Effects of Maternal Multimicronutrient Supplementation on the Mental Development of Infants in Rural Western China: Follow-up Evaluation of a Double-Blind, Randomized, Controlled Trial
OBJECTIVE. We investigated the benefits of maternal multimicronutrient supplementation during gestation on the mental and psychomotor development of infants.
METHODS. In a double-blind, randomized, controlled trial, pregnant women (N = 5828) in 2 rural counties in western China were assigned randomly to receive multimicronutrient (5 minerals and 10 vitamins at levels approximating the recommended daily allowance), folic acid plus iron, or folic acid supplementation daily from ∼14 weeks of gestation until delivery. We assessed a subset of the newborns (N = 1305) from the 3 supplementation groups by measuring their mental and psychomotor development with the Bayley Scales of Infant Development, at 3, 6, and 12 months of age. Multilevel analyses were used to compare the mental development and psychomotor development raw scores at 3, 6, and 12 months.
RESULTS. Multimicronutrient supplementation was associated with mean increases in mental development raw scores for infants at 1 year of age of 1.00 and 1.22 points, compared with folic acid only and folic acid plus iron supplementation, respectively. However, supplementation did not increase significantly the psychomotor development raw scores up to 1 year of age.
CONCLUSION. Compared with iron and folic acid supplementation, the administration of multimicronutrients to pregnant women improved the mental development of their children at 1 year of age.
- dietary supplements
- Bayley Scales of Infant Development
- controlled trial
Micronutrient malnutrition is widespread and constitutes one of the main nutritional problems throughout the world.1 Micronutrient deficiencies are among the 10 leading contributors to the global burden of disease.2 Currently, >2 billion of the world's people are estimated to have deficiencies in key vitamins and minerals.3 The majority of the world's people live in low-income countries, and they are typically deficient in >1 micronutrient. Pregnant women tend to have relatively greater requirements for most micronutrients, compared with the general population, and they are more susceptible to the harmful consequences of deficiencies,4 which increases the risk of inadequate intake.
Commonly used, cost-effective strategies to ameliorate micronutrient deficiency are supplementation and fortification. Different micronutrients are provided to pregnant women around the world. However, multiple micronutrients are required simultaneously when the diet is poor. With a view toward overcoming this problem, the United Nations Children's Fund, the World Health Organization, and the United Nations University have formulated a combination of 5 minerals and 10 vitamins (at levels approximately equivalent to the recommended daily allowance) for pregnant women.5 Some trials have revealed benefits of this multimicronutrient, in terms of increasing birth weight and decreasing early infant mortality rates,6–10 but the impact on the functional outcomes of infants is not clear. Therefore, we conducted this population-based, randomized, controlled trial to assess the effects of maternal multimicronutrient supplementation on infant mental development (MD) and psychomotor development (PD).
Study Design and Population
The details of this double-blind, cluster-randomized, controlled trial have been described elsewhere.9 Briefly, we conducted this trial in 2 poor rural counties in western China. We used computer-generated random numbers, stratified according to county and township, and randomly assigned villages to the 3 supplementation groups (daily folic acid, folic acid plus iron, or multimicronutrient supplements) before recruitment. Pregnant women in the same village received the same supplement tablets daily from enrollment until delivery. Women in the folic acid supplement group received 400 μg of folic acid per day, those in the folic acid plus iron supplement group received 400 μg of folic acid and 60 mg of iron per day, and those in the multimicronutrient supplement group received the following multimicronutrients: 400 μg of folic acid, 30 mg of iron, 5 μg of vitamin D, 10 mg of vitamin E, 1.4 mg of thiamine, 1.4 mg of riboflavin, 18 mg of niacin, 1.9 mg of vitamin B6, 2.6 μg of vitamin B12, 70 mg of vitamin C, 800 μg retinol equivalents of vitamin A, 2.0 mg of copper, 65 μg of selenium, 15 mg of zinc, and 150 μg of iodine per day. These amounts are consistent with the suggested composition of multimicronutrient supplements for prenatal use, as recommended by the United Nations Children's Fund, the World Health Organization, and the United Nations University.5 The control group received folic acid only, because it is general practice in China to recommend folic acid supplements (400 μg per day) for pregnant women. The 3 types of supplement tablets were indistinguishable from each other in both appearance and taste, were packaged in the same blister packs of 15 tablets each, and were marked with different expiration dates. The marked codes remained unknown to the investigators and participants until the study was completed. The tablets underwent composition analysis before being distributed. The study was approved by the Committee for Science and Research at Xi'an Jiaotong University.
Eligibility and Surveillance of Pregnancy
Village doctors regularly visited all women of reproductive age who were not already pregnant, menopausal, sterilized, or widowed, to identify new pregnancies (on the basis of a human chorionic gonadotropin urine test), and informed the women and their families about this program. When a newly pregnant woman was identified, she received an initial prenatal care checkup at the township hospital or county hospital. Baseline information was collected and a written consent form was signed or fingerprinted (for illiterate women) at that time. The village doctor then distributed a 15-tablet pack to each enrolled pregnant woman, retrieving the used packs to count the remaining tablets every 2 weeks (1 tablet should have been remaining if the patient was fully compliant). The women were instructed to consume 1 tablet every day, with no other vitamin or mineral supplements unless recommended by a study obstetrician. We organized regular meeting and supervision systems to maximize medication adherence.
Follow-up Monitoring and Data Collection
The pregnant women were monitored at ≥3 prenatal care checkups in different stages of pregnancy. For hospital deliveries, obstetricians provided birth details and anthropometric data. For home deliveries, a field team visited the homes to collect the corresponding birth and anthropometric information for the newborns within 72 hours after delivery. A subgroup of singleton neonates (born between January 2004 and December 2004, the middle 1 year of the total 3.5 years of recruitment until January 2006) was included in the postnatal surveillance. Sample size calculations indicated that a minimum of 1200 infants (400 infants in each group) would be needed to detect a moderate difference of 1.2 (20% of SD) in the mean MD raw score, with 80% power and α = .05.
We assessed the MD and PD of this subgroup of infants until 1 year of age by using the Bayley Scales of Infant Development (BSID), which included items regarding sensory/perceptual acuity, discrimination, memory, early verbal communication, body control, coordination of large muscles, fine manipulation skills, and dynamic movement for different ages of <42 months. These scales have been translated into Chinese and locally standardized to become culturally appropriate. The reliability and validity of these standardized scales have been shown to be satisfactory.11 The BSID were administered at the hospital or the child's own home in a standardized manner, when the infant was not hungry, sleepy, or restless, by rigorously trained examiners who had demonstrated high levels of consistency with each other. The examiners, participating women, and researchers administering the interventions were all blinded successfully with respect to treatment group. It was intended that the infants would be assessed at 3, 6, and 12 months of age; however, because of logistic problems, this schedule could not always be followed. If the infant was ill, was unavailable, or would not cooperate, then another assessment was arranged for a later date. The data were grouped for analysis around the scheduled time points.
The MD and PD raw scores signify the items that a child passes on the MD and PD scales of the BSID, respectively. The MD index scores are nonlinear transformations of the raw scores, by using standard procedures that are based on data for US children.12,13 Although we have a standard procedure adapted for urban Chinese children, our preliminary results revealed different developmental trajectories for urban children and rural children. Therefore, the MD and PD raw scores were compared in the final analyses.
We obtained information regarding the participating pregnant women, birth outcomes, and development of the infants in individual files and linked them with unique numbers. The data were checked manually for completeness at different times and were double-entered into a data management system. We subjected the data to range checks and logical checks for accuracy; in the case of any inconsistencies, recorders were sent back to the field within a few days. The primary analyses were based on intention to treat. Baseline characteristic of subjects were compared across treatment groups by using analysis of variance or χ2 tests. Because of the multilevel structure of the data and the sampling method, a 4-level analysis was developed to compare the MD and PD raw scores, with county set to level 4, township to level 3, village to level 2, and individual to level 1. The multilevel model approach seems to be a good method for analyzing data with a hierarchical structure, and it can be applied in cluster sampling investigations.14 Analyses were conducted with SPSS 12 (SPSS, Chicago, IL). MLwiN 2.0 (Institute of Education, London, England) was used for the multilevel modeling.
Estimations of the mean differences and 95% confidence intervals (CIs) were made according to the categories of supplementation and were adjusted for potential confounding factors. All reported P values were 2-tailed, and values of <.05 were considered to be statistically significant.
We considered the following variables as potential confounders in the multivariate adjusted analysis: infant's age, gender, gestational age at birth, Apgar scores at 1 and 5 minutes, birth weight, and history of pathological jaundice and pneumonia, mother's age at delivery, BMI at enrollment, educational level, and occupational class, number of supplement tablets consumed, father's educational level and occupational class, and family's socioeconomic status. Age-adjusted analyses were also conducted.
Interactions between micronutrient supplementation and confounders were tested through the addition of cross-product terms to the multivariate model. To minimize the possibility of low supplementation, we repeated the analyses after stratifying the data according to the number of supplement tablets consumed (<150 or >150 tablets). Analyses stratified according to gender, gestational age, and mother's age also were conducted.
Figure 1 shows the profile of this trial. A total of 5828 pregnant women from 531 villages were enrolled in the study, and these women gave birth to 4864 children. A subgroup of 1305 newborns was monitored, including 471 infants of mothers who received folic acid supplements, 438 infants of mothers who received folic acid plus iron, and 396 infants of mothers who received multimicronutrients. Ten infants (0.8%) were lost to follow-up monitoring, 63 infants lacked 2 of the 3 assessments in the appropriate month, 237 infants lacked 1 assessment in the appropriate month, and 995 infants (76%) were assessed on all 3 occasions at the appropriate ages.
Table 1 shows the baseline characteristics of the pregnant women and their infants. The values for mean gestational age of the fetus at enrollment, mean gestational age at birth, mean age of the mother at delivery, mean BMI at enrollment, and mean birth weight of the child were similar. The mean numbers of supplement tablets consumed were also very similar, that is, 170 in the folic acid only group, 172 in the folic acid plus iron group, and 170 in the multimicronutrient group (P = .68, analysis of variance). The proportions for the educational level and occupational classification of the parent, gender of the newborn, socioeconomic status (considering the house type and property in the household as 2 proxy measures), and history of pathological jaundice or pneumonia were comparable. The mean Apgar scores of the infants at 1 and 5 minutes after birth were significantly different among the 3 treatment groups, but the absolute differences were small. No important adverse event or side effect was reported for any of the treatment groups.
With adjustment for the children's age, there was no significant difference in MD and PD raw scores among the different supplementation groups at 3 and 6 months of age. At 12 months of age, the mean MD raw scores were 104.42 points (95% CI: 103.8-105.1 points) for the multimicronutrient group, 103.22 points (95% CI: 102.6-103.8 points) for the folic acid plus iron group, and 103.33 points (95% CI: 102.7-103.9 points) for the folic acid only group (Table 2). Infants of mothers who received multimicronutrient supplementation had a higher mean MD raw score than did those in the other 2 groups. The increases in the MD raw scores were 1.09 points (95% CI: 0.22–1.97 points) and 1.20 points (95% CI: 0.32–2.08 points) in comparison with the folic acid only and folic acid plus iron groups, respectively. No significant increases in the PD raw scores at 12 months of age were found for the multimicronutrient group, compared with the folic acid and folic acid plus iron groups.
The multivariate-adjusted results did not change substantially when we included the potential confounders in the analysis (Table 2). Multimicronutrient supplementation was associated with a positive effect on children's MD, increasing the mean MD raw score at 12 months by 1.22 points (95% CI: 0.32–2.12 points) in comparison with the folic acid plus iron group and by 1.00 points (95% CI: 0.12–1.89 points) in comparison with the folic acid only group (P = .02). The mean PD raw score at 12 months of age for the multimicronutrient supplementation group was similar to those for the folic acid plus iron group and the folic acid only group, with mean differences of 0.34 points (95% CI: −0.10 to 0.79 points) and 0.26 points (95% CI: −0.18 to 0.69 points), respectively.
When the data were stratified according to the number of supplement tablets consumed, gender, gestational age at delivery, and mother's age at delivery, the results revealed that daily, oral, multimicronutrient supplementation during pregnancy was consistently associated with increases in infants' MD raw scores at 12 months of age, particularly for mothers who consumed ≥150 tablets, male infants, and younger mothers (mother's age at delivery of <24 years) (Table 3). No interaction between supplementation and corresponding confounders was noted when we performed additional analyses for interactional effects (data not shown).
In this population-based, double-blind, randomized, controlled trial conducted in rural western China, we found that maternal multimicronutrient supplementation improved MD in children at 1 year of age, compared with folic acid supplementation alone or folic acid plus iron supplementation, but did not affect PD significantly. The effects were robust, when adjusted for potential confounders or limited to stratified subcategories.
The multimicronutrient supplementation in our study was composed of 5 minerals and 10 vitamins and has been tested in several populations. The benefits of this maternal supplementation on mothers' and children's health were demonstrated previously, in terms of increased birth weight in randomized, controlled trials conducted in Guinea Bissau, Nepal, Zimbabwe, and China,6–9 prolonged gestational periods in Zimbabwe and China,8,9 and reduced early infant mortality rates in Indonesia.10 The positive effects persisted into childhood, with increases in both weight and body size at 2.5 years of age.15 In contrast, a study in Mexico failed to reveal benefits in either birth weight or length.16 The only study related to infant cognitive development suggested small benefits of early food and multimicronutrient supplementation for 7-month-old infants of low-BMI mothers in Bangladesh.17 The present study has provided new evidence for the benefits of micronutrient supplementation with respect to infant mental and PD at 1 year of age.
There is evidence that different micronutrients play a role in children's MD. Previous studies and reviews suggested that iodine deficiency is associated with poor development18 and iodine deficiency during pregnancy has negative effects on the developing fetus and MD of the offspring.19,20 Conversely, no effect of zinc supplementation alone, at daily doses of 25 mg and 30 mg, on children's MD and PD has been found.21,22 Similarly, weekly supplementation with vitamin A in addition to iron during gestation was found to have no effect on MD or PD.23 However, there is evidence that multiple vitamins administered together result in a significant improvement in PD.24 Multimicronutrient supplementation is hypothetically preferable to supplementation with folic acid plus iron or folic acid alone; our results make an important contribution in support of this supposition.
A long-term, follow-up study of a randomized, controlled trial from Australia involving 420 pregnant women who received 20 mg of iron daily from 20 weeks of gestation until delivery failed to demonstrate any significant benefits in the intelligence quotient and behavior of their children at 4 years of age, compared with placebo treatment.25 This result was consistent with a previous systematic review of randomized, controlled trials, which concluded that iron supplementation improves MD scores modestly and has no convincing effect on the intelligence test scores or the PD scores of children <27 months of age.26 Similarly, our results revealed that iron plus folic acid supplementation did not show additional benefits in MD and PD, compared with folic acid alone. Furthermore, the amount of iron used for the iron plus folic acid group was 60 mg, which was twice that used for the multimicronutrient group. Our data thus provide additional evidence against an association between gestational iron supplementation and infant MD. No clear cause-effect relationship between iron deficiency and subsequent cognitive or behavioral performance has been demonstrated.27
Although our trial showed a statistically significant effect on infant MD, the degree of improvement was relatively small, representing a ∼6-day advance in development at 1 year of age. Our findings and similar previous results17 suggest that prenatal multimicronutrient supplementation makes a relatively limited contribution to the MD and PD of infants.
Our study had several strengths. It was a randomized, controlled trial, our subjects were recruited from the general population, our sample size was appropriate, and we achieved a high retention rate.
Our study also had certain limitations. First, the randomization method we used was based on villages rather than individual women, which might have introduced a larger random error. However, we included a large number of villages (N = 531) and the average number of subjects in each village was small, which minimized the potential for random error. Randomization was performed with approximately equal distribution, to ensure balance across the groups, and a multilevel model was used to accommodate the cluster sampling method. Second, the design of this study did not enable us to identify which micronutrient (or combination of a few) made the major contribution to the beneficial effect observed, because all of the nutrients were contained within the same tablet. Third, we did not include all possible confounding variables (such as smoking, alcohol use, and energy consumption) in our analysis, mainly because of the very small numbers of smokers and drinkers among women and the low levels of cigarette and alcohol use by women in the study region. Randomization and our large sample size likely resulted in balancing of these confounders across the groups. Finally, the follow-up period was relatively short and the predictive relationship between BSID scores at 1 year and long-term MD was relatively poor, which may limit the implications of our findings.
This large, population-based, randomized, controlled trial indicated a positive effect on the MD of children at 1 year of age as a consequence of maternal multimicronutrient supplementation. Additional long-term studies are needed to evaluate the effect of this multimicronutrient formula.
This work was supported by a grant from the National Natural Science Foundation of China (grant 30300287) and a grant from the United Nations Children's Fund (grant YH101-H12/03). Neither of the funding sources had any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication.
We are indebted to Dr Liu Xiaohong for training and supervising the testers and to Lin Dongtao for editing the manuscript. We also thank all of our supervisors for their tremendous efforts in maintain the quality of our data.
- Accepted December 22, 2008.
- Address correspondence to Hong Yan, MSc, Division of Epidemiology and Biostatistics, Department of Public Health, Xi'an Jiaotong University School of Medicine, 76 Yanta West Rd, Xi'an 710061, China. E-mail:
This study has been registered as an International Standard Randomized Controlled Trial (no. ISRCTN08850194).
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Evidence shows that multimicronutrient supplementation during pregnancy can increase birth weights, prolong gestational periods, and decrease early infant mortality rates. However, the effects on the functional outcomes of infants remain unclear.
What This Study Adds
We found that multimicronutrient supplementation was associated with significant improvement in the MD of infants at 1 year of age, compared with folic acid only or folic acid plus iron supplementation.
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