infants are at risk for delayed developmental milestones.

There have been at least two observational studies among children with B-12 deficiency. In the first study, infants of macrobiotic mothers in The Netherlands had delayed motor and language development compared to infants of omnivores (53). At age 12 y, the children had higher methylmalonic acid levels and scored lower than the omnivores on standardized assessments, including the Raven’s progressive matrices, Digit Span and Block Design, even though their current diet contained almost their recommended daily intake of vitamin B-12 (54). The second study was conducted among Guatemalan school-age children. Children with vitamin B-12 deficiency had slower reaction time on neuropsychological tests of perception, memory and reasoning, along with academic problems including lower academic performance, lower teacher ratings, more attentional problems and more delinquent behavior (55,56). These observational studies provide evidence that vitamin B-12 deficiency is associated with poorer cognitive performance, but intervention trials are needed for confirmation.

Most of the research examining the impact of micronutrient deficiencies on children’s development has hypothesized a direct effect, possibly through changes in neuroanatomy or neurotransmission (57). However, it is also possible that behavior changes associated with micronutrient deficiencies alter the caregiving that the child receives, thereby compromising the child’s development even further. For instance, if an iron deficient child is wary and unable to elicit or to benefit from nurturant interactions from a caregiver, that child may be denied the enrichment that is known to promote early development. The result could be a child who experiences both the neurological changes that have been associated with iron deficiency together with limited environmental enrichment. This process, whereby nutritional deficiencies are partially mediated through caregiving behavior, is known as functional isolation (58). Future research should consider how the caregiving system is related to child development and whether it mediates the effects of micronutrient deficiencies.

The findings linking micronutrient deficiencies to child development point to the importance of effective prevention programs that begin prenatally or early in life and extend through the periods of vulnerability, which may include adolescence. There are many unanswered questions regarding micronutrient deficiencies and child development that require further research, including the initial severity and timing of the deficiency, the long-term consequences on academic achievement, the specific processes involved and the impact of multiple micronutrient deficiencies.