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.

Determinants that influence brain and cognitive development during the first 1000 days from conception to 2 years of age can have long-term effects on brain architecture and cognitive ability. ¹ Studies in high-income countries have shown the long-term cognitive consequences of early life experiences, such as intrauterine growth restriction, ² preterm birth, ³ adverse events, ⁴ and early educational experiences. ⁵ Children in low-income and middle-income countries (LMICs) have a greater burden of risk factors for poor cognitive and behavioural development than those in high-income countries. ⁶ However, few studies in LMICs have assessed the association between early life experiences and later cognitive, motor, and socioemotional ability. Identification of the biomedical and socioenvironmental determinants that most strongly predict cognitive, motor, and socioemotional function is needed for strategic design and integration of child development programmes with existing reproductive, maternal, neonatal, and child health (RMNCH) programmes.

Research in context

Evidence before this study

The long-term effects of maternal nutrition and the interplay of early life biomedical and socioenvironmental determinants on child cognition are unclear. A better understanding is needed to prioritise public health investments to optimise human development. Of the 20 follow-up studies of randomised trials comparing maternal supplementation with three or more micronutrients to iron and folic acid (IFA), only four assessed child motor and cognitive development, and with equivocal results. These studies did not typically use a wide range of tests for multiple cognitive domains in school age children, nor detail the relative contributions of other biomedical and socioenvironmental determinants. Such evidence is important to inform policy makers of which types of interventions are likely to most effectively support children to achieve their developmental potential. We therefore examined citations in four systematic reviews of risk factors for poor child development in low-income and middle-income countries (LMICs). We identified 56 studies that enrolled pregnant women or infants younger than 2 years in LMICs and later assessed cognitive, motor, or socioemotional ability at age 5 years or older. Only five of these analysed biomedical and socioenvironmental determinants, and few included two crucial socioenvironmental determinants, maternal depression and stimulation from the home environment. Additionally, four studies assessed only general intellectual ability, while one reported on general intellectual ability, numeracy, knowledge, and achievement but did not probe specific cognitive domains. One study in Bangladesh included 2853 younger children aged 5 years, while the other four included less than 350 children with limited power to discern effects. As such, detailed analyses and quantification of long term effects of MMN and other early life socioenvironmental and biomedical determinants on multiple defined domains in older children has not been previously reported.

Added value of this study

Our study is the first, to our knowledge, to assess the long term effect of maternal MMN versus IFA on multiple cognitive, motor, and socioemotional domains in school-age children, and the first, to our knowledge, to assess procedural memory. It is the only long-term longitudinal study in a LMIC with a sample of more than 2000 children to assess the relative association of biomedical and socioenvironmental determinants, including home environment and maternal depression, with multiple domains of child abilities. We report significant effects of maternal MMN on procedural memory, on general intellectual ability in children of anaemic women, and positive shifts overall on cognitive, fine motor, and socioemotional ability.

Implications of all the available evidence

The beneficial effects of maternal MMN supplementation on birth weight, small for gestational age, and stillbirths in recent meta-analyses, and on mortality in SUMMIT, especially in anaemic women, tend to support policy change from IFA to MMN for maternal supplementation. Our findings suggest that to achieve thriving populations in multiple domains of children's abilities, current biomedical-centered programmes and interventions are not sufficient, and that additional interventions addressing socioenvironmental determinants are required.