Control of iron deficiency in the first 1000 days in life: prevention of impaired child development

S. Chang

Research output: Thesisinternal PhD, WU


Evidence indicates that the first 1000 days of life (the period from the woman’s pregnancy continuing into the child’s second year) is the most critical period. This is where nutritional deficiencies have a significant and often irreversible adverse impact on child survival and growth affecting their ability to learn in school and productivity in later life. Sufficient iron supply and intake during pregnancy and in children under two years of age are an important component for nutrition interventions during these critical 1000 days. A causal relationship between iron deficiency and poorer brain function has not been demonstrated yet. In addition, there is ample evidence that the high frequency of iron deficiency anemia (IDA) in the developing world has substantial health and economic costs.  It is therefore of public health significance to explore effective and optimal approaches for iron supplementation and iron fortification among high risk populations (i.e., pregnant women, infants and young children).

This thesis addresses some of the above outstanding areas, aiming at i) exploring the long-term effect of IDA in pregnancy and IDA in children under 2 years on cognitive and psychomotor function and social emotional behaviour, ii) understanding the impact of prenatal multiple micronutrient supplementation on health outcomes of newborns, and iii) investigating iron absorption from a complementary food fortified with a mixture of FeSO4 and NaFeEDTA.

The human brain is vulnerable during critical periods of development, including the last trimester of fetal life and the first 2 years of childhood - a period of rapid brain growth termed the “brain growth spurt”. We found that iron deficiency anemia in the third trimester of pregnancy is associated with impaired mental development of the child before 24 months of age.  The children whose mothers had iron deficiency anemia showed a significantly lower Mental Development Index (MDI) at 12, 18 and 24 months of age. The adjusted mean difference was 5.8 (95% Confidence interval [CI] 1.1 to 10.5), 5.1 (95% CI 1.2 to 9.0) and 5.3 (95% CI 0.9 to 9.7) respectively. Further analysis showed MDI in the prenatal IDA and non-prenatal IDA groups were similar with supplementation of iron-folic acid (60 mg iron), but significantly lower in the prenatal IDA group with supplementation of folic acid or multiple micronutrients. Prenatal iron supplementation with sufficient iron protects child development even when women’s IDA was not properly corrected during pregnancy (chapter 2).

In a second study, we compared social emotional affect and behavior of three groups of non-anemic 4-year-old children: children with IDA in infancy whose anemia was not corrected before 24 months (chronic IDA, n=27); children with IDA in infancy whose anemia was corrected before 24 months (corrected IDA, n=70), and children who were non-IDA in infancy and at 24 months (n=64). Children’s social referencing, wariness, frustration tolerance behavior and affect were observed in a laboratory setting. The whole procedure was videotaped. Child affective and behavioral display was coded using a time-sampling (5-second segments) coding scheme. Preschool aged children whohad chronic IDA in the first 2 years of life showed affected social emotional behavior. In contrast, children whose anemia was corrected before 24 months were comparable to children who were non-iron deficient and anemic throughout the first 2 years of life in terms of behavior and affect (chapter 3).

Overall, our results indicate that adverse effects can be reduced and/or prevented with iron supplementation during critical periods of brain development.WHO recommends universal distribution of iron-folic acid supplements to pregnant women in developing countries to prevent and treat iron deficiency anemia. However, pregnant women are often deficient in several other nutrients concurrently, all of which can negatively affect their own health as well as their infants’ health, growth and development across the life course. Multiple micronutrient supplements containing iron and other micronutrients should be more efficient to help to reduce anemia, because other nutrients often lacking in the diets of pregnant women in poor populations, including vitamin A, riboflavin and vitamin B6 and B12, are also needed for hemoglobin synthesis. Improving maternal status of multiple micronutrients could also benefit pregnancy outcome, infant micronutrient stores at birth and breast milk content of micronutrients.

In a randomized double blind controlled trial described in chapter 4, we examined the impact of prenatal supplementation with multiple micronutrients or iron-folic acid compared to folic acid alone on birth weight, duration of gestation and maternal hemoglobin concentration in the third trimester. In total 5828 pregnant women were involved. The results suggest multiple micronutrients are as effective as iron folic acid in increasing maternal hemoglobin concentration, birth weight and mean duration of gestation. Our study also shows good adherence can be achieved with multiple micronutrients during pregnancy.

Using 2000 and 2005 Food and Nutrition Surveillance data, we found that complementary feeding practices are suboptimal in both rural and poor rural areas in China, although significant improvements in practices have been made from year 2000 to year 2005.  The percentage of consuming meat/eggs more than 4 times a week among 6-9 months children was only 30%, for other age groups only around 50% or less. The high energy and nutrient requirements relative to body size, the capacity to only consume small amounts of foods indicate that nutrient-dense foods must be provided from 6 months until the second and third year of life. Inclusion of animal products can meet the energy and nutrients gap in some cases, but this increases costs and may not be feasible for the lowest-income groups. Furthermore, the amount of animal products that can feasibly be included are generally not sufficient for iron, calcium and sometimes zinc. Thus strategies to optimize nutrient intake from locally available foods may need to be combined with other approaches such as complementary food fortification in order to fully address the problems of micronutrient malnutrition (chapter 6).

In-home fortification of complementary food is an effective approach to provide additional iron and other nutrients to infants and young children in developing countries. To determine whether iron absorption is enhanced with a mixture of FeSO4 and NaFeEDTA, we conducted an iron absorption study with a crossover design in two groups with children aged 24 to 31 months. A complementary food consisting of millet porridge with cabbage, tofu, and pork-filled wheat flour dumplings was fortified with 2 mg iron as either FeSO4 or NaFeEDTA (study 1) or 4 mg iron as FeSO4 or a mixture of 2 mg each of FeSO4 and NaFeEDTA (study 2). Iron absorption was determined based on erythrocyte incorporation of stable iron isotopes. In study 1, the geometric mean iron absorption(±SD)  was 8.0% (3.1, 20.8) and 9.2% (3.1, 27.0) from food fortified with FeSO4 and NaFeEDTA, respectively. In study 2, iron absorption was significantly higher from food fortified with 4 mg iron as 1:1 mixture of FeSO4/NaFeEDTA than from food fortified with FeSO4 only; the geometric mean iron absorption was 6.4% (3.0, 13.5) and 4.1% (1.9, 8.9), respectively. We concluded that the equal mixture of FeSO4 and NaFeEDTA significantly enhanced iron absorption and can be a strategy to ensure adequate iron absorption from phytate-containing complementary foods (Chapter 5).

The studies in this thesis provide further evidence on the association between IDA during the first critical 1000 days of live and the long-term impact on child development. Our research results and the meta-analysis of 12 randomized controlled trials (including our trial in China) suggest that the daily provision of multiple micronutrients is an optimal approach for pregnant women in developing countries including China in terms of the health outcome of newborns. The benefits of giving at least 30 mg iron daily to pregnant women shown in our study as well as by others  can provide guidance to policy makers on the development of a prenatal nutrient supplementation standard in China. Moreover, enhanced iron absorption from a mixture of FeSO4 and NaFeEDTA as a fortificant supports China’s current practice on the use of NaFeEDTA   for in-home fortification of complementary food.Considering our study findings and research by others, the following research is proposed for the near future. 1) Continuing research into the causal relationship of iron deficiency and child behaviour; 2) Developing of better measurement tools to assess child development; 3) Exploring the causality of anemia in the region.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • Kok, Frans, Promotor
  • Brouwer, Inge, Co-promotor
  • Chen, J., Co-promotor, External person
  • Guansheng Ma, --, Co-promotor
Award date8 Oct 2012
Place of PublicationS.l.
Print ISBNs9789461733825
Publication statusPublished - 2012


  • iron deficiency anaemia
  • preschool children
  • infants
  • child feeding
  • supplemental feeding programs
  • supplementary feeding
  • food supplements
  • fortification
  • china
  • child development
  • cognitive development

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