THE FIRST 1,000 DAYS OF LIFE: THE BRAINS WINDOW OF OPPORTUNITY

Sarah Cusick, PhD and Michael K. Georgieff, MD,

The importance of nutrition in early brain development

The rst 1,000 days of life - the time spanning roughly between conception and ones 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 signicant 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 words 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 inuences of infectious disease, environmental hazards, and
societal and household violence, all contribute to this loss of potential. Unlike many other inuences that are
immutable or tremendously dicult to change, nutrition is something we can control. The critical or
sensitive periods of brain development susceptible to specic nutritional deciencies are increasingly well
dened, making prevention of long-term decits with well-timed nutritional interventions during the fetal
period and rst 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 decits alone has
been estimated to have the power to increase the worlds 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 rst 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 signicant 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 rst 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 exibility. The rst 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 decit.

While all nutrients are important for brain development and function, optimal overall brain development
depends on providing sucient quantities of key nutrients during specic sensitive time periods in these
rst 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
specic nutrient requirements. A critical nutrient at one time period may have little or no effect in another
epoch. Identication of these periods is typically made rst in animal models and conrmed with
nutritional supplementation studies in pregnancy or early infancy that yield benecial 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, exemplies the necessity of adequate nutrition at specic times of brain growth to ensure full
developmental potential.

Iron deciency is the most common nutritional deciency 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 deciency (3). The periods of peak brain iron requirement and
therefore of highest risk of iron deciency-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 deciency anemia
compared to infants without iron deciency 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 deciency anemia in late pregnancy had a signicantly lower mental
development index score than children of non-iron-decient mothers at 12, 18, and 24 months of age (5).
This decit, 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 signicantly better scores in
working memory, inhibitory control, and ne 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 studys 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 rst 1,000 days, it is not
surprising that the roots of some of the humans 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 nding that early life deviation from expected trajectory due
to a nutrient deciency 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 decit, 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 rst place through nutritional decit
prevention programs than to depend on replacement therapy once a decit has occurred. Feeding the fetal,
newborn, and young child brain is one of the best ways we can achieve this goal.

References

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 dicult 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 deciency 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.