User:Minihaa/PhD thesis Iodine nutrition in pregnancy

__INDEX__

Iodine – an essential micronutrient
Like fluorine, chlorine and bromine, iodine is a halogen in the periodic table of elements. The name halogen means “salt producing”, and the halogens react easily to form different salt compounds. Examples are sodium chloride (NaCl) in table salt, and potassium iodide (KI) which is often added in small amounts to salt to increase the iodine intake in populations.

In all vertebrates, including humans, iodine is an essential micronutrient through being an intrinsic component of the thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), p. 26). In fact, this is the only known function of iodine in the human body. Thyroid hormones are important in regulating cell metabolism and in controlling tissue growth and maturation, particularly of the nervous system. The hormones are synthesized in the thyroid gland situated at the front base of the neck.

If iodine intake is adequate, the body of an adult contains about 15-20 mg of iodine, 70-80% of this within the thyroid gland. In a situation of long-term insufficient iodine intake, the iodine store in the thyroid may fall to less than 20 µg. The recommended daily intake of iodine for adolescents and adults is 150 µg/day, and to cover the recommended intake of iodine for a whole lifetime (0-85 years), a total of less than 5 gram (or one teaspoon) of iodine is needed.

Prevalence of iodine deficiency
Iodine is very abundant in the sea, but it is unevenly distributed in the soil. In many regions of the world the natural content of iodine in the soil, farming produce and drinking water is low. The World Health Organization (WHO) estimates that almost 2 billion people worldwide are dependent on iodine fortification or supplementation to prevent iodine deficiency (ID). To monitor iodine status in a population, WHO recommends measuring UIC in a random sample of school aged children. About 90% of ingested iodine is excreted in the urine within 24- 48 hours, and if population median urinary iodine concentration (UIC) falls below 100 µg/L, the population is considered iodine deficient by WHO criteria (Table 1). Tremendous effort has been made during the last few decades to prevent ID, and severe ID has been almost completely eradicated. Still, mild-to-moderate ID remains one of the most prevalent nutrient deficiencies in the world. Surprisingly, Europe is the continent with the highest estimated prevalence of ID and about 1/3 of school aged children have an inadequate iodine intake.

Table 1 Epidemiological criteria for assessing iodine nutrition in population groups based on median urinary iodine concentration by the World Health Organization

a Applies also to adults, but not pregnant and lactating women.

b Excessive, meaning in excess of the amount required to prevent and control iodine deficiency.

In pregnancy, the iodine turnover increases due to an upregulated production of thyroid hormones, transfer of iodine and thyroid hormones to the developing foetus, and an increase in renal clearance. Therefore, iodine recommendations for pregnant women are higher, and a median UIC ≥150 µg/L is the recommended cut-off for defining iodine sufficiency in pregnant women according to WHO. There is, however, a lack of knowledge about what represents the optimal level of iodine intake in pregnancy, and the recommendations vary. In the UK the recommendation is the same as for non-pregnant women (140 µg/day), in the Nordic countries it is 175 µg/day , the European Food Safety Authority recommends 200 µg/day , in the U.S. 220 µg/day is recommended , and WHO recommend 250 µg/day. The U.S. Institute of Medicine has also set an estimated average requirement of iodine for pregnant women of 160 µg/day. In Europe, more than half of pregnant women are probably ID by WHO criteria (see Figure 1). Mild-to-moderate ID in pregnancy can be defined as median UIC of 50-150 µg/L.

Figure 1 Global scorecard on iodine nutrition in pregnant women 2017 illustrating median urinary iodine concentration (mUIC) by country. Published by the Iodine Global Network. Retrieved from http://www.ign.org/cm_data/IGN_Global_Map_PW_30May2017_1.pdf Accessed: 2018-05-07. (Archived by WebCite® at http://www.webcitation.org/6zEimmPjZ)

Thyroid hormones and brain development
A human brain contains of over 80 billion nerve cells (neurons) and more than a hundred trillion contact points between neurons (synapses), p. 185). In addition, a comparable number of non-neuronal brain cells provide support to the brain , p. 24). The “wiring” connecting the nerve cells is estimated to add up to a distance equalling four trips around the world, p. 2), and a typical number of contact points for a single nerve cell is about 5000- 10,000 (19, p. 31). At birth, the human brain already contains most of the neurons it will ever have , p. 190).

Thyroid hormones are essential in guiding the extremely complex process of brain development. They are involved in regulating many key steps such as neurogenesis, cell migration, cell differentiation and synaptogenesis. Disturbances in the levels of thyroid hormones may result in irreversible impairments since the brain-cells develop in a strictly timed sequence of events. Recent evidence suggests that even moderate changes in maternal thyroid function, especially during early gestation, might have negative and irreversible effects on child cognitive development and increase the risk of neurodevelopmental disorders.

Before the foetal thyroid begins to function from gestational week (GW) 18-20, the foetus is entirely dependent on supply of maternal thyroid hormone, especially of T4. Also after GW 20, the foetal thyroid hormone production is not adequate, and the transfer of maternal T4 to the foetus continues until birth. The placental transfer of maternal T3, the active form of the thyroid hormones, is extremely low, protecting the foetus from fluctuations in T3. Instead, T3 is generated locally in the foetal brain from maternal T4 through a process that is tightly regulated. This makes the foetus vulnerable to a low maternal T4. Animal studies have shown that a low maternal T4 is associated with lower foetal brain T3, which in turn is associated with irreversible changes in foetal brain cytoarchitecture characterized by blurred neocortical layering (i.e. nerve cells not reaching their destination causing distortion or blurring in the layers of cells that are usually more distinctly organized). In 2018, Levie et al. published a meta-analysis of individual participant data from three European prospective birth cohorts (INMA, ALSPAC, and Generation R, n=9036 mother child pairs) demonstrating that a low maternal free T4 (FT4) (below the 5th percentile) in the first half of pregnancy was associated with lower verbal and non-verbal child intelligence quotient (IQ). They also found a non-significant, but suggestive association with increased risk of autistic traits. Their results confirmed findings of previous human observational studies. However, no effect on child IQ was seen in two randomised controlled trials (RCTs) investigating T4-treatment (levothyroxine medication) of pregnant women with low T4. Explanations for the null findings may be that the treatment was initiated too late in pregnancy (GW 13-18), the dosage might have been too high, and that the studies were underpowered to detect small changes in IQ.

Consequences of ID in pregnancy
In ID, the pregnancy-related increased demand for thyroid hormones may not be met adequately. Indeed, this is well documented in severe ID which is associated with goitre (adaptive swelling of the thyroid gland), maternal and foetal hypothyroidism (i.e. low levels of thyroid hormones and high levels of thyroid stimulating hormone (TSH)), growth retardation, and serious neurologic and cognitive deficits in children, in addition to increased risk of pregnancy loss and infant mortality.

Less is known about the potential consequences of mild-to-moderate ID which can be defined as a median UIC in pregnant women of 50-150 µg/L. Although the association between iodine intake and thyroid disorders is documented to be U-shaped , and both low and high intakes are associated with increased risks, mild ID is not associated with an increased prevalence of thyroid disorder. However, when iodine intake is marginally low, auto-regulatory processes are effectively initiated in the body in order to save iodine. This includes a shift towards a higher production of T3 at the cost of T4, saving one iodine atom and securing an adequate level of active thyroid hormones in the mother. However, it may at the same time result in a reduced thyroid hormone-supply to the foetus.

Results from two observational studies published in 2013 indicated that even mild-to moderate ID in pregnancy might be harmful and affect child IQ and school performance. However, studies on iodine supplementation in pregnancy in mild-to-moderate ID show conflicting results. This might be explained by several factors. The studies on supplementation varied greatly in design and in iodine status of the study populations. As for the T4 treatment studies mentioned above, most studies on iodine supplementation was initiated after the first trimester, and the first trimester is identified as the time period were the foetus seems to be most vulnerable to maternal thyroid dysfunction. Also, in some studies, rather high doses of iodine supplements were given which may increase the risk of thyroid dysfunction caused by iodine excess. A few studies have indicated that in mild-to-moderate ID, the thyroid seems to be vulnerable to an abrupt increase in iodine supply causing a temporary “stunning effect” with lower maternal thyroid hormone production. Finally, in studies where the median UIC is only slightly below the recommended cut-off for defining adequacy of 150 µg/L, probably very few of the women were truly iodine deficient. This might for example explain the null-finding in the most recent RCT published, an impressive study from India and Thailand following 315 children of supplemented and non supplemented mothers up to age 5-6 years.

Velasco et al. published a review in March 2018 summarizing the available evidence from animal and human studies for the effect of ID on brain development. Animal studies support the human observational studies and show that even mild-to-moderate ID can lead to irreversible changes in brain development. However, effects might be small and difficult to detect in randomized controlled studies in humans that are often limited in size. In 2017, a Cochrane systematic review on effect of iodine supplement use in pregnancy was published, and the authors concluded “There were insufficient data to reach any meaningful conclusions on the benefits and harms of routine iodine supplementation in women before, during or after pregnancy”.

Therefore, although mild-to-moderate ID is highly prevalent in pregnant women, there is still great uncertainty about the potential consequences for child development, about what represents the optimal range of iodine intake for pregnant women, and whether iodine supplements in pregnancy are beneficial in mild-to-moderate ID.

Figure 3 and Figure 4 are reprints of results from a study where rats were fed diets containing different amounts of iodine from three months pre-pregnancy and through pregnancy and lactation, and the offspring were tested for multiple measures of brain development. Results in this study show that even mildly ID diets resulted in reduced motor performance in the offspring (Figure 3), and they also documented changes to cell structures in the brain (Figure 4), and to signalling pathways important for motor coordination. In this study, they found that iodine supplements given to the pregnant rats from day 0 of gestation effectively prevented negative effects of mild ID.

Potential interaction with other nutrients or thyroid disrupting substances Several other nutrients and non-nutrients are also known to affect thyroid hormone signalling. Examples are iron, selenium, zinc, thiocyanate in cigarettes, glucosinolates in cruciferous vegetables, and also a range of pollutants with thyroid-disrupting properties. It has been hypothesized that deficiencies in other micronutrients may aggravate ID and contribute to alter thyroid function. It has also been hypothesized that mild-to-moderate ID might make the developing foetus more vulnerable to thyroid disrupting chemicals which are often halogen-containing organic compounds (i.e. with fluorine, chlorine or bromine). Today, there is an increasing concern about persistent organic pollutants in the environment causing adverse effects on child neurodevelopment, often via effects on thyroid hormone signalling. In the twentieth century there was a substantial increase in population IQ (estimated to ~3 IQ points increase per decade) in both low- and high-income countries, and this phenomenon is often referred to as “the Flynn effect” credited to the researcher Flynn who first summarized the documentation in the 1980ies. Currently, newer data indicate that this trend has gone

into reverse, and IQ is declining. A possible explanation to this “negative Flynn effect” has been suggested to be the increased exposure to thyroid disrupting chemicals in combination with a high prevalence of mild-to-moderate ID in pregnant women.

Preventing iodine deficiency – an international effort
In 1917, the first study documenting that iodine supplements could prevent goitre (thyroid enlargement) caused by ID was published. Switzerland was the first country in the world to introduce a salt iodization programme in 1922. However, prevention of ID did not gain speed until studies were published in 1970-90 documenting that ID not only cause goitre, but also reduce the cognitive function, and ID was estimated to be the leading cause of preventable mental retardation around the world. In 1980, the first global estimate of ID was published by WHO reporting that ~20-60% of the world’s population were iodine deficient.

Since then, tremendous effort has been made to eradicate ID, and many countries with a history of severe ID are today considered iodine sufficient due to salt iodization. This process has been guided by important international organisations such as WHO and the International Council for Control of Iodine Deficiency Disorders (established in 1986, and today named the Iodine Global Network (IGN)). Surprisingly, while elimination of ID is now an integral part of the nutrition strategies in most developing countries, it has not been prioritized by the health authorities in many industrialized countries. Particularly Europe is lagging behind and remains the continent with the highest prevalence of ID. Today, severe ID is almost completely eradicated, but mild-to-moderate ID is still prevalent in many countries and especially among pregnant women.

Iodine nutrition in Norway
In Norway, the natural iodine content in the soil and drinking water is low, and drinking water contains 0.5-5 µg/L. Before 1950, endemic goitre due to ID was documented in several regions of Norway, particularly in inland areas where the consumption of seafood was low. Moderate to severe ID affected the health of both humans and livestock, but in 1950 iodine was added to livestock feed to improve animal health. This action consequently and “accidentally” boosted the iodine content of cow’s milk making it the most important dietary source of iodine for milk-drinking Norwegians since then. Iodine was also added to table salt at a voluntary basis in 1938, and this salt is still available on the market. However, only 5 µg of iodine was added per gram of salt, so the contribution to the dietary intake was negligible. Based on a few, small, random studies measuring urinary iodine concentrations, the Norwegian population was considered iodine replete from the 1950’ies onwards, and the recent history of endemic ID was more or less forgotten.

In 2013, findings in the Norwegian Mother and Child Cohort Study (MoBa) indicated that ID had re-emerged in pregnant women in Norway. This could be explained by trends in the diet characterized by a substantial decrease in milk consumption combined with a low intake of seafood. Due to few food sources, iodine intake was highly dependent on individual food choices and the use of iodine-containing supplements. About the same time, it was also discovered that the iodine concentration in Norwegian milk was almost halved since year 2000. This could be attributed to a change in feed composition with more use of rapeseed ingredients containing goitrogens inhibiting iodine uptake. Since 2012, the iodine concentration in the feed has been increased and the Norwegian milk now contains ~16 µg/dl. Nevertheless, this does not secure an adequate iodine intake for all women of childbearing age since many women have a low consumption of milk. In MoBa, 28% consumed less than 2 dl milk/yoghurt per day.

In 2018, the Directorate of Health issued an advise for all women of childbearing age with a low milk intake (i.e. <3 dl milk including yoghurt per day, or <5 dl per day if fish intake is low) to take an iodine supplement (100 µg/day). Pregnant and lactating women with a low milk intake (<6 or 8 dl per day depending on fish intake) are recommended a supplement providing 150 µg iodine per day. However, the knowledge about iodine in the population is very low, and these recommendations are currently “well hidden” on a web page and not very actively communicated. More recent studies (published in 2017-18) have confirmed that large groups of the Norwegian population, including women of childbearing age, and pregnant and lactating women, have insufficient iodine intake. Median UIC of the pregnant women in these studies range from 84 to 92 µg/L, well below the cut-off for median UIC used to define an adequate iodine intake for pregnant women by WHO (i.e. ≥150 µg/L). Although strongly recommended by WHO, there is still no established routine monitoring of iodine status in Norway, but the Norwegian Scientific Committee for Food Safety are currently assessing different strategies to implement adequate salt iodization to prevent ID.

MoBa - a unique opportunity to explore impact of prenatal iodine nutrition To our knowledge, the Norwegian Mother and Child Cohort Study (MoBa) is the world’s largest pregnancy cohort in terms of participants (more than 114,000 mother-child pairs and 75,000 fathers) and the extensive collection of data (multiple questionnaires and biological samples). MoBa can also be linked to several national registries through a personal ID number, like the Norwegian Patient Registry, the Norwegian Prescription Database, and the Norwegian New-born Registry. MoBa is of unique value for research on iodine nutrition in pregnancy because of its size, but also since there is data on habitual iodine intake in the first half of pregnancy based on an extensive and validated MoBa food frequency questionnaire (FFQ). Data on maternal habitual diet in the first half of pregnancy provides an indicator for long-term diet and iodine intake also prior to pregnancy. Mothers reported their use of iodine-containing supplements in the MoBa FFQ, but unfortunately, the question on supplement-use was not clear as to what time period it covered (i.e. current use, average use since becoming pregnant, or use only while using). Thus, data on supplement use is limited to any use/no use in gestational week 0-22, and to timing of initiation of use (this was asked about in other questionnaires).

In MoBa, maternal habitual iodine intake from food did not vary by maternal age, marital status, and income, and varied only to a very small extent (up to 7%) with body mass index (BMI), parity, education, and smoking. The large number of participants makes it possible to explore potentially weak and non-linear associations to multiple outcomes on child neurodevelopment, and biological samples facilitate studying mechanisms, interactions, and mediating factors. Thus, data from MoBa can provide further insight into what is the optimal range of iodine intake for pregnant women, and it can also suggest what the neurodevelopmental consequences of prenatal ID are.

Neurocognitive function and mental health – relevance for society If strategies to prevent mild-to-moderate ID can prevent loss of cognitive ability and IQ points, this is important and highly cost-effective both at a societal level, but also at a personal level, since IQ is associated with educational attainment and income, as well as general health and wellbeing. A potential loss of 1-3 IQ points due to mild-to-moderate ID may not make a big difference to an individual’s intellectual capacity, but it can substantially increase the risk of being intellectually disabled (IQ<70) and decrease the chance of being highly intelligent (IQ>130) at a population level. Also, since mild-to-moderate ID affects such large parts of the population, a loss of even just 1 IQ point can have substantial economic consequences.

In Norway, an estimated 15-20% of children and adolescents under age 18 years have reduced function due to symptoms of mental disorders such as anxiety, depression and behaviour disorders, and about half of these meet the requirements for a psychiatric diagnosis. Attention difficulties, attention-deficit/hyperactivity disorder (ADHD) and behaviour disorders are most common in younger children and in boys, whereas in older children and in girls, anxiety and depression are predominant and the incidence is rising. In most children, symptoms are temporary, and surveys indicate that about 1/3 of 16-year-olds have at some stage had enough symptoms to meet the criteria for a psychiatric diagnosis. In 2017, the use of ADHD medication in children aged 10-14 years was 1.5% in girls and 4.1% in boys, and in adolescents aged 15-19 years use of antidepressants were 3.1% in girls and 1.2% in boys. The worldwide prevalence of ADHD in children and adolescents is estimated to be 5-7%.

If mild-to-moderate ID is a causal factor for mental health disorders, then securing adequate iodine nutrition is an important part of preventive medicine. “Mental health and well-being are fundamental to our collective and individual ability as humans to think, emote, interact with each other, earn a living and enjoy life” (WHO, 2013 ). According to WHO, mental-, neurological- and substance use disorders account for nine out of the 20 leading causes of years lived with disability worldwide and 10% of the global burden of disease.