Iodine status in pregnancy and child neurodevelopment: the influence of genetic variation, selenium status and thyroid function on the relationship

Iodine is an essential trace mineral required to make thyroid hormones that are crucially important for the development of the brain and nervous system of the baby during pregnancy. Though UK authorities believe that iodine intake is adequate, my work and that of others has recently shown that there is a degree of iodine deficiency in the UK, notably in young and pregnant women.

In a preliminary study, we have shown that the level of iodine deficiency in the UK is affecting cognition in the offspring. We measured iodine status in a sub-set of women who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC recruited pregnant women in the 1990s to investigate the effect of environmental factors in pregnancy on child development. Urinary iodine concentration measured during pregnancy showed the group to be mildly-to-moderately iodine deficient by WHO criteria. Children of the 61% of women deficient in iodine had a higher risk of being in the bottom 25% of intelligence quotient (IQ) scores at age 8 and reading accuracy scores at age 9, than children whose mothers were not deficient in iodine.

The overarching aim of this project is to investigate factors that influence maternal iodine status and the consequent effect on child neurodevelopmental outcomes. The project will also develop methods of identifying iodine deficiency in individuals in the clinical setting.

The project will extend the ALSPAC work to include a greater number of outcomes (e.g. hearing and behaviour) and to explore other influences on the observed relationships, such as genetic variation in relevant pathways, maternal selenium status and maternal thyroid function. There are no data on genetic variation in relevant pathways that may influence urinary excretion of iodine and therefore affect the iodine concentration of a urine sample (UIC). This is an important consideration for research that uses UIC to classify women as having adequate or deficient levels of iodine, as we have done in our ALSPAC study. The ALSPAC data set includes the results of a large genome-wide association study (GWAS) of the mothers and this data will be used to evaluate whether there are genetic variations in pathways that are associated with iodine levels in the urine and if these genetic variations then have a subsequent effect on the relationship with child outcomes.

In addition to iodine, selenium is also important for thyroid function and, much like iodine, selenium intake is low in the UK. It is therefore possible that maternal selenium status interacts with maternal iodine status to affect thyroid function and childhood outcomes, though this has not been explored; these relationships will be investigated in relation to child developmental outcomes in ALSPAC. I will also investigate whether the low dose of selenium that was used in the "Selenium in Pregnancy Intervention" (SPRINT), had an effect on thyroid antibodies and maternal thyroid function during pregnancy, a time when adequate thyroid hormone supply is critical for brain development.

Though the findings from ALSPAC are important for understanding the role that iodine and related factors have in fetal brain development, their importance is limited by its being an observational study that cannot prove causality. I will be involved with two trials of iodine supplementation on measures of child cognition; one trial will be in pregnancy and the other in schoolchildren.

Finally, as there is currently no method for diagnosing iodine deficiency in individuals, I will explore alternative biomarkers of iodine status in pregnancy and develop a screening tool that can be used in clinical practice to identify those women at risk of iodine deficiency.

Iodine, through thyroid hormones, is crucial for brain development, particularly during pregnancy. Though the UK is considered iodine-sufficient, my work and that of others has shown mild-to-moderate iodine deficiency in UK pregnant women. We have shown that the level of iodine deficiency in the UK is affecting child cognition. Urinary iodine was measured in 951 women of the Avon Longitudinal Study of Parents and Children (ALSPAC) and the group was mildly-to-moderately iodine deficient. Children of the 61% of women deficient in iodine had a higher risk of being in the bottom quartile of IQ scores at age 8, reading accuracy at age 9, and key stage 2 maths scores than children whose mothers were not deficient in iodine.

The overarching aim of this project is to investigate factors that influence maternal iodine status and the consequent effect on child neurodevelopmental outcomes. The project will also develop methods of identifying iodine deficiency in individuals in the clinical setting.

The project will investigate genetic variation in pathways of iodine and thyroid metabolism on measured iodine status in pregnancy and the consequent effect on child outcomes in ALSPAC. Associations between maternal selenium, iodine status and thyroid function will be studied in ALSPAC. The effect of selenium supplementation on maternal thyroid function and iodine status will be evaluated using data from a low-dose (60mcg/day) selenium supplementation trial in UK pregnant women (SPRINT). The fellowship will provide research time required to be involved in two randomised controlled trials - in pregnant women and schoolchildren - to assess the effect of iodine supplementation on child cognition. Finally, as there is currently no method for diagnosing iodine deficiency in individuals, the project will explore alternative biomarkers of individual iodine status assessment in pregnancy and methods to identify those at risk of deficiency in the clinical setting.

WHO WILL BENEFIT FROM THIS RESEARCH?
1) Pregnant women
2) Future generations
3) School children
4) Department of Health
5) The commercial private sector
6) The dairy industry

HOW WILL THEY BENEFIT?
1) Pregnant women will receive evidenced-based dietary information to improve their intake of iodine and prevent iodine deficiency. They will also have the possibility of being screened for iodine deficiency by clinicians, thus enabling appropriate advice to be provided.
2) Future generations as the research has the potential to show that iodine status in pregnancy, in combination with maternal thyroid function and selenium status, is associated with neurodevelopment.
3) If the iodine supplementation in schoolchildren shows that there is a benefit on cognition and therefore school performance, school children will benefit from greater academic attainment and therefore greater earning potential. This would have a benefit on the whole country, as an increase in IQ is associated with GDP.
4) Policy makers and government will have evidence-based information to inform the public and develop policies to their benefit. The UK does not currently monitor the iodine status of the population, and this is partly because the adverse consequences of mild iodine deficiency are not well documented, thus there is little obvious benefit to the cost associated with urinary iodine concentration monitoring. This fellowship has the potential to provide further evidence of the risks associated with mild iodine deficiency in the UK and therefore provide Government bodies with the evidence required. In Australia and New Zealand, there has been a re-emergence of iodine and in 2009, it became mandatory for Australian and New Zealand bakers to replace ordinary salt with iodised salt in bread baking and there has been a notable improvement of iodine status of the population. The Fellowship, through the iodine supplementation study in schoolchildren, may provide the evidence that the UK should follow the example of New Zealand and Australia.
5) Dietary supplement companies will have an impetus to develop a specific iodine supplement as there is currently no such supplement on sale in the UK. There will be an opportunity to develop functional foods sold on the basis of increased iodine content.
6) Milk is considered to be the principal source of iodine in the UK and the Fellowship is likely to provide further evidence that this is the case. In addition, the fellowship may show the benefits of improved iodine supply, which the dairy industry can then use to market their products as rich iodine sources and thus of nutritional benefit.

TIME FRAME
Government action, such as the mandatory use of iodised salt in bread-making, will take some time but the publication of results from the Fellowship will hopefully provide an impetus for change. Advising pregnant women to take an iodine-containing supplement (as is done in the US, Australia and New Zealand) will also take time to implement as this will require waiting for the results of the trial (WISP) in 2020. However, dietary advice to pregnant women can be changed promptly following the publication of my results. Other countries provide information on iodine during pregnancy, for example New Zealand and Australia, and therefore UK pregnancy advice can rapidly be brought in line with these countries by using the results generated from the dietary aspect of the Fellowship project. The screening tool can start to be implemented following publication of the methodology, and combined with improved information on iodine available to health professionals and pregnant women, it is possible that the iodine status of UK pregnant women could be improved within 2-3 years of the publication of results. The commercial sector and the dairy industry will be able to benefit very quickly from the findings of the fellowship project by making changes in product formulations and information on websites respectively.