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Community and International Nutrition
Research Communication

Subclinical Prenatal Iodine Deficiency Negatively Affects Infant Development in Northern China^1,2

Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ 07102 and ^* Feinstein Center for a Hunger Free America, University of Rhode Island, Providence, RI 02903

³To whom correspondence should be addressed. E-mail: naseem{at}axon.rutgers.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Although mild-to-moderate levels of iodine deficiency (ID) have been associated with poor cognitive outcomes in children, little is known about subclinical prenatal ID and infant development. In this study, the association between elevated cord blood thyroid stimulating hormone (TSH, thyrotropin) and infant development was examined in Northern China. Three groups of infants with elevated cord blood TSH were compared with infants with normal TSH levels on an information processing task at 7 mo, and in cognitive and motor developmental assessments at 13 mo. Infants with elevated TSH had poorer information processing skills and lower scores on the cognitive development index. There were no differences in motor abilities. Relationships between socioenvironmental factors and iodine status were assessed. Infants from more rural settings and those whose mothers had completed fewer years of schooling and had lower paying occupations had higher cord blood TSH levels. A regression analysis indicated that maternal education was predictive of cognitive performance among infants with elevated TSH but not control infants. The findings suggest that subclinical prenatal ID has negative effects on infant development and that, in some instances, maternal education may ameliorate these effects.

KEY WORDS: • prenatal iodine deficiency • infant development • cognitive performance

Approximately 1.6 billion people in the world are at risk for iodine deficiency (ID);³ of these, 50 million are children (1–3). ID poses a substantial public health problem worldwide including parts of Europe, Asia, Africa and South America (1). In China, 460 million people live in iodine-deficient areas, 6 million children are born annually in ID areas and 8 million individuals suffer from goiter, an indicator of ID (4). The effects of severe maternal ID on infant development are well documented (1,2,4,5) and studies have demonstrated an association between mild-to-moderate levels of ID and cognitive and growth outcomes in adults and school-aged children (1,6–8). However, little is known about how to reliably assess levels of ID during gestation; even less is known about the effects of mild prenatal ID on early infant development. The purpose of this report was to present findings from a retrospective pilot investigation on the association between prenatal ID as measured by cord blood thyroid stimulating hormone (TSH, thyrotropin) and cognitive and motor development in 7- and 13-mo-old infants.

Current understanding of the association between ID and development is limited by the characteristics of the population studied. Frequently, studies compare the development of infants from endemic areas in which new cases of cretinism are still evident, with infants from nonendemic areas in which cretinism has been eliminated. In most cases, these areas are not comparable in terms of social and environmental factors and studies rarely control for potentially confounding effects (e.g., maternal education and socioeconomic status). For example, studies have shown that socioeconomic status, parental education and occupation directly affect infant cognitive and behavioral development (9).

In addition, much of the research on ID has focused almost exclusively on brain development because of the assumption that iodine deficiency disorders are not associated with socioenvironmental factors such as poverty. Inherent in this argument is the understanding that the presence or absence of iodine depends on geographical conditions such as iodine availability in the soil, thus affecting individuals in a region irrespective of economic and social status. This is in contrast to nutritional deficiencies such as protein energy malnutrition, which are commonly understood to be confounded by the economic and cultural conditions of a region [for review, see (9)]. However, with the advent of iodized salt and other policy efforts aimed at modifying iodine intake, variations in the use and availability of iodized salt may be based on environmental factors. For example, iodized salts are more readily available in urban compared with rural communities and are often more expensive than noniodized salts (10,11). Both of these factors would place lower income and rural families at greater risk for ID.

The present study used elevated cord blood TSH as the key index of prenatal ID to assess the effects of ID on cognitive and motor development in 7- and 13-mo-old infants. A retrospective design was used to compare three groups of infants with varying levels of elevated cord TSH with control infants with normal levels of cord TSH (iodine replete). Information processing, and cognitive and motor development were assessed. In addition, the relationships between TSH, socioenvironmental factors (e.g., parental education, parental occupation and place of residence) and cognitive and physical development were assessed.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Participants.

Between June 1993 and December 1997, infants (n = 284) from a nonendemic region of Northern China were selected to participate in this study. Infants were assigned to one of four groups depending on cord TSH⁴ levels gathered from hospital birth records (Table 1). Those with TSH levels < 5 mU/L [iodine replete, (12)] were recruited into the nonelevated control group (group 1), whereas infants with TSH levels between 10 and 19 mU/L (group 2), 20 and 29 mU/L (group 3) and 30 mU/L (group 4) were selected to be in the three elevated categories. Information on maternal education, occupation and place of residence was collected at the time of recruitment, and infant birth weight and gestational age were obtained from hospital records. Groups were matched in terms of age, gender and community of residence (urban vs. rural). The gender distribution was approximately the same in all four groups and there were no between-group differences in birth weight or gestational age; all infants had normal birth weights (>2500 g) and were full term (>38 wk gestational age).

Procedure.

Trained research assistants assessed infants in their homes. The infant information processing assessment was conducted at 7 mo of age and developmental assessments were administered at 13 mo of age. This study was approved by the Internal Review Board for Human Subjects from the University of Vermont.

Measures.

Infant information processing was assessed using the Fagan Test of Infant Intelligence (FTII) (13) at 7 mo (n = 275). This is a paired preference visual attention measure that captures early information skills such as recognition memory and speed of processing. Infants are familiarized to a pair of visual stimuli (a face) and then presented with one familiar and one novel stimulus. Introduction of a novel stimulus typically produces preferential looking to the novel image because it contains more information than the familiar stimulus, reflecting both discrimination abilities and memory for the familiar stimulus. The dependent variable is the percentage of novelty preference, i.e., the ratio of the amount of time a child looks at the novel visual stimuli compared with the total exposure time. Higher scores suggest greater novelty preference and more efficient information processing (13). The FTII has good predictive validity and has been shown to be associated with performance on cognitive assessments at 12 y of age (14–16). Studies with high risk groups of infants (those with low birth weight or Down’s Syndrome) have shown that novelty preference scores < 53% reliably predict below average cognitive performance on intelligence tests (13,17).

Infant cognitive and motor development was assessed at 13 mo (n = 135) using the Bayley Scales of Infant Development-II (BSID-II) (18). The BSID-II provides two different indices, one of cognitive development (mental development index; MDI) and one of motor development (psychomotor development index; PDI). Performances on the cognitive and motor indices are compared with an age-equivalent normative population for whom the performance mean is 100 with a 16-point SD.

Cognitive development was assessed by presenting children with a variety of objects requiring them to perform a range of skilled tasks. For example, infants were asked to find toys hidden under cups (memory), respond to spoken requests such as "wave hello" (receptive language) and imitate the actions of the tester such as pushing a toy car or patting a toy. The split half reliability coefficient for the 13-mo age range is 0.88. Concurrent validity is also relatively strong; the manual reports 75% agreement in classification between performance on the MDI and the Denver Developmental Screening Test (version 2).

Motor development was assessed similarly to the MDI and included both fine and gross motor skills. Items assessing fine motor skills included the ability to grasp and pick up small object using finger pads. Gross motor skills included items such as walking alone and standing on one foot. The split half reliability coefficient for the 13-mo age range is 0.84.

Data analysis.

In the first set of analyses, differences among the four TSH groups⁵ for the three outcome measures (7-mo information processing and 13-mo cognitive and motor abilities) were evaluated using a one-way ANOVA. When significant differences (P < 0.05) were revealed, post hoc means analyses were conducted using Fisher’s Least Significant Difference test.

In a second set of analyses, TSH was used as a continuous variable to investigate the linear association between TSH, socioenvironmental factors and cognitive and motor outcomes. First, ANOVA was used to assess whether TSH differed as a function of maternal⁶ education, occupation and place of residence. Pearson’s product moment correlation was used to assess the association between TSH, infant outcomes, and socioenvironmental factors. Preliminary analyses revealed a significant but weak association between performance on the FTII at 7 mo and MDI scores at 13 mo (r = 0.21, P < 0.05), but not PDI (P = 0.90). Maternal education and occupation were highly correlated (r = 0.84, P < 0 0.00). On the basis of previous research demonstrating the importance of maternal education on child development, it was selected as the key socioenvironmental variable for further analysis. Two separate regression analyses were used to predict cognitive outcomes from cord blood TSH, maternal education and their interaction. The criterion variables were novelty preference from the FTII for the first analysis and the MDI score for the second analysis. In both cases the predictions from the interaction term to performance on the outcome measures was tested first. If the interaction term was not significant, it was removed from the model order to assess the predictive association of only TSH and maternal education. All analyses were carried out using SPSS version 11 for Windows (Chicago, IL).

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Cord blood TSH and cognitive and motor development.

The novelty preference score for the four groups ranged from 57.5 to 59.6%, well within the expected range; 97% of infants demonstrated the expected preference for novelty (Table 2). Infants with the highest TSH cord blood concentration (groups 3 and 4) had lower novelty preference than infants in the nonelevated and the mildly elevated (groups 1 and 2; P < 0.05). Similarly, the overall mean MDI score was well within the standard range, and the three elevated TSH groups scored significantly lower than infants in the nonelevated, control group (P < 0.05). There were no differences in performance on the PDI.

Cord blood TSH concentration was higher in infants of mothers who had completed only primary school (P < 0.05) and who were classified as unemployed or a farmer (P < 0.05) compared with all other education and occupation groups (Table 3). The TSH level in infants from rural settings was higher than that in infants from urban settings, (P < 0.05).

The association between cord blood TSH and maternal education in predicting performance on the FTII and the MDI was investigated in regression analyses. Results of the first analysis revealed a main effect for cord blood TSH and maternal education such that infants with elevated cord blood TSH levels and those whose mothers had completed fewer years of school had lower novelty preference scores. There was no interaction between maternal education and TSH in predicting performance on the FTII at 7 mo. In the second analysis, there was a significant main effect of TSH, such that infants with elevated TSH levels had lower MDI scores. More importantly there was a significant interaction between maternal education and cord blood TSH level in predicting performance on the MDI at 13 mo (Table 4). Among infants with elevated TSH, higher levels of maternal education were associated with higher MDI scores, whereas maternal education was not related to performance on the MDI among infants in the control group.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

The relationship between iodine deficiency and poor performance on cognitive tasks has been reported in a number of studies with adults and school-aged children. For example, Huda and colleagues (6) reported performance differences between children with a history of iodine deficiency and normal controls on complex tasks such as reading, spelling, mathematics and an associative learning task, favoring the control groups. Tiwari and colleagues (7) reported a negative association between iodine deficiency and associative learning (e.g., human maze learning and pictorial learning) in children between 8 and 18 y of age. However, to our knowledge, the present study is the first to show that cognitive deficits associated with prenatal iodine deficiency are evident as early as 7 mo of age and that, consistent with previous research (19–22), cord blood TSH is a sensitive indicator of prenatal iodine deficiency.

In this study we were interested in determining whether prenatal ID had consequences for children’s cognitive and motor development, and whether these consequences emerged as a result of a threshold type effect (i.e., a certain amount of deficiency is required before effects can be noted) or whether they were more linear in nature (i.e., a dose-response effect). To assess the threshold hypothesis, individuals were recruited into one of four groups and findings from these analyses were somewhat mixed. That is, the analysis with the FTII showed differences between the two highest and two lowest TSH groups, whereas results from the MDI showed differences between nonelevated and elevated groups. When TSH was utilized as a continuous variable, there was a significant linear association between TSH and performance on both cognitive tasks. The latter result suggests a dose response, i.e., as the level of ID deficiency increases, the poorer the performance on cognitive tasks. However, when the two findings are considered together, they suggest that iodine deficiency in nonendemic regions has consequences for fetal development that are independent of the degree of deficiency. It is important to note, however, that none of the groups performed in the risk range on either the FTII or the MDI.

To our knowledge, this is the first study to use an infant information-processing task, such as the FTII, in an iodine-deficient population, and the results reported here are of particular interest because of the predictive validity of the instrument (14,15,16,23). Research with other at-risk infants (e.g., infants born prematurely or those with low birth weight) (13,23) indicated that 25% of the variance in performance on later (6–18 y) achievement and intelligence tasks can be accounted for by infant information processing assessments such as the FTII (16). Other studies have shown that infant information processing tasks involve cognitive processes such as speed of encoding, recognition memory and attention (14–17,23). The current study revealed that even mild prenatal ID may have long-term consequences for the development of information processing skills (such as attention, recognition memory and speed of encoding) and hence may influence later cognitive abilities.

At the same time, evidence that the development of higher order skills (such as language and relatively simple problem-solving abilities), as assessed by the MDI, may be vulnerable to prenatal iodine levels and that these effects may also be sensitive to external environmental factors, such as maternal education, raises additional questions. Until now, research on ID has assumed that environmental confounders were less important; however, the results presented here suggest that possible adverse effects of mild ID may be ameliorated by socioenvironmental factors such as maternal education. These findings are in keeping with research on nutritional deficiencies, particularly protein energy malnutrition, in which maternal education has been shown to play a protective role in infant development (9,24).

In conclusion, the present study suggests that even mild levels of ID have negative effects on infant development. However, the retrospective, cross-sectional nature of the study precludes our ability to examine the directionality of associations and the mechanisms that may support these relationships. If the present results are upheld in subsequent research, that mild levels of prenatal iodine deficiency have a direct effect on cognitive processes and that these effects are observable at later ages, then public health efforts will have to be expanded to include the consequences of mild ID on later cognitive achievement such as school performance.

	FOOTNOTES

 
¹ Preliminary analyses presented at the Sixteenth Biennial Meeting of the International Society for the Study of Behavioural Development, July 11–14, 2000, Beijing, China [Choudhury, N., Gorman, K. S. & Cheng, B. (2000) Relationship between maternal TSH levels and infant and toddler performance: a cross-sectional study of families in Laioning Province].

² Supported in part by a grant from the Thrasher Research Fund and by funds awarded to the Institute of Endemic Disease, Liaoning Province, PRC by the United Nations Development Programme.

⁴ Abbreviations used: BSID-II, Bayley Scales of Infant Development-II; FTII, Fagan Test of Infant Intelligence; ID, iodine deficiency; MDI, mental development index; PDI, psychomotor development index; TSH, thyroid stimulating hormone (thyrotropin).

⁵ Cord blood TSH is widely used as an indicator of prenatal iodine status, and recent studies have shown that it is an effective method of identifying newborns with abnormal thyroid profiles (25) and by extension, an indicator of prenatal ID. Cut-off values for the 4 groups in this study are based on recommendations from the American Academy of Pediatric (26), WHO, UNICEF and ICCIDD (12,26).

⁶ Initial screening of the data showed that all four TSH groups had acceptable levels of skew and kurtosis.

⁷ Similar information on fathers was also collected; however, paternal data were not associated with infant outcomes and are not presented here.

Manuscript received 2 April 2003. Initial review completed 6 May 2003. Revision accepted 18 July 2003.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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