MM Black, University of Maryland School of Medicine, 737 W. Lombard Street, Suite 161, Baltimore, MD 21201, USA. E-mail: email@example.com. Phone: +1-410-706-0213, Fax: +1-410-706-5090.
This article examines the association of iron deficiency (ID) and iron deficiency anemia (IDA) with children's development and behavior, with the goal of providing recommendations to prevent the developmental loss associated with these conditions. Children's risk for ID and IDA is particularly high during the second 6 months of life when prenatal stores are depleted. Longitudinal studies from infancy through adolescence and early adulthood suggest that socioemotional development is uniquely vulnerable to ID and IDA, perhaps being associated with shared neural pathways, and the effects of early iron deficiencies may be irreversible. In addition to direct effects on brain function, ID and IDA may also affect child development indirectly through non-responsive mother-child interactions. Maternal ID is a global problem that may contribute to high rates of maternal depression and non-responsive caregiving. Intervention trials illustrate that children benefit from both nutritional intervention and early learning interventions that promote responsive mother-child interactions. Recommendations to reduce the developmental loss associated with ID and IDA are to reduce the incidence of these conditions by efforts to prevent premature birth, delay cord clamping, ensure adequate maternal iron status, provide iron-rich complementary foods, and ensure access to postnatal interventions that promote responsive mother-infant interaction patterns and early learning opportunities for infants.
Iron deficiency (ID) is the most common single-nutrient deficiency in the world. In many low- and middle-income countries, the prevalence of iron-deficiency anemia (IDA) among children under 5 years of age is at least 25%, and is often higher.1,2 ID, defined as low body iron stores, is a leading cause of anemia and has been associated with adverse psychomotor, cognitive, and socioemotional development.3 Although the causal link between ID and adverse child development is unclear, evidence from animal studies suggests ID may affect neurological development through brain functions, specifically myelination, dopamine and norepinephrine metabolism, and neuronal energy metabolism.4
Several longitudinal studies have suggested that ID and IDA among young children can cause long-lasting negative effects on children's behavior and development, compromising their cognitive and socioemotional functioning as adolescents and young adults, even if the ID has been corrected.5,6 Recent reviews concluded that the evidence for irreversibility is plausible, particularly for IDA, but not completely confirmed.7–9 ID and IDA often occur in the context of poverty, chronic food insecurity, and low access to iron-rich foods, factors that may also interfere with a child's development.
IRON DEFICIENCY IN CHILDHOOD
Significance of developmental timing
Infants born preterm, with low birth weight, or from mothers who are anemic or diabetic are at risk for ID.10,11 ID in utero appears to have direct effects on indicators of brain maturation in premature infants. Within the first day following delivery, neonates exposed to low iron in utero have exhibited reduced brain maturation.12 The long-term effects of low fetal iron status were evaluated in a low-income US population at birth and at 5 years of age.13 Children with umbilical cord serum ferritin concentrations <76 µg/L had significantly lower scores on tests of auditory language comprehension and ability to follow instructions compared to children with higher levels of cord iron.
Full-term infants are thought to have adequate iron stores until 4–6 months of age.10 The Institute of Medicine estimates the dietary iron requirement of infants through 6 months of age to be 0.27 mg/day, well within the average iron content of breast milk. However, rapid development and high nutritional demands during the second 6 months of life, in combination with the depletion of prenatally acquired iron stores, increase the iron requirement of children to 11 mg/day, which is beyond the amount available from breast milk. Following this vulnerable 6–12 month period, the iron requirement drops to 7 mg/day between the ages of 1 and 3 years, an amount that may be readily supplied through the introduction of iron-rich foods.10
Impact on cognitive, social-emotional, and motor development
In many studies IDA has been linked to cognitive and socioemotional difficulties among young children,8 and to poor fine and gross motor development.14 Among infants under 12 months of age, differences were apparent on brain-based measures; however, global measures may not be sensitive to differences associated with ID early in life.15 In a series of studies using brain-based measures conducted among urban African American infants in the United States, IDA was associated with poorer socioemotional functioning, worse motor functioning, and lower scores in object permanence and short-term memory.16–18
Electrophysiological studies performed early in life shed light on the biological effects of ID and IDA. In one study, infants diagnosed with IDA at 6 months were treated and their auditory brainstem responses and visual evoked potentials were tested through 4 years of age.19 At 12 and 18 months of age, the infants with a history of IDA had slower conduction velocity than non-anemic infants and at the age of 4 years, the formerly IDA infants had longer latencies on both measures compared with non-anemic children. These results suggest that ID or IDA early in life may alter myelination, affecting transmission through the auditory and visual systems and leading to long-lasting functional deficits, which may not be responsive to iron supplementation.19
Infants who experience ID or IDA are at increased risk for low scores on tests of mental performance and may be fearful, inattentive, and solemn with low levels of initiation and exploration.20,21 In one study, iron-deficient infants at 9 months of age were more shy, were less easily soothed, and showed less positive affect compared with iron-sufficient infants.18 The behavioral differences reported among children with ID and IDA, including less responsivity, less likelihood of engaging in social looking (i.e., looking toward their mothers), slower display of positive affect, slower exploration of the environment, and poorer emotional tone, may interfere with the mutually responsive mother-child interaction patterns that form the basis of a child's early development.22 When children are non-responsive, mothers may feel a sense of frustration and maternal caregiving behaviors can be disrupted. Thus, one possibility is that mothers and their children with ID or IDA establish interaction patterns that do not promote healthy cognitive and socioemotional development, thereby contributing to long-lasting deficits.
The Special Nutritional Supplemental Program for Women, Infants, and Children (WIC) routinely evaluates hemoglobin levels for anemia after infants are 9 months of age. In an evaluation of low-income infants enrolled in the Florida WIC Program, children who were anemic early in life were more likely to experience academic problems at 10 years of age, compared to children who were not anemic.23 WIC provides iron-rich food and nutritional education to pregnant women, mothers, infants, and young children. Evaluations of WIC have shown reductions in low-birth-weight deliveries and improvements in infants' iron status, growth, health, and development.24,25
Costa Rican adolescents with a history of chronic, severe ID (with or without anemia) during infancy showed no catch-up in motor development despite iron therapy in infancy.26 In the same cohort, children with ID in infancy showed poorer executive functioning and poorer recognition memory as young adults (19 years) and more internalizing and externalizing behavior problems compared with children who were iron sufficient as infants.27 Thus, ID in infancy may have prolonged consequences for children, even into young adulthood, particularly in social-emotional domains.4,9
Mechanisms linking iron deficiency to children's development
Evidence from electrophysiological studies suggests delayed brain maturation in infants with IDA.28 Iron has multiple roles in neurotransmitter systems and may affect behavior through its effects on dopamine metabolism.29 The association between iron ID and dopamine metabolism is highly relevant to children's early cognitive development, as dopamine clearance has strong effects on attention, perception, memory, motivation, and motor control.4,29 For example, low cerebral iron may interfere with myelination and dopaminergic function, potentially disrupting sleep cycles, motor control, learning, and memory.4,30 Two randomized controlled trials (in Zanzibar and Nepal) showed that sleep duration improved with iron and either folic acid or zinc supplementation among children 10–12 months of age.31 However, sleep state organization was altered in 4-year-old Chilean children despite treatment for IDA in infancy.28 Thus, additional evidence is needed to understand the effects of ID/IDA and iron treatment on sleep patterns.
Another possibility is that, in addition to the direct effects of ID on brain functioning, ID may increase children's hesitation and wariness, making them less able to evoke and benefit from the social and environmental opportunities that promote early child development (see Figure 1). The possibility of distorted mother-child interactions is increased when maternal ID is considered. Mothers and children frequently share micronutrient status32– often because they consume similar diets.33
Nutrition intervention trials
Intervention trials for ID in the first year of life have produced mixed results. Some have indicated that ID produces long-lasting and irreversible effects on cognition and developmental potential, while others showed that developmental delays were largely reversed with supplementation.4 However, many of the early studies had methodological or design flaws that may interfere with clear interpretation. For example, many were not controlled trials of iron supplementation, did not include standardized, age-appropriate measures of cognitive and social-emotional outcomes, or were not blinded.
Reviews of double-blind, placebo-controlled preventive and therapeutic iron treatment trials found evidence for poorer functioning on cognitive and behavioral tasks among infants (0–2 years of age) with IDA, compared to children without anemia.3,9,21 Among formerly anemic children older than 2 years of age, task performance tended to improve with iron treatment. In contrast, little improvement was observed among children under 2 years of age. These findings suggest that not only are children under 2 years of age uniquely vulnerable to the effects of ID, but ID during a time of rapid brain development may be irreversible.
MATERNAL IRON DEFICIENCY
ID affects over 50% of women of childbearing age and may approach 80% in some low- and middle-income (LAMI) countries where consumption of iron-rich animal source food is low.34,35 Similar to research with children, evidence suggests that maternal ID compromises maternal cognition and interactive behaviors, especially caregiving. Poor maternal iron status has been linked to depression, stress, and low cognitive functioning across varying populations.36,37 Micronutrients, including iron, can play major roles in mood disorders, such as depression.36–39 ID has been linked to depression through shared neurotransmitter pathways, particularly dopamine,40,41 raising the possibility that the high rates of maternal depression in LAMI countries may be partially attributable to maternal ID.
Depression is the most common psychiatric problem in the world and a major source of disability in LAMI countries, particularly among women.35 The debilitating effects of depression can extend to the next generation, interfering with infants' growth and development, and leading to negative trajectories of academic and adaptive experiences.42
The burden of depression is higher in LAMI countries compared to high-income countries because rates of depression are higher and there are few resources for intervention.43 Compared with non-depressed women, depressed women are more likely to be poorly educated, be from low-income families, and have more children.43 Studies from high-income countries have shown clear associations between maternal depression and children's well-being, partially mediated through maternal caregiving behavior.38,44 In two recent reviews (including a systematic review and a meta-analysis) of studies from LAMI countries, an association between maternal depressive symptoms and poor infant growth was found across most studies.45,46 As in high-income countries, a study of South African mother-child dyads indicated that depression can interfere with consistent caregiving behavior, leading to disruptions in infant attachment.47 Infants of depressed mothers are at risk for delayed cognitive, motor, and behavioral development, as found in Bangladesh.48 Although interventions to treat depression administered by community health workers can be efficacious,49 there is variability in findings. In South Africa, a home-based intervention on caregiving sensitivity and responsivity beginning in pregnancy was efficacious in reducing depressive symptoms at 6 months post partum (though not sustained) and in promoting infant attachment at 12 months.50 Additional strategies may be necessary to reduce symptoms of depression. ID was not measured, but both maternal and child ID may have been contributing factors.36
Maternal emotional and cognitive functioning may alter mother-child interaction, which, in turn, may affect infant behavior and development.48 Behavioral interaction patterns, such as maternal sensitivity and responsivity, also operate through dopaminergic pathways, raising the possibility that the association between maternal depression and poor caregiving behavior may be partially attributed to maternal ID.10 Evidence suggests that maternal ID negatively affects mother-child interactions.32,42 While there is a genetic component to major depression, much of the depression among women in LAMI countries may be related to psychosocial conditions (e.g., poverty) or to ID, and are, therefore, potentially modifiable. In a trial conducted in South Africa, iron treatment improved women's iron status, cognitive processing, depressive symptoms, and parenting behavior.32,42 Thus, while IDA among infants may impact their development directly or through their interactions with caregivers, IDA among caregivers may alter their caregiving behavior, with indirect effects on the infant (see Figure 1).
EARLY INTEGRATED NUTRITION AND PSYCHOSOCIAL APPROACHES
A recent review found that over 200 million children under 5 years of age in LAMI countries are not reaching their developmental potential, primarily due to nutritional deficiencies (e.g., iron, iodine deficiency), stunting, and lack of opportunities for cognitive and socioemotional stimulation.51,52 Interventions combining nutrition and early learning opportunities (psychosocial stimulation) have been successful at reducing the negative effects of these deficiencies and promoting early child development.53
In LAMI countries where rates of infant ID are high, the World Health Organization recommends direct methods of improving children's iron status through iron supplementation or fortification.54 Earlier interventions may also be effective. Delayed umbilical cord clamping at birth was evaluated in a meta-analysis of 15 international control trials.55 These studies found that waiting at least 2 minutes after birth before clamping the umbilical cord resulted in improved measures of iron status throughout infancy. In addition to adequate iron, early child development also requires sensitive and responsive caregiving.27 Interventions to promote mother-child interactions and developmentally appropriate play benefit children's cognitive and socioemotional development.53 Long-term effects of early intervention are evident in school performance at age 6 years,56 college attendance,57 and young adult cognitive and psychological functioning.52,56 A recent systematic review of 56 studies representing 30 quasi-experimental or randomized controlled intervention trials from 23 countries in Asia, Africa, Europe, and Central and South America examined the effects of early childhood intervention by calculating Cohen's D effect sizes and conducting meta-analyses for children's cognition, behavior, health, and schooling.58 They found sustained benefits in all areas. Interventions that were educational or integrated (e.g., education and nutrition) were more likely to benefit children's cognition than interventions that were solely nutritional or economic (e.g., supplemental foods, cash transfers). Interventions that targeted infants and toddlers were particularly beneficial. The effects of early intervention varied by context, with smaller effects in the least economically developed countries, perhaps because early intervention cannot overcome the absence of basic support for children's health and development (e.g., poverty, food insecurity, poor hygienic conditions). The interventions also varied in quality and in their ability to measure effectiveness on children and on the economics of the country, leading to recommendations that investment in future early childhood intervention programs focus on implementation issues of design and accountability so that highly effective programs can be identified and replicated.58
We identified one integrated intervention trial that focused exclusively on children with IDA.15 Six- and 12-month-old children with IDA, along with a cohort of non-anemic, healthy children, were randomized to receive a weekly home-based intervention or surveillance. The children with IDA received therapeutic iron supplementation that improved their iron status, although not to the level of the healthy children. At baseline, infants with IDA had lower scores on a measure of socioeconomic development, with no differences on scores of mental or motor development. After intervention, infants with IDA showed improved cognitive and socioemotional scores, consistent with gains shown by healthy children. However, deficits in socioemotional behavior remained, as compared to healthy children, and infants with IDA in the surveillance group demonstrated worsening socioemotional development.15 These findings highlight the importance of correcting ID and providing developmental interventions, as well as focusing on early mother-child interactions. Additionally, this study suggests that while nutritional interventions for children with IDA may be effective in ameliorating some consequences of ID, the socioemotional effects are resistant and long lasting. Thus, interventions among infants with IDA should be designed to include both nutritional supplementation and enhanced parent-child interaction and socioemotional development.
The primary recommendation is to prevent ID and IDA among children, with a focus on infancy. Although many countries have initiated iron-supplementation or -fortification policies, caution is warranted as excess iron may increase risk of infection in young children. When iron-sufficient children in a malaria-endemic area of Zanzibar were supplemented with iron, participants experienced an increased risk of hospitalization and mortality compared to controls.59 The response of the public health community has been mixed, with the World Health Organization concluding that iron supplementation should be given only to children with ID,60 and a recent Cochrane Review concluding that it is safe to give iron supplementation in malaria-endemic areas as long as there is adequate malaria control and treatment.61 These reports illustrate the importance of collaborative efforts to promote child health and development by preventing malaria and ensuring adequate iron status. In addition, innovative strategies, such as micronutrient-fortified, lipid-based spreads or cereals may ensure children's iron status, while placing them at lower risk than with supplemental iron.62 Because ID may occur in the context of protein-calorie or other micronutrient deficiencies, comprehensive strategies are needed that look beyond an exclusive need for iron sufficiency.
Additional research into complementary foods and feeding practices is necessary to strengthen programs to prevent ID in young children.11 Although most infants are protected through the first 4–6 months of life, some circumstances are associated with increased risk (e.g., maternal ID, low birth weight, early cord clamping, and the early or prolonged introduction of cow's milk, or iron-insufficient complementary food).10,11 Vulnerability increases during the second 6 months of life when prenatal stores have been depleted and the need for iron increases beyond what breast milk can provide. Recent recommendations from the American Academy of Pediatrics focus on iron-rich complementary foods.10 Strategies are necessary to make micronutrient-rich complementary foods available to infants in LAMI countries where the risk of ID is high.
The period of vulnerability for ID and IDA is also a time of rapid brain growth and child development, as infants expand their skills of social interaction, communication, exploration, cognition, manipulation, and movement.6,8 Ensuring that infants have adequate iron status along with early learning opportunities to develop cognitive, socioemotional, and motor skills increases the likelihood that they will enter school ready to learn and behave in an age-appropriate manner.58 Ensuring iron sufficiency among mothers of infants may reduce the high rates of postpartum maternal depression that have been reported in LAMI countries, thereby promoting early caregiving behaviors and responsive mother-infant interactions. If maternal ID is linked through depression and caregiving behavior to children's growth and development, research is needed to develop and evaluate strategies to ensure adequate iron status among both mothers and infants. Facilitating access to multidisciplinary nutrition interventions that also promote responsive mother-infant interaction patterns and early learning opportunities are key to reducing the long-term effects of ID.
Declaration of interest. The authors have no relevant interests to declare.