Elizabeth L. Prado

Nutrition and brain development in early life

Presented here is an overview of the pathway from early nutrient deficiency to long-term brain function, cognition, and productivity, focusing on research from low- and middle-income countries. Animal models have demonstrated the importance of adequate nutrition for the neurodevelopmental processes that occur rapidly during pregnancy and infancy, such as neuron proliferation and myelination. However, several factors influence whether nutrient deficiencies during this period cause permanent cognitive deficits in human populations, including the childs interaction with the environment, the timing and degree of nutrient deficiency, and the possibility of recovery. These factors should be taken into account in the design and interpretation of future research. Certain types of nutritional deficiency clearly impair brain development, including severe acute malnutrition, chronic undernutrition, iron deficiency, and iodine deficiency. While strategies such as salt iodization and micronutrient powders have been shown to improve these conditions, direct evidence of their impact on brain development is scarce. Other strategies also require further research, including supplementation with iron and other micronutrients, essential fatty acids, and fortified food supplements during pregnancy and infancy.

Test selection, adaptation, and evaluation : a systematic approach to assess nutritional influences on child development in developing countries

BACKGROUND Evaluating the impact of nutrition interventions on developmental outcomes in developing countries can be challenging since most assessment tests have been produced in and for developed country settings. Such tests may not be valid measures of childrens abilities when used in a new context. AIMS We present several principles for the selection, adaptation, and evaluation of tests assessing the developmental outcomes of nutrition interventions in developing countries where standard assessment tests do not exist. We then report the application of these principles for a nutrition trial on the Indonesian island of Lombok. SAMPLE Three hundred children age 22-55 months in Lombok participated in a series of pilot tests for the purpose of test adaptation and evaluation. Four hundred and eighty-seven 42-month-old children in Lombok were tested on the finalized test battery. METHODS The developmental assessment tests were adapted to the local context and evaluated for a number of psychometric properties, including convergent and discriminant validity, which were measured based on multiple regression models with maternal education, depression, and age predicting each test score. RESULTS The adapted tests demonstrated satisfactory psychometric properties and the expected pattern of relationships with the three maternal variables. Maternal education significantly predicted all scores but one, maternal depression predicted socio-emotional competence, socio-emotional problems, and vocabulary, while maternal age predicted socio-emotional competence only. CONCLUSION Following the methodological principles we present resulted in tests that were appropriate for children in Lombok and informative for evaluating the developmental outcomes of nutritional supplementation in the research context. Following this approach in future studies will help to determine which interventions most effectively improve child development in developing countries.

Extending the Developmental Milestones Checklist for use in a different context in Sub‐Saharan Africa

Sub‐Saharan Africa bears a disproportionate amount of global diseases related to neurodevelopmental delays in infancy, including malnutrition, malaria and HIV. Evaluating interventions to prevent such delays requires developmental assessment tools appropriate for Sub‐Saharan Africa. This study aimed to develop and evaluate such a tool.

Effects of maternal and child lipid-based nutrient supplements on infant development: a randomized trial in Malawi

BACKGROUND Maternal and infant undernutrition is associated with poor infant development; however, few studies have examined the impact of combined pre- and postnatal dietary supplementation on infant development. OBJECTIVE Our objective was to determine whether provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) to mothers during pregnancy and the first 6 mo postpartum, and to children aged 6-18 mo, improves infant development in Malawi. DESIGN We randomly assigned 869 pregnant women to receive one of the following daily: an iron and folic acid (IFA) capsule, a multiple micronutrient (MMN) capsule containing 18 micronutrients, or a 20-g sachet of SQ-LNSs containing 22 vitamins and minerals, protein, carbohydrates, essential fatty acids, and 118 kcal. Children in the lipid-based nutrient supplement (LNS) group only received SQ-LNSs from 6 to 18 mo of age. We monitored the acquisition of 11 developmental milestones monthly by maternal report; observed the attainment of 7 motor milestones at 6, 12, and 18 mo of age; and conducted a comprehensive assessment of motor, language, and socioemotional development and executive function at 18 mo of age. The primary analysis was by intention-to-treat. RESULTS By maternal report, children in the LNS group achieved walking alone (B = 0.53; 95% CI: 0.11, 0.94; P = 0.034) and waving goodbye (B = 0.60; 95% CI: 0.12, 1.08; P = 0.040) earlier than the IFA group and standing with assistance earlier than the MMN group (B = 0.51; 95% CI: 0.12, 0.89; P = 0.029). By researcher observation, there was a trend (P = 0.052) for a greater percentage of children in the LNS group (58%) to walk alone at age 12 mo than in the IFA (49%) and MMN (49%) groups. At age 18 mo, there were no significant differences between groups in any scores. CONCLUSION Although provision of SQ-LNSs to pregnant women and infants in Malawi may affect the age of acquisition of certain developmental milestones, it did not affect our assessments of motor, language, socioemotional, or executive function skills at 18 mo of age. This trial was registered at clinicaltrials.gov as NCT01239693.

The Effect of Maternal Multiple Micronutrient Supplementation on Cognition and Mood during Pregnancy and Postpartum in Indonesia: A Randomized Trial

Maternal caregiving capacity, which is affected in part by cognition and mood, is crucial for the health of mothers and infants. Few interventions aim to improve maternal and infant health through improving such capacity. Multiple micronutrient (MMN) supplementation may improve maternal cognition and mood, since micronutrients are essential for brain function. We assessed mothers who participated in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind cluster-randomized trial in Indonesia comparing MMN supplementation to iron and folic acid (IFA) during pregnancy and until three months postpartum. We adapted a set of well-studied tests of cognition, motor dexterity, and mood to the local context and administered them to a random sample of 640 SUMMIT participants after an average of 25 weeks (SD = 9) of supplementation. Analysis was by intention to treat. Controlling for maternal age, education, and socio-economic status, MMN resulted in a benefit of 0.12 SD on overall cognition, compared to IFA (95%CI 0.03–0.22, p = .010), and a benefit of 0.18 SD on reading efficiency (95%CI 0.02–0.35, p = .031). Both effects were found particularly in anemic (hemoglobin<110 g/L; overall cognition: B = 0.20, 0.00–0.41, p = .055; reading: B = 0.40, 0.02–0.77, p = .039) and undernourished (mid-upper arm circumference<23.5 cm; overall cognition: B = 0.33, 0.07–0.59, p = .020; reading: B = 0.65, 0.19–1.12, p = .007) mothers. The benefit of MMN on overall cognition was equivalent to the benefit of one year of education for all mothers, to two years of education for anemic mothers, and to three years of education for undernourished mothers. No effects were found on maternal motor dexterity or mood. This is the first study demonstrating an improvement in maternal cognition with MMN supplementation. This improvement may increase the quality of care mothers provide for their infants, potentially partly mediating effects of maternal MMN supplementation on infant health and survival. The study is registered as an International Standard Randomized Controlled Trial, number ISRCTN34151616. http://www.controlled-trials.com/ISRCTN34151616

Effects of pre- and post-natal lipid-based nutrient supplements on infant development in a randomized trial in Ghana

BACKGROUND Maternal and infant undernutrition is negatively associated with infant development. AIMS We tested the hypothesis that provision of small-quantity lipid-based nutrient supplements (SQ-LNS) to pregnant women and infants positively affects infant development. STUDY DESIGN In a partially double-blind randomized controlled trial, we compared the following daily maternal supplements during pregnancy and until 6months post-partum: iron/folic acid capsule (IFA), capsule containing 18 micronutrients (MMN), or 20g SQ-LNS. Children in the SQ-LNS group also received SQ-LNS from age 6 to 18months. The study is registered as NCT00970866. SUBJECTS 1320 pregnant women in Ghana enrolled in the trial; 1173 of their children participated in developmental assessment. OUTCOME MEASURES We monitored the acquisition of 10 developmental milestones monthly by parental report, observed the attainment of 6 motor milestones at 6, 12, and 18months, and conducted detailed assessment of motor, language, socio-emotional, and executive function at 18months. RESULTS By researcher observation, a greater percentage of children in the SQ-LNS group (53%) was able to walk alone at 12months than in the IFA group (43%; RR=1.23, 95% CI=1.02-1.49; p=0.025). We found no significant differences between groups in milestone acquisition by parent report or in any scores at 18months. The difference in mean z-scores between groups ranged from 0.03-0.13 for motor (p=0.84), 0.01-0.08 for language (p=0.46), 0.01-0.02 for socio-emotional (p=0.75), and 0.00-0.02 for executive function (p=0.95). CONCLUSION While provision of maternal and child SQ-LNS in Ghana may affect walking at 12months, it did not affect infant development at 18months.

Selecting measures for the neurodevelopmental assessment of children in low- and middle-income countries

ABSTRACT Diseases affecting millions of children in low- and middle-income countries (LMICs), such as malnutrition, micronutrient deficiency, malaria, and HIV, can lead to adverse neurodevelopmental outcomes. Thus, a key health outcome in children is neurodevelopmental status. In this paper, the neurodevelopmental screening and testing measures most commonly utilized in LMICs are reviewed, and a matrix is presented to help researchers and clinicians determine which measures may be most useful for various LMIC inquiries. The matrix is based on an Internet literature review of 114 publications for the period January 1998 to February 2016, reporting the psychometric properties of instruments tested in LMIC children. The measures are classified as screening tests or more detailed tests that include both comprehensive batteries of general development and tests of specific domains. For completeness, two experts have reviewed this paper, as well as the authors. An overview of the tests used to date is presented, including the benefits and drawbacks of each test, in order to provide researchers and developmental clinicians with a way to decide which tests may be best suited to their developmental assessment goals. Remarkable progress has been made in neurodevelopmental testing in children in LMICs over the past two decades but there remains a need for additional research in this area to develop new tests, better evaluate and adapt current tests, and assess test validity and reliability across cultures.

Children's Computation of Complex Linguistic Forms: A Study of Frequency and Imageability Effects

This study investigates the storage vs. composition of inflected forms in typically-developing children. Children aged 8–12 were tested on the production of regular and irregular past-tense forms. Storage (vs. composition) was examined by probing for past-tense frequency effects and imageability effects – both of which are diagnostic tests for storage – while controlling for a number of confounding factors. We also examined sex as a factor. Irregular inflected forms, which must depend on stored representations, always showed evidence of storage (frequency and/or imageability effects), not only across all children, but also separately in both sexes. In contrast, for regular forms, which could be either stored or composed, only girls showed evidence of storage. This pattern is similar to that found in previously-acquired adult data from the same task, with the notable exception that development affects which factors influence the storage of regulars in females: imageability plays a larger role in girls, and frequency in women. Overall, the results suggest that irregular inflected forms are always stored (in children and adults, and in both sexes), whereas regulars can be either composed or stored, with their storage a function of various item- and subject-level factors.

Maternal multiple micronutrient supplementation and other biomedical and socioenvironmental influences on children's cognition at age 9–12 years in Indonesia:follow-up of the SUMMIT randomised trial

BACKGROUND Brain and cognitive development during the first 1000 days from conception are affected by multiple biomedical and socioenvironmental determinants including nutrition, health, nurturing, and stimulation. An improved understanding of the long-term influence of these factors is needed to prioritise public health investments to optimise human development. METHODS We did a follow-up study of the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind, cluster-randomised trial of maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA) in Indonesia. Of 27 356 live infants from birth to 3 months of age in 2001-04, we re-enrolled 19 274 (70%) children at age 9-12 years, and randomly selected 2879 from the 18 230 who were attending school at a known location. Of these, 574 children were oversampled from mothers who were anaemic or malnourished at SUMMIT enrolment. We assessed the effects of MMN and associations of biomedical (ie, maternal and child anthropometry and haemoglobin and preterm birth) and socioenvironmental determinants (ie, parental education, socioeconomic status, home environment, and maternal depression) on general intellectual ability, declarative memory, procedural memory, executive function, academic achievement, fine motor dexterity, and socioemotional health. The SUMMIT trial was registered, number ISRCTN34151616. FINDINGS Children of mothers given MMN had a mean score of 0·11 SD (95% CI 0·01-0·20, p=0·0319) higher in procedural memory than those given IFA, equivalent to the increase in scores with half a year of schooling. Children of anaemic mothers in the MMN group scored 0·18 SD (0·06-0·31, p=0·0047) higher in general intellectual ability, similar to the increase with 1 year of schooling. Overall, 18 of 21 tests showed a positive coefficient of MMN versus IFA (p=0·0431) with effect sizes from 0·00-0·18 SD. In multiple regression models, socioenvironmental determinants had coefficients of 0·00-0·43 SD and 22 of 35 tests were significant at the 95% CI level, whereas biomedical coefficients were 0·00-0·10 SD and eight of 56 tests were significant, indicating larger and more consistent impact of socioenvironmental factors (p<0·0001). INTERPRETATION Maternal MMN had long-term benefits for child cognitive development at 9-12 years of age, thereby supporting its role in early childhood development, and policy change toward MMN. The stronger association of socioenvironmental determinants with improved cognition suggests present reproductive, maternal, neonatal, and child health programmes focused on biomedical determinants might not sufficiently enhance child cognition, and that programmes addressing socioenvironmental determinants are essential to achieve thriving populations. FUNDING Grand Challenges Canada Saving Brains Program.

Linear Growth and Child Development in Burkina Faso, Ghana, and Malawi

OBJECTIVES: We aimed to produce quantitative estimates of the associations between 4 domains of child development and linear growth during 3 periods: before birth, early infancy, and later infancy. We also aimed to determine whether several factors attenuated these associations. METHODS: In 3700 children in Burkina Faso, Ghana, and Malawi, growth was measured several times from birth to age 18 months. At 18 months, language, motor, socioemotional, and executive function development were assessed. In Burkina Faso (n = 1111), personal-social development was assessed rather than the latter 2 domains. RESULTS: Linear growth was significantly associated with language, motor, and personal-social development but not socioemotional development or executive function. For language, the pooled adjusted estimate of the association with length-for-age z score (LAZ) at 6 months was 0.13 ± 0.02 SD, and with ΔLAZ from 6 to 18 months it was 0.11 ± 0.03 SD. For motor, these estimates were 0.16 ± 0.02 SD and 0.22 ± 0.03 SD, respectively. In 1412 children measured at birth, estimates of the association with LAZ at birth were similar (0.07–0.16 SD for language and 0.09–0.18 SD for motor development). These associations were weaker or absent in certain subsets of children with high levels of developmental stimulation or mothers who received nutritional supplementation. CONCLUSIONS: Growth faltering during any period from before birth to 18 months is associated with poor development of language and motor skills. Interventions to provide developmental stimulation or maternal supplementation may protect children who are faltering in growth from poor language and motor development.