#acl 4498E,4497E,4502E:read,write Default = Effect of iodine deficiency on fetal development during pregnancy = <> Iodine is an essential part of life. This micronutrient is required for the biosynthesis of thyroid hormones and contributes to normal growth and development. The body itself cannot produce iodine, and we are therefore at risk of experiencing deficiency if our diet doesn't reach the requirements. Pregnant and lactating women are particularly vulnerable, due to increased iodine demand [[#kilde1|(Toloza et al, 2020)]]. According to research, it is estimated that two billion suffer from iodine deficiency. (Andersson et al, 2005) The most visible symptom of the insufficiency is the goiter, an increased size of the thyroid gland. Still, the most common problem is the impaired neurodevelopment, especially in early life [[#zimmermann|(Zimmermann, 2011)]]. When a female is carrying a child the demand for iodine will significantly increase. The reason for this is the amplified production of maternal thyroid and the loss of iodine in the urine. The fetus itself also requires iodine which is another reason why pregnant women must consume more iodine. A maternal iodine deficiency can be classified depending on the severity. It can range from mild defects in motor development, to severe cases resulting in cretinism [[#lee|(Lee and Pearce, 2015)]]. The recommended amount for iodine intake during the different life stages can be seen in ''Table 1. '' ||'''Life stage''' ||||'''Recommended amount''' || ||Birth to 6 months ||||110 mcg || ||Infants 7-12 months ||||130 mcg || ||Children 1-8 years ||||90 mcg || ||Children 9-13 years ||||120 mcg || ||Teens 14-18 years ||||150 mcg || ||Adults ||||150 mcg || ||Pregnant teens and women ||||220 mcg || ||Breastfeeding ||||290 mcg || ''Table 1: Visual representation of recommended amount of Iodine [[#us|(National institutes of Health, 2021)]] '' === Thyroid synthesis === The medical explanation for iodine importance is its effect on the thyroid hormone synthesis. In the thyroid gland there are produced two important hormones, the triiodothyronine (T3) and the thyroxine(T4). They act on almost all cells in the body, affecting protein synthesis, metabolism, and bone growth. Both hormones are partly composed of iodine, and a decrease in the mineral would therefore have a negative impact on the T3 and T4 production [[#kilde1|(Toloza et al, 2020)]]. An active pump mechanism transports iodine into the thyroid. This pump also works as a trap, to capture iodine ions in the thyroid gland. Under normal circumstances this means that there will be 40 times higher iodine concentration in the thyroid gland compared to the blood. But when the body is iodine deficient this gradient can increase to 200 times more iodine! Lysosomal peroxidase converts iodine ion to atomic ion. The atomic ion then binds to the tyrosine residues of the thyroglobulin and monoiodotyrosine (MIT) is produced. With 2 iodine atoms, diiodotyrosine (DIT) is formed. MIT + DIT = triiodothyronine (T3) and DIT + DIT = tetraiodothyronine (T4). These are then endocytosed into the epithelium where they are degraded intracellularly and T3 and T4 are secreted to the bloodstream. Thyroid stimulating hormone (TSH) stimulates almost every step of the thyroid synthesis and storage. Thyroid hormones are essential for many processes in the body. Basic metabolic rate can increase up to 60% in the presence of thyroid hormones, mainly because of the increased activity of NA+/ K+ ATPase. Glyconeogenesis and glycogenolysis are increased, the lipid metabolism is increased as a whole, and the fatty deposit is reduced. In the protein metabolism the thyroid hormones stimulate both synthesis and breakdown of the proteins. In case of a pregnant female, there will be deiodinase which will convert T4 to T3 when it goes through the placenta. In the fetus T3 is the one binding to cell receptors and starts the development of different parts of the nervous system. Therefore, a lack of iodine which results in hypothyroidism can result in an undeveloped neural system in the fetus, which will be permanent [[#toloza|(Toloza et al, 2020)]]. === Range of iodine deficiency in pregnancy === The iodine deficiency outcomes can be looked on as an iceberg, see Figure 2. Where the top and visible part is cretinism which occurs in 1-10% in severe iodine-deficiency. Then you have the part which is “not visible” and under water, which is the less severe brain damage. The part under water is much bigger and occurs in 30% of the cases of iodine-deficiency (Chen and Hetzel, 2010). In other words, the iodine deficiency can be placed on a spectrum. It can range from lesser cognitive defects to different types of iodine deficiency disorders (IDDs´) [[#chen|(Chen and Hetzel, 2010)]]. [[attachment:isberg.png|{{attachment:isberg.png|Figure 1: Visual representation of the severity of iodine deficiency. Most of the cases talked about are the severe ones even though they are not that common as the less severe deficiency|width=400 height=750}}]] ||'''Figure 1''' ''Visual representation of the severity of iodine deficiency. Most of the cases talked about are the severe ones even though they are not that common as the less severe deficiency.'' || === The influence of iodine in the diet and ADHD in children === The severity of ADHD may be influenced by the diet of the pregnant and lactating woman. Deficiency of iodine and certain other minerals and fatty acids may influence the development of the hyperkinetic syndrome significantly. The background behind this claim is their role in the normal development of the brain functions. The conclusion is that among others, chronic iodine deficiency can increase the symptoms of ADHD in children [[#konikowska|(Konikowska et al, 2012)]]. A study from Norway proved that there was an association with low iodine concentration and child language delays, reduced fine movements and behavior problems. The study stated that there was no notable protective effect with iodine supplementation during pregnancy in the case of ADHD. In similarity with the previous study, also this research revealed that the low iodine intake was not associated with the development of the diagnosis, but rather higher scores of ADHD symptoms [[#velasco|(Velasco et al, 2018)]]. === Relationship between thyroid hormones and brain development and cancer === The thyroid hormones regulate the maturation and development of the brain. Hyperthyroidism, as well as hypothyroidism causes abnormalities in both the function and the organization of the nervous system. Genomic and non-genomic effects of the hormone influence the chromatin function, and because of that, it plays a role in several processes of the nervous system, such as controlling metabolism proliferation and maturation. The conclusion is that the relationship between the thyroid hormones and its target organs may lead to cancer proliferation [[#liegro|(Liegro et al, 2021)]]. === Congenital iodine deficiency syndrome (cretinism) === Congenital iodine deficiency syndrome is one of the most severe outcomes of iodine deficiency during pregnancy. At the same time, it's known to be the most preventable cause of brain damage [[#chen|(Chen and Hetzel, 2010)]]. Creationism can be categorized into two groups: neurological and myxedematous, see figure 4. The first and most common is neurological cretinism. Its characteristics are cognitive delay, dysfunctions with speech and hearing, as well as abnormal and uncoordinated movements of the limbs. If the thyroid does not create or release thyroid hormones for a longer period, the second type of cretinism called myxedematous will be induced. Characteristics for myxedematous is abnormal skeletal and body development such as dwarfism, retardation of different body parts and sexual retardation (Toloza et al, 2020). Endemic cretinism is also a term that can be used when it is associated with endemic goitre as well as severe iodine deficiency. Goitre is an enlargement of the thyroid gland, and the term endemic goitre refers to the condition but when it is caused by something else than iodine-deficiency [[#chen|(Chen and Hetzel, 2010)]]. ||'''Features''' ||||'''Myxdematous cretinism''' ||||'''Neurological cretinism''' || ||Mental retardation ||||Present, less severe ||||Present, often severe || ||Deaf mutism ||||Not seen ||||Usually present || ||Cerebral diplegia ||||Not seen ||||Often seen || ||Squint ||||Not seen ||||Often seen || ||Stature ||||Severe growth, retardation usual ||||Usually normal || ||General feature ||||Coarse dry skin and low, rough voice ||||No physical sign || ||Reflexes ||||Long latency ||||Exaggeration of reflexes || ||ECG ||||Small voltage QRS complexes and other abnormalities of hypothyroidism ||||Normal || ||X-ray limbs ||||Epiphyseal dysgenesis: delayed ossification at multiple epiphyses ||||Normal || ||Effect of thyroid hormones ||||Improved ||||No effect || ''Table 2, shows the characteristic differences between myxdematous and neurological cretinism. [[#chen|(Chen and Hetzel, 2010)]]'' === Animal experiment of the effect of iodine deficiency === A pregnant sheep was induced to severe iodine deficiency to be able to see the effects on the fetus. The differences seen at 140 days were significantly different to the healthy control fetus. The fetus from a severe iodine deficiency mother showed weighs less, no wool, enlargement of the thyroid and deformations of bones and skull. The brain was also lightweight, and less DNA was detected. Marmoset, which is a primate, was also experimented on. Iodine deficiency was induced through feed and the newborn showed less hair and a reduction in T4 compared to the control animal. Same un-developments were seen in the brain of the marmoset as in the sheep. These findings show how iodine deficiency can affect the brain of a primate. The same experiment method was used on rats, and the same results were seen: goitre, increased density of brain cells and delayed maturation. With this in the background we can see how underdeveloped the brain will be in different animal species due to iodine deficiency [[#chen|(Chen and Hetzel, 2010)]]. As referred to earlier in the thyroid synthesis the thyroid hormone's presence makes the synthesis of proteins possible. In other words, if there is an iodine deficiency the protein anabolism would also decrease, which would mean less proteins and therefore less muscle mass. The thyroid hormone is also responsible for the myelination and synaptic connectivity between neurons. Without the hormone that would not happen, and we would see severe underdevelopment of the brain. The enlarged thyroid gland is developed when the thyroid gland is unable to secrete thyroid hormones to the bloodstream. This results in higher amounts of TSH as there is negative feedback. This explains why the fetuses has enlarged thyroid gland, less brain weight and weighs less, see figure 2. {{attachment:sau.png|visual representation of how iodine deficiency can look in sheep fetus. A: the mother was iodine deficient. B: the mother had normal concentration of iodine. Redrawn from Chen and Hetzel, 2010|width=400 height=750}} ||'''Figure 2''' ''visual representation of how iodine deficiency can look in sheep fetus. A: the mother was iodine deficient. B: the mother had normal concentration of iodine. Redrawn from [[#chen|Chen and Hetzel, 2010]]'' || === Prevention === The main reason for prevention worldwide is the risk of mental and neurological underdevelopment that can occur in the fetus if the mother is iodine deficient. Iodization of salt is the main prevention for iodine deficiency, and is used for both animals and humans. Where the deficiency is endemic, iodine supplementation can be given if no iodized salt is available. This strategy is an effective one. 110 was the number of countries with iodine deficiency as a public health problem in 1993, in 2003 this number was 54. Checking the salt quality is therefore also an important process to keep the concentration of iodine in the salt not too low nor too high [[#andresson|(Andresson et al, 2005)]]. Lactating, pregnant women and children under 2 years are classified as susceptible groups for iodine deficiency by WHO-UNICEF-International Council for the Control of Iodine Deficiency Disorders. It is proven that children at a young age with iodine deficiencies are more likely to have underdevelopments in their brain and a reduced cognition. A trial proves that in areas with moderate to severe iodine deficiency without iodine salt programs, supplementations of iodine should be considered to the lactating mothers. [[#velasco|(Velasco et al, 2018)]]. [[#ley|Ley and Turck (2021)]] state in their article that there is no scientific evidence that iodine supplementation in mildly to moderately deficient areas will reduce the risk in these areas. Iodine is also used as supplementation in animal feed to increase the iodine concentration in the animal food origin. The poultry industry and its diet are supplemented with iodine in either salt form or in a mineral mix. Iodine is important for the laying hens because it contributes to thyroxine and therefore also in the metabolism. It also influences the growth and performance of the birds [[#opalinski|(Opaliński et al, 2012)]]. Yeast has been used for a long time in animal feeding and is proved to have a good effect on animal production and the animal’s health. It is especially important when the use of antibiotics is decreasing. Iodine enriched yeast has therefore been used in several studies and was collected in [[#opalinski|Opaliński et al, 2012]]. This research wrote that there were no found effects on egg production after increased iodine in the feed. They concluded that higher iodine concentration was found in eggs laid by hens that received iodine-enriched yeast. The use of iodine-enriched yeast could therefore be considered as a supplement to hens to eliminate iodine deficiency in the human population. Dairy products are also a good source of iodine for humans. Milk is one of the most important sources. Therefore, multiple papers have been written about the factors influencing the iodine concentration in milk. The range of iodine concentration recommended is narrow, and preferably the concentration should not be higher or lower. Some factors influencing how much is supplemented are the feeding conditions, housing, temperatures and nipple dipping. Studies have shown that half of the supplemented iodine ends up in the milk. If an animal is just fed on unsupplemented feed and water, it will not meet the iodine concentration requirement. Its therefore important to find the right concentration and factors influencing [[#flachowsky|(Flachowsky et al, 2014)]]. This study concluded that controlling the factors regulating iodine concentration in milk, needs more research to understand the whole metabolism in humans and animals, and to further work against eliminating iodine deficiency. === Conclusion === As mentioned, iodine deficiency can have major consequences on the fetal development during pregnancy. Since our body can’t produce the mineral by itself, pregnant and lactating women are vulnerable for developing deficiency, due to increased iodine demand. The severity can range from mild to severe cases. Several research show the importance of iodine during pregnancy for the fetal development. One example being the experiment about the pregnant sheep which proved that the fetus weighed less, had no wool, had an enlarged thyroid and deformed bones and skull when experiencing deficiency. Luckily iodine deficiency is relatively easy to avoid with the help of the right feed and water. Prevention is therefore key in this case, and a pregnant female should be conscious about the risks if iodine needs are not met. === References === <> Andresson M, Takkouche B, Egil I, Allen HE, Benoist B (2005): Current global iodine status and progress over the last decade towards the elimination of iodine deficiency. Bulletin of the World Health Organization 83: (7) 518-525. <> Chen ZP, Hetzel BS (2010): Cretinism revisited. Best Pract Res Clin Endocrinol Metab 24(1):39-50 <> Flachowsky G, Franke K, Meyer U, Leiterer M, Schöne F (2014): Influencing factors on iodine content of cow milk. Eur J Nutr. 53(2):351-65. <> Konikowska K, Regulska BI, Różańska D (2012): The influence of components of diet on the symptoms of ADHD in children. Rocs Panstw Zakl Hig 63(2): 127-34 <> Lee SY, Pearce EN (2015): Reproductive endocrinology: Iodine intake in pregnancy--even a little excess is too much. Nature reviews. Endocrinology, 11(5), 260–261. <> Ley D, Turck D (2021). Iodine supplementation: is there a need? Curr Opin Clin Nutr Metab Care. 1:24(3):265-270. <> Liegro CM, Liegro I, Schiera G (2021): Involvement of Thyroid Hormones in Brain Development and Cancer. Cancers(Basel) 30:13(11):2693 <> Opaliński S, Dolińska B, Korczyński M, Chojnacka K, Dobrzański Z, Ryszka F (2012): Effect of iodine-enriched yeast supplementation of diet on performance of laying hens, egg traits, and egg iodine content. Poultry science. 91(7): 1627-1632 <> Toloza FJK, Motahari H, Maraka S. (2020): Consequences of Severe Iodine Deficiency in Pregnancy: Evidence in Humans. Frontiers in Endocrinology 11: (409) <> Velasco I, Bath SC, Rayman MP (2018): Iodine as Essential Nutrient during the First 1000 Days of Life. Nutrients. 1:10(3):290. <> Zimmermann MB (2011): The role of iodine in human growth and development. Semin Cell Dev Biol 22:(6) 645-52 === Other reference materials === <> U.S. Department of Health and Human Services. (2021, March 22). Office of dietary supplements - iodine. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Iodine-Consumer/