Sarah Cusick, PhD and Michael K. Georgieff, MD
The first 1,000 days of life - the time spanning roughly between conception and one’s second birthday - is a unique period of opportunity when the foundations of optimum health, growth, and neurodevelopment across the lifespan are established. Yet too frequently in developing countries, poverty and its attendant condition, malnutrition, weaken this foundation, leading to earlier mortality and significant morbidities such as poor health, and more insidiously, substantial loss of neurodevelopmental potential. As a species, we have come from a history of "malnutrition" being synonymous with "undernutrition" - the serious lack of obtaining even adequate amounts of nutrition. In the modern era, while undernutrition remains the major challenge worldwide, we humans are now faced with the negative effects of "overnutrition" in the form of obesity and risky nutrition in the form of unbalanced diets or diets contaminated with potential toxins. Each of these conditions can be considered "malnutrition" in the true sense of the word’s roots (bad nutrition) and each has been shown to potentially reduce brain development.
At least 200 million children living in developing countries fail to meet their developmental potential (1). Along with undernutrition, concomitant influences of infectious disease, environmental hazards, and societal and household violence, all contribute to this loss of potential. Unlike many other influences that are immutable or tremendously difficult to change, nutrition is something we can control. The critical or sensitive periods of brain development susceptible to specific nutritional deficiencies are increasingly well defined, making prevention of long-term deficits with well-timed nutritional interventions during the fetal period and first years of life a true possibility. Interventions based on the knowledge of these critical windows have the potential to exert a profound global impact, as correction of nutritional deficits alone has been estimated to have the power to increase the world’s intelligence quotient by 10 points (2).
Sensitive periods of brain development
While the human brain continues to develop and change throughout life, the most rapid period of brain growth and its period of highest plasticity is in the last trimester of pregnancy and the first two years of life. The human brain at 5 months post-conception is a smooth, bi-lobed structure that looks somewhat like a coffee bean. By 9 months, i.e. term birth, it has gyri and sulci indicative of significant complexity, looking far more like the walnut-like adult brain. At birth, rapidly developing brain areas include the hippocampus and the visual and auditory cortices. In the first postnatal year, there is rapid growth of the language processing areas as well as early development of the prefrontal cortex that will control "higher processing" such as attention, inhibition, and flexibility. The first 1,000 days are characterized by rapid rates of neuronal proliferation (cell numbers), growth and differentiation (complexity), myelination, and synaptogenesis (connectivity). Thus, this time period harbors the greatest opportunity to provide optimal nutrition to ensure normal development and also the time of greatest brain vulnerability to any nutrient deficit.
While all nutrients are important for brain development and function, optimal overall brain development depends on providing sufficient quantities of key nutrients during specific sensitive time periods in these first 1,000 days. The brain is not a homogenous organ, but instead consists of multiple separate regions, each with a unique growth trajectory, that ultimately interconnect to make the complex organ that drives behavior. Thus, there is not a single common growth trajectory or single sensitive period. Rather, the different regions (e.g., the hippocampus, striatum, cortex) and processes (e.g., myelination) of the brain exhibit growth trajectories that span and peak at different times, each time period (and region) having specific nutrient requirements. A critical nutrient at one time period may have little or no effect in another epoch. Identification of these periods is typically made first in animal models and confirmed with nutritional supplementation studies in pregnancy or early infancy that yield beneficial cognitive and behavioral outcomes.
Iron: A key nutrient and a paradigm of nutrient-brain interactions
While the brain requires all nutrients for growth, certain nutrients, including protein, polyunsaturated fatty acids, iron, zinc, copper iodine, choline, folate and vitamins A, B6, and B12 are particularly critical. Of these, iron, exemplifies the necessity of adequate nutrition at specific times of brain growth to ensure full developmental potential.
Iron deficiency is the most common nutritional deficiency in the world. Globally, an estimated 47% (293 million) of all preschool-aged children and 42% (56 million) of all pregnant women are anemic, with approximately half attributable to iron deficiency (3). The periods of peak brain iron requirement and therefore of highest risk of iron deficiency-induced neurobehavioral impairment are: 1) the fetal/neonatal period and 2) infancy/toddlerhood (6 months to 3 years). The developing brain at these time points requires iron for proteins that regulate myelin production, neurotransmitter synthesis, and neuronal energy production. These processes in turn support speed of processing in the brain, as well as behaviors such as affect and emotion, and learning and memory. In a recent review, 19 out of 21 studies reported impaired mental, motor, socio-emotional, or neurophysiologic functioning in infants with iron deficiency anemia compared to infants without iron deficiency anemia (4).
Iron supplementation in key periods to prevent later impairment
Iron supplementation during these key periods of peak iron need, particularly during pregnancy, has proven to be an effective deterrent of later neurodevelopmental impairment. In a recent study in China, children born to mothers with iron deficiency anemia in late pregnancy had a significantly lower mental development index score than children of non-iron-deficient mothers at 12, 18, and 24 months of age (5). This deficit, however, was corrected in children of mothers who received iron and folic acid supplementation throughout pregnancy, but not in children whose mothers who had received folic acid alone or a multiple micronutrient supplement that contained half as much iron. Similarly, in Nepal, daily iron/folic acid supplementation beginning in early pregnancy resulted in significantly better scores in working memory, inhibitory control, and fine motor functioning in children at 7 to 9 years of age (6). However, daily iron/folic acid with or without zinc supplementation of children from an average age of 22 months until 36 months with mothers who had not received micronutrient supplementation during pregnancy had no effect on aspects of intellectual, executive, or motor function at age 7-9 years (7). As hypothesized by the study’s authors, it is possible that the window of opportunity was missed.
Plasticity vs. vulnerability
Based on what is now known about the magnitude of brain development in the first 1,000 days, it is not surprising that the roots of some of the human’s most complex behaviors are laid down very early in life; well before there is obvious behavioral expression of those areas. Indeed, one of the most striking aspects of developmental nutritional neuroscience is the finding that early life deviation from expected trajectory due to a nutrient deficiency can affect brain function in adulthood, long after repletion of the nutrient. While the young brain is enormously plastic in its ability to recover from early insults and, hopefully, it is never too late to at least partially correct a deficit, the window of opportunity does narrow with advancing age. The science suggests that it is far better policy to build the brain right in the first place through nutritional deficit prevention programs than to depend on replacement therapy once a deficit has occurred. Feeding the fetal, newborn, and young child brain is one of the best ways we can achieve this goal.
1- Walker SP, Wachs TD, Gardner JM, Lozoff B, Wasserman GA, Pollitt E, Carter JA; International Child Development Steering Group. Child development: risk factors for adverse outcomes in developing countries. Lancet. 2007;369(9556):145-57.
2- Morris SS, Cogill B, Uauy R. 2008 Maternal and Child Undernutrition Study Group. Effective international action against undernutrition: why has it proven so difficult and what can be done to accelerate progress? Lancet 16;371(9612):608-21.
3- World Health Organization. Vitamin and Mineral Nutrition Information System. Http://www.who.int/vmnis/database/anaemia/anaemia_data_status_t3/en/index.html. Accessed April 2, 2013.
4- Walker et al. (2007) op. cit.
5- Chang S, Zeng L, Brouwer ID, Kok FJ, Yan H. Effect of iron deficiency anemia in pregnancy on child mental development in rural china. Pediatrics. 2013; 131(3):e755-63. doi: 10.1542/peds.2011-3513. Epub 2013 Feb 11.
6- Christian, P et al., Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA, 2010. 304(24): p. 2716-23.
7- Murray-Kolb, L.E., et al., Preschool micronutrient supplementation effects on intellectual and motor function in school-aged Nepalese children. Arch Pediatr Adolesc Med, 2012. 166(5): p. 404-10.