Iodine as Essential Nutrient during the First 1000 Days of Life

1Thyroid hormones intervene directly or indirectly in many metabolic and developmental processes such as thermal and metabolic regulation, somatic growth and development and function of the central nervous system (CNS). Iodine requirements during gestation increase to fulfil both foetal needs and altered maternal thyroid physiology.

2Iodine is considered to be an essential micronutrient as it is obtained exclusively through diet or iodine supplements, and it cannot be replaced by any other nutrient in human development. This essentiality becomes even more obvious in the early stages of intrauterine life since adequate iodine intake in pregnancy is needed to achieve optimal foetal neurodevelopment. The foetus, followed by the young child, is the most vulnerable to iodine deficiency (ID).

3For years, it was believed that ID was a problem restricted to certain geographic areas and specific individuals (e.g., malnourished) and that it resulted in a well-defined clinical spectrum (hypothyroidism, goitre and brain damage). However, the re-emergence of iodine deficiency in some industrialized countries has reawakened concern about the cognitive consequences of this deficiency.

4Foetal programming is a concept that links nutritional and environmental conditions during embryonic and foetal development with risk of diseases in later life. The first 1000 days of life have been established as a “window of opportunity” for potential interventions able to determine crucial pathways of human growth and development.

5The aim of this review is to summarize the current knowledge from both animals and human studies on iodine deficiency as a key factor in foetal programming, particularly, on brain development and neurological or behavioural disorders, such as lower intelligence quotient (IQ) or attention deficit hyperactivity disorder (ADHD).

6We searched MEDLINE, EMBASE and Web of Science using the following MeSH terms as inclusion criteria: iodine, iodine supplementation, children, foetus, neurodevelopment, brain, cognitive function. These results were then divided into experimental studies (summarised in Table 1) and studies in humans.

7An additional search was performed to assess the potential effectiveness of iodine supplementation during pregnancy and childhood on cognitive and neuropsychological outcomes, including only the information obtained from systematic reviews and meta-analysis (Table 2). Since the inclusion criteria was the study design, the review included information from areas of mild to moderate iodine deficiency as well as severe iodine deficiency. Eleven studies met the inclusion criteria and there were no studies to exclude.

8Pregnancy is accompanied by significant changes in thyroid function, resulting from a complex combination of factors specific to gestation that together stimulate the maternal thyroid gland. During the first half of gestation, human chorionic gonadotropin produced by the placenta has an effect resembling that of thyroid-stimulating hormone (TSH) (due to the structural homology between the molecules) and acts to stimulate directly the maternal thyroid. During this period, the foetal thyroid is inactive so the foetus is entirely dependent on thyroxine of maternal origin. Despite the fact that the foetal thyroid begins to function from 18 to 20 weeks of gestation, iodine supply still remains solely through the mother.

9Pregnancy involves a higher demand for thyroid hormones. In healthy pregnant women with an adequate iodine intake, the thyroid gland regulates the release of hormones to achieve a new balance and maintains this balance until the end of the gestational process. In general, the higher hormone need can only be met by a proportional increase in hormone release, which depends directly on the intake of iodine through the diet.

10The adaptation to increased iodine nutritional needs is achieved without difficulty by the thyroid gland when intrathyroidal iodine stores are sufficiently replete. Conversely, when the thyroid gland responds inadequately (due, for instance, to iodine deficiency), such changes in thyroid requirements may not be adequately met and adaptation mechanisms cannot succeed. Obviously, the more severe the iodine deficiency, the more serious will be the foetal and maternal consequences. An inadequate thyroidal response has even been shown to occur in healthy pregnant women residing in areas where iodine deficiency is not greater than mild-to-moderate.

11Since the first epidemiological studies conducted by Pharoah and Thilly in the 1970s, the association between severe iodine deficiency in pregnant women and foetal neurological damage has been extensively reviewed and demonstrated in the scientific literature.

12For a long time, it was believed that the main factor responsible for alterations in foetal neurological development was maternal hypothyroidism (defined as elevated serum TSH concentrations with low free thyroxine (FT4) in the early stages of pregnancy. Thus, when a pregnant woman was found to have normal thyroid function, neurodevelopmental alterations in the foetus were thought to be unlikely.

13However, for the last two decades, epidemiological and experimental studies have demonstrated that foetal neurodevelopment is not only affected when the mother is hypothyroid, but also when she is “hypothyroxinemic” in the early stages of pregnancy. Isolated hypothyroxinemia in pregnancy is defined as the presence of a free thyroxine (FT4) value below the 2.5th percentile with a thyrotropin (TSH) level within the reference range. The damage is caused by decreased availability of maternal T4 to the developing brain. Figure 1 shows the differences between the classic and current understanding of the physiology of prenatal iodine deficiency.

14In all mammalian species, the placenta actively transports iodide from the maternal to the foetal circulation to provide iodide for thyroid hormone synthesis.

15Under normal conditions, embryonic tissues have a set of security mechanisms to protect their development. Some of these mechanisms are physical barriers (placenta and ovular membranes) that avoid free transfer of maternal thyroid hormones to the foetus, preventing it from being exposed to the same plasma fluctuations that occur in the maternal bloodstream. Another security mechanism is the presence of deiodinase enzymes in the placenta and foetal cerebral tissues. Deiodinase enzymes, particularly type 2 (DIO2) present in the developing brain, convert maternal fT4 to tri-iodothyronine (T3), since the direct transfer of maternal T3 is extremely low.

16In nutritional iodine deficiency, the organism activates self-regulating mechanisms such that T3 is synthesized preferentially over T4 as a way to conserve iodine. This leads to maternal hypothyroxinemia, where plasma T4 levels fall, but circulating T3 and TSH levels remain normal.

17Maternal hypothyroxinemia appears in healthy pregnant women (without any clinical signs or underlying thyroid pathology) and indicates maternal inability to transfer adequate T4 to the embryo for its proper neurological development.

18Maternal hypothyroxinemia during the first half of gestation has been associated with permanent and irreversible neurological alterations in the embryo and the foetus. Experimental animal studies have contributed to a better characterization of cerebral areas affected by inadequate availability of fT4 (Table 1).

19Traditionally, it was thought that maternal hypothyroxinemia was exclusively due to a dietary intake of iodine that was inadequate to meet iodine needs during pregnancy. However, recent studies have demonstrated the existence of maternal hypothyroxinemia even in iodine-sufficient areas, possibly in relation to environmental endocrine disrupters, drugs or auto-immune thyroid disease. Whatever the cause, the insufficient supply of T4 to developing neural tissues seems to be the basis of adverse permanent cognitive and or behavioural sequels in the progeny.

20In humans, cerebral cortical development occurs between the 6th and the 24th week of gestation. Thyroid hormones are involved either directly or indirectly in most of the neurodevelopmental processes of the embryo and the foetus. This explains why thyroid deficiency in early pregnancy causes irreversible effects.

21Thyroid hormone receptors have been shown to be expressed profusely both in neurons and in glial cells (astrocytes and oligodendrocytes). At the neuronal level, T3 binds to a thyroid- hormone receptor, activating gene transcription; this favours the expression of certain patterns of genes involved in axonal and dendrite outgrowth, and in synapse formation, myelination, cell migration, and proliferation of specific cell populations. For proper neuronal organization (e.g., synaptic transmission, laminar cytoarchitecture of the cerebral cortex), appropriate interaction with glial cells is required. It is clear that foetal neurodevelopment follows a very precise and constrained sequence of events. The response period of the cell is called “competence”. The same cell will not respond before or after this period. It is also apparent that the maturation sequence is not formed by a succession of independent events, but rather by a cascade where each anomalous event will affect subsequent development.

22It is clear then, that any situation compromising maternal thyroid hormone transfer to the foetus will disturb the neuronal migration process. As a result, neurons will not reach their final destination in the upper layers and their abnormal positioning will cause alterations in the laminar architecture of the cerebral cortex. In biopsies performed in experimental animals, maternal thyroid hormone deficiency was found to cause permanent and irreversible lesions in the cerebral-cortex cytoarchitecture. As with gestational hypothyroidism, hypothyroxinemia causes blurred neocortical layering (Figure 2).

23Once the almost universal involvement of thyroid hormones in the development and proliferation of foetal neural tissue is recognised, it is not difficult to foresee the complex spectrum of neurologic disorders that can be associated with iodine deficiency at the early stages of intrauterine development. The permanent lesions of the cerebral cortex, hippocampus and cerebellum will offer relatively well-defined characteristics:lack of damage at the encephalic trunk or spinal cord will prevent direct motor symptoms, but motor coordination will be altered;lesions will affect higher-order integrative cortical areas with a poorly defined anatomical basis, including silent areas of the associative cortex;there will be no clinical expression during the perinatal period, with later onset of symptoms during infancy or school age;such lesions can hardly be detected by the current techniques for prenatal diagnosis such as ultrasounds or foetal MRI.

24lack of damage at the encephalic trunk or spinal cord will prevent direct motor symptoms, but motor coordination will be altered;

25lesions will affect higher-order integrative cortical areas with a poorly defined anatomical basis, including silent areas of the associative cortex;

26there will be no clinical expression during the perinatal period, with later onset of symptoms during infancy or school age;

27such lesions can hardly be detected by the current techniques for prenatal diagnosis such as ultrasounds or foetal MRI.

28Important population changes (such as salt-iodization programmes, strategies of iodine supplementation or fortification and even silent iodine prophylaxis) have contributed to a progressive eradication of the most severe clinical features of perinatal iodine deficiency. The epidemiology of ID has evolved from goitre and mental disability to a new clinical spectrum of neuropsychological disorders associated with maternal hypothyroxinemia.

29Different reviews and meta-analyses have attempted to quantify the effect of iodine deficiency on cognitive and neuropsychological development in children (Table 2); however, the conclusions differ significantly between reviews as a result of: (i) the inclusion of studies from regions with both severe and mild-to-moderate ID; (ii) differences in study inclusion criteria, with some reviews focusing on the effect of iodine deficiency whereas others evaluated the impact of iodine supplementation or fortification; (iii) different tests used to measure developmental domains; and (iv) simply the year that the review was carried out. It is clear that changes in iodine nutritional status (e.g., from the application of universal salt iodization) over recent decades have substantially modified the significance of the effect of iodine deficiency or indeed of supplementation in targeted populations.

30The most recent study, a randomised, double-blind, placebo-controlled trial of iodine supplementation in mildly iodine-deficient pregnant women from Thailand and India found no effect on child neurodevelopment at age 5–6 years. It should be pointed out, however, that although the median urinary iodine concentration (131 µg/L) classified the women as iodine deficient, in one of the countries (India), pregnant women were actually iodine sufficient (median 188 µg/L); furthermore, both Thailand and India are countries with iodized salt programmes where the general population is iodine-sufficient. It is therefore likely that the women will have entered pregnancy with sufficient thyroidal iodine stores to supply their own needs and those of their foetuses over the course of the pregnancy.

31Considering iodine deficiency as urinary iodine concentration (UIC) below 150 µg/L in pregnant women, two observational studies performed in the UK and Australia have evaluated associations with offspring cognition. In the ALSPAC cohort, children of iodine-deficient mothers (defined as iodine-to-creatinine ratio below 150 µg/g) had a significantly higher risk of suboptimal cognitive outcomes on the subscales of verbal IQ, reading accuracy and reading comprehension at 8–9 years, as well as a mean total IQ that was lower by 3.4 points. In Australia, children born to mothers with UIC below 150 µg/L had lower spelling scores at the age of 9 years, though the association with grammar and English literacy were attenuated after adjusting for maternal occupation and education. These findings persisted in adolescence in spite of the children growing up in an iodine-replete environment following the introduction of mandatory fortification of bread with iodized salt in 2009. By contrast, the Generation R cohort in The Netherlands, which is iodine-replete, did not find a significant relationship between maternal low UIC and children’s non-verbal IQ or language comprehension, although the effect sizes were similar to those of the ALSPAC study.

32More recently, a population-based observational study from Norway (MoBA) showed that low maternal iodine intake (below the Estimated Average Requirement of 160 µg/day) during pregnancy was associated with child language delay, behaviour problems and reduced fine motor skills at the age of three years. It was notable that iodine supplementation during pregnancy did not show a protective effect.

33In spite of amelioration of the iodine status in the general population of many countries, we are witnessing a new scenario where impaired cognitive outcomes are augmented by a myriad of behavioural disorders such as attention-deficit/hyperactivity disorder (ADHD) or autism. The evidence currently available indicates an increased risk of ADHD in the offspring of mothers with abnormal serum thyroid hormone concentrations during early pregnancy; ADHD has been described in cases of hyperthyroidism iodine deficiency maternal hypothyroxinemia and mild thyroid-hormone insufficiency. The MoBA study in Norway found that a low iodine intake (<200 µg/L) was associated with higher ADHD symptom scores, but not with the diagnosis of ADHD. Although iodine supplements during pregnancy were more effective than levothyroxine (LT4) in a pilot study aimed at improving neuro-intellectual outcomes, they did not reduce the risk of ADHD. Indeed, the MoBA study showed a negative association between multivitamin/mineral supplements containing iodine and ADHD-like symptoms.

34Additionally, severe maternal hypothyroxinemia in early gestation has been consistently associated with offspring autistic symptoms. Other subtle psychopathological symptoms have been described in areas of marginal ID, i.e., deficits in inhibition, working memory and global executive functioning in children of mothers with low UIC.

35This spectrum of neuropsychological disorders can be understood through a developmental biology approach, where the structural alterations of cortical lamination observed in experimental animal models may help to explain the development of behavioural and mental disorder throughout the life course.

36Iodine deficiency during the early stages of human development leads to antenatal consequences that share similarities with neural tube defects (NTD) due to folate deficiency:for both entities, the nutritional predisposing conditions are known;the mechanisms that trigger morphological alterations are known; in both cases, the neuronal migration process is disturbed. In the case of NTD, neurones are stopped in their migration to the neural crest, whereas in iodine deficiency, neurones are stopped in their migration to the upper layers of cerebral cortex (Figure 2).an effective prophylaxis is available, ideally from preconception to the end of neurogenesis.

37for both entities, the nutritional predisposing conditions are known;

38the mechanisms that trigger morphological alterations are known; in both cases, the neuronal migration process is disturbed. In the case of NTD, neurones are stopped in their migration to the neural crest, whereas in iodine deficiency, neurones are stopped in their migration to the upper layers of cerebral cortex (Figure 2).

39an effective prophylaxis is available, ideally from preconception to the end of neurogenesis.

40From the very early stages of pregnancy, iodine requirements and the fT4 levels in maternal serum are modified; the existence of maternal hypothyroxinemia in the first trimester interferes directly with embryogenesis and foetal neurodevelopment. Additionally, recent evidence suggests that maternal hypothyroxinemia has an epigenetic effect in the offspring that potentiates the regulated expression of certain genes through mRNA transcription and/or the downregulation of specific micro RNAs (miRNAs). These facts suggest that ID acts as a chronic nutritional deficiency aggravated by pregnancy and maternal hypothyroxinemia that can imprint cells of central nervous system of the offspring and exert effects postnatally.

41In addition to pregnant and lactating women, children under two years of age have been identified as vulnerable groups for ID by WHO-UNICEF-International Council for the Control of Iodine Deficiency Disorders (ICCIDD).

42New evidence supports a life-course perspective on childhood development with adverse early experiences having long-term physiological and epigenetic effects on brain development and cognition. In this regard, iodine plays a pivotal role that substantially contributes to postnatal development and plasticity of neural tissues.

43Although the effects of prenatal ID cannot be completely overcome by iodine supplementation in children, intervention trials have shown that providing iodine alone or in combination with other micronutrients in populations with concurrent deficiencies can provide infants and young children with adequate micronutrient requirements.

44A recent randomised, double-blind, placebo-controlled trial compared the effectiveness of direct iodine supplementation in infants with indirect iodine supplementation (by providing iodine supplements to breastfeeding mothers) and found that the latter was more effective. In areas of moderate-to-severe ID without effective iodised salt programmes, iodine supplementation for lactating mothers should be therefore considered.

45“Nurturing care” is the term that has been coined to include nutritional, environmental and emotional support to promote the development of key brain regions that will have lifelong benefits, including improved health and wellbeing, and increased ability to learn and earn. It seems obvious that adequate iodine intake is essential for this goal to be reached, but it should be realised that the effectiveness of iodine supplementation is dependent on its use during multiple and overlapping critical time-windows when development of specific capacities and abilities can most powerfully be enhanced.

46Iodine is an essential nutrient, particularly crucial for the neurodevelopment. In spite of the limitation of a non-systematic review, the main strength of this review is that we have gathered the most substantial information from both animals and human studies, in order to provide a fuller understanding of the role of iodine in brain development and the potential consequences of its deficiency at the early stages of human life.

47Pregnancy involves a higher demand for thyroid hormones, which may not be adequately met even in healthy pregnant women residing in areas where iodine deficiency is not greater than mild-to-moderate. Foetal neurodevelopment is not only affected when the mother is hypothyroid, but also when she is “hypothyroxinemic” in the early stages of pregnancy and studies have demonstrated the existence of maternal hypothyroxinemia even in iodine sufficient areas. In all mammalian species, the placenta actively transports iodide from the maternal to the foetal circulation to provide iodide for thyroid hormone synthesis. Any situation compromising maternal thyroid hormone transfer to the foetus might lead to permanent lesions of the cerebral cortex, hippocampus and cerebellum. In spite of amelioration of the iodine status in the general population of many countries, we are witnessing a new scenario where impaired cognitive outcomes are augmented by a myriad of behavioural disorders such as attention-deficit/hyperactivity disorder (ADHD) or autism. In summary, Iodine deficiency acts as a chronic nutritional deficiency aggravated by pregnancy and maternal hypothyroxinemia that can imprint cells of central nervous system of the offspring and exert effects postnatally. Iodine also plays a pivotal role that substantially contributes to postnatal development and plasticity of neural tissues.