Mild to moderate iodine deficiency in pregnancy: A matter of debate

During the last few decades painstaking eff orts have been made to eliminate iodine defi ciency through the world. Nowadays in regions where dietary iodine intake is adequate or borderline, the main focus is increasing dietary iodine supply in the target population during pregnancy and the fi rst years of life. Severe iodine defi ciency during pregnancy increases the risk of irreversible brain damage, intellectual disability, neurologic abnormalities, stunted growth, increased pregnancy loss, infant mortality, impairments in child development and cretinism. The potential eff ects of mild-to-moderate iodine defi ciency are debated. Results from animal studies and observational human studies indicate that maternal mild-to-moderate iodine defi ciency disturbs thyroid function in pregnancy and it also may aff ects fetal neurodevelopment. The eff ect of supplementation of iodine on thyroid function of pregnant women and their newborn, neurodevelopment of infants and cognitive performance of children have been investigated using iodine nutrition in pregnancy, based on median urinary iodine concentration. However they have found confl icting results regarding the benefi ts or harms of iodine supplementation in pregnancy. Although many epidemiological, interventional and clinical studies have supported the association between thyroid function in pregnant women and later psychomotor and mental development of their children, the eff ect of iodine supplementation in pregnant women on neurodevelopment of children is inconclusive. Even in areas with well-established universal salt iodization program, pregnancy could be at risk of having iodine defi ciency and despite WHO/ICCIDD/UNICEF recommendation which believe that dietary iodine fortifi cation during pregnancy depends primarily on the extent of pre-existing iodine deprivation, systematic dietary fortifi cation needs to be implemented in this vulnerable group. However, iodine supplementation of mildly iodine defi cient pregnant women may not have benefi cial eff ects in their thyroid function or neurodevelopment of their children.


Introduction
Pregnancy has a profound impact on the thyroid economy and function as it entails. Iodine is considered an essential nutrient. It is required for the synthesis of the growth-regulating thyroid hormones. Growth, neurologic development, reproductive activity, protein synthesis and enzymatic function and many critical metabolic activity are related by thyroid hormones. One of very important their effect is in the development of central nervous system and skeletal system during fetal and infantile periods [1][2][3]. Iodine is an essential part of thyroid hormones, both thyroxin (T4) and tri-iodothyronin (T3) [4]. Based on age and physiological status, each individual needs between 90 to 290 μg, mean 150 μg, of iodine per day [5]. Iodine suf iciency during pregnancy is extremely important for proper fetal development. During early pregnancy the fetus depends entirely on maternal thyroid hormones and therefore, on maternal iodine intake [6]. After birth, neonates and infants require adequate amount of iodine intake for their proper physical and neurological growth.
In severely iodine de icient areas, pregnancy results in marked hypothyroidism and impairment of fetal neurocognitive development. But adequately powered RCTs are lacking regarding the impact of mild-to-moderate iodine insuf iciency on child neurodevelopment. Minor neuropsychological defects have been described in children born to mothers exposed to mild to moderate iodine de iciency during pregnancy and it may subtly affect fetal development [7,8]. A meta-analysis of 6,180 mother-child pairs demonstrated that children of mothers with lower iodine status during irst trimester of pregnancy, had lower verbal IQ at 1.5 to 8 years of age [9]. This and other studies point to the importance of iodine nutrition for proper fetal development, however, the effects of iodine supplementation during pregnancy on neurodevelopment of offspring are not clear. Iodine supplementation of 150 or 200 μg per day from early pregnancy to delivery in two separate randomized clinical trials failed to demonstrate any effect on cognitive, language or motor scores of children at ages 1.5 to 2 years [10,11].

Physiological changes of thyroid gland during normal pregnancy
The normal rise in estrogen during pregnancy induces roughly a doubling in serum thyroid binding globulin (TBG) concentrations, consequently a signi icant increase in circulating total T4 and T3 levels [12]. The placenta secretes huge amounts of human chorionic gonadotropin (hCG) which acts as a TSH agonist and increases T4 production by approximately 50% during the irst trimester of pregnancy [13]. In normal pregnancy, there is an increase in glomerular iltration rate which is accompanied by an increase kidney clearance of iodine, this physiological change along with increased degradation of T3 and T4 by type 3 deiodinase in the placenta and transfer of iodine to the fetus, increase maternal thyroid demands. Therefore, requirement for iodine nutrition is increased during pregnancy to adopt for thyroid activity of mother and demand of T4 and iodine transfer to the fetus [6,14]. In women with iodine de iciency, such adaptive mechanisms fail due to lower intake and stores of iodine [15].

The global burden of iodine defi ciency
The high prevalence of goiter has been noticed during the last century in many parts of the world. In addition, alteration of neuromotor and physical growth during childhood from mild to severe degree (cretinism) were reported in many countries, and all the above indings were related to iodine de iciency disorders (IDD), as named by Hetzel [16]. Worldwide, considerable efforts were planned to overcome IDD in the last century. Iodine Global Network (IGN, a non-pro it, nongovernment organization) reports substantial progress in proper iodine nutrition in the majority of countries of the world and demonstrates yearly global scorecard of iodine nutrition in population, using urinary iodine concentration (UIC) of schoolchildren. The most recent score card of IGN [17] shows that 115 countries of the world have optimal iodine intake and only 23 countries remain iodine de icient. It is noteworthy that 14 countries are classi ied as having iodine excess, which emphasizes the importance of proper monitoring to reduce excess iodine nutrition.
Majority of countries still conduct urinary iodine survey of schoolchildren for monitoring their programs of iodine nutrition, while it has been shown that because of increased iodine demand in pregnancy, iodine de iciency in pregnancy may be seen along with proper iodine nutrition of schoolchildren. In Europe, according to a 2015 estimate, women in approximately two-thirds of countries with available data were iodine de icient during pregnancy [18]. Additionally, a recent systematic review of 13 studies by Candido, et al. from different regions of the world, including 14,042 pregnant women showed that the prevalence of insuf icient iodine status ranged from 16.1 to 84.0%, and the median of iodine intake was insuf icient in 75% of the studies [19]. It is reported that in some iodine suf icient countries like USA, Japan, Iran, Austria, England, Norway, Italy, Sweden and etc. pregnant women are iodine de icient [20][21][22][23][24][25][26][27].

Thyroid hormones and pregnancy outcomes
Thyroid hormones promote brain development in fetus and neonate and their integrity is critical for fetal growth and some aspects of pregnancy. These effects are mediated through direct actions on maternal and fetal metabolism [28]. The fetus is dependent on the maternal thyroid hormones in the irst trimester, therefore, maternal thyroid disarrangement may adversely affect the maturation of the fetal nervous system [29][30][31]. In addition alteration in the maternal thyroid function may accompany multiple obstetric complications [32,33]. Many cohort studies have focused in the role of derangement in maternal thyroid function on preterm delivery and neonatal birth weight [34][35][36]. Both overt hypo-and overt hyperthyroidism of pregnant women are associated with a rise in prenatal morbidity and mortality [37,38]. However, studies in subclinical thyroid dysfunctions have not shown consistent effects on pregnancy outcomes [38]. Some studies have shown an association between subclinical maternal hypothyroidism and preterm delivery [29,31], while others have not [39,40].
Two studies have found an unexpected inverse relationship between maternal free thyroxin (FT 4 ) levels and birth weight [36,37]. In a large prospective population-based cohort study in pregnant Spanish women by Gemma León, et al. the in luence of maternal thyroid function during early pregnancy on fetal birth weight and preterm delivery has been assessed [41]. The authors found a statistically signi icant inverse association of TSH and FT 4 levels at the irst half of pregnancy with birth weight, after adjusting for gestational age and other potential confounding factors. As regards to available data, universal thyroid screening in pregnancy is being undertaken in several countries, although it remains a matter of debate [42].

Thyroid hormones and fetal brain development
For normal development of fetal brain, thyroid hormones play a critical and essential role. Until the 13 th weeks of gestation, fetal thyroid is not developed and fetal source of thyroid hormones comes from the transfer of maternal hormones via the placenta [43]. Thyroid hormone dependent neurodevelopment begins in the second half of the irst trimester and includes neuronal proliferation and neuronal migration which will continue into the early part of the second trimester [44]. The second stage of thyroid hormone neurodevelopment includes neurogenesis, neuronal migration, axonal growth, dendritic branching and synaptogenesis, glial cell differentiation and migration, and the onset of myelination [45] (Figure 1). https://doi.org/10.29328/journal.afns.1001028

Determining iodine defi ciency and Iodine requirement in pregnancy
In order to produce enough thyroid hormones to meet fetal requirements, a 50% increase in iodine intake is recommended during pregnancy and lactation (Table 1) to maintain normal metabolism [46]. The most commonly used index for assessing iodine status in a population is the median urinary iodine concentration (MUIC) as determined from a casual or spot urine sample. UIC measurements as well as the consideration of regional and population differences are of great importance when evaluating and monitoring the effectiveness of forti ication programs [47]. A MUIC > 100 μg/L is indicative of adequate iodine status in children, men and non-pregnant women. Based on the WHO recommendation the iodine intake in pregnant and lactating women as measurement of MUIC is regarded as follows: insuf icient, below 150 μg/L, adequate, 150 -249 μg/L, more than adequate, 250 -499 μg/L, excessive, 500 μg/L [48].
Many international societies and organizations, including WHO recommend iodine supplementations for pregnant women in order to meet the increased iodine requirement of pregnant women, in particular in areas of iodine de iciency [49]. However, available data from observational and clinical trials do not provide meaningful conclusions regarding effectivity and safety of iodine supplementation for all pregnant women [50]. Only in women with severe iodine de iciency, iodine supplementation shows a reduction in the risk of hypothyroidism. If needed, iodine supplementation should be implemented before conception, in order to protect fetal brain from unwanted effects of iodine de iciency [51]. But from a public health and epidemiological perspective, it should be considered that immigrating women with a low income or without access to the public health system have a poor adherence both to the salt iodization policy and iodine supplements in preconception and pregnancy. Their intake of iodine-rich-foods also is limited. The identi ication of barriers to health care access could be useful to promote speci ic health interventions in this target population [52].

Iodine defi ciency and pregnancy outcomes
It is now well established that iodine de iciency of pregnant woman could be potentially associated with both maternal and fetal adverse outcomes [53]. Severe iodine de iciency is associates with preterm labor, gestational hypertension, pregnancy loss and gestational diabetes. In addition, small gestational age and impaired fetal neurodevelopment may occur with very poor iodine nutrition.
The irst report of the association between iodine de iciency and stillbirth/abortion dates back to 1939 [54]. Two decades ago a study published in 2000 from West Africa, showed that severe iodine de iciency was associated with increased risk of stillbirths or recurrent miscarriages [55]. In a prospective cohort study published in 2018 from Henan Province of China, it has been shown that the rates of preeclampsia, placenta Previa and fetal distress was lower among pregnant women with iodine suf iciency (UIC 150-249 μg/L) than those women with severe iodine de iciency (UIC < 50 μg/L) [56]. In contrast to these indings, some recent evidence has shown that there is no association of severe iodine de iciency with some adverse materno-fetal outcomes. In the LIFE prospective cohort study, the risk of pregnancy loss was not elevated in women with severe iodine de iciency compared to the iodine suf icient group [57]. Similarly in ALSPAC study [58] the incidence of materno-fetal outcomes were not signi icantly different among severely iodine de icient pregnant women (UIC < 50 μg/L) compared to the iodine suf icient group. Another frequently attributed impact of severe iodine de iciency before and during pregnancy is increased rates of goiter, thyroid nodules formation [59,60] and the induction of maternal hypothyroxinemia [61]. A few clinical studies indicate that iodine supplementation during pregnancy reduces maternal thyroid size [62] and the risk of maternal hypothyroxinemia [63,64]. In contrast to the potential effects of severe iodine de iciency on pregnancy outcomes, the potential impact of mild-to-moderate iodine de iciency on fertility and pregnancy outcomes remains largely unknown [65]. A few studies have investigated associations between iodine status and risk of adverse pregnancy outcomes in mild-to-moderate iodine de iciency [66,67].  For birth weight, some studies have reported reduced birth weight in mild-to-moderate iodine de iciency [68,69]. In a population-based cohort study it has been shown that even mild-to-moderate iodine de iciency may affect thyroid function in pregnant women and leads to adverse pregnancy outcomes [70] however a systematic review reported no evidence of the effect of salt iodization or iodine supplement on prenatal growth in mild-to-moderate iodine de iciency [71]. Recently the last Norwegian Mother, Father and Child Cohort Study [72] has shown that a low iodine intake was associated with restricted fetal growth and a higher prevalence of preeclampsia in women with mild-tomoderate iodine de iciency. Results also indicated increased risk of sub-fecundity and preterm delivery. The result of this study and other studies indicate that any necessary iodine supplementation should be initiated before pregnancy to achieve adequate iodine intake before conception, because of susceptibility of the fetal brain to iodine de iciency [73].

Iodine defi ciency and neurodevelopment of off spring
Iodine plays a very important role in neurodevelopment and organogenesis of human fetus [74]. From the beginning of embryon until 16-20 weeks of gestation, the fetus is depended on the supply of maternal thyroid hormones. Conversion of maternal T4 to T3 via placental deiodination produces adequate amount of FT3 for fetal neurodevelopment. Binding of T3 to neuronal cell receptor activates the transcription and expression of genes involved in neurodevelopment, such as myelination, cell migration and synapse formation [75,76]. Thus, fetal development is dependent on adequate thyroid hormone, and maternal hypothyroidism is associated with serious and irreversible fetal and offspring damages.
In 1960s, a large trial of 165,000 people in Papua New Guinea pointed to the importance of adequate dietary iodine in prevention of cretinism [77]. Injection of iodized oil before conception or in early pregnancy in women with severe iodine de iciency decreased the incidence of cretinism and improve cognition and psychomotor development of children, compared to placebo control group. Late on, another study in China showed that in a remote province with endemic cretinism, iodized oil given early in pregnancy improved cognitive outcomes, compared to those given iodine later in pregnancy [78]. Results from animal studies and observational human studies indicate that maternal mild-to-moderate iodine de iciency also may affect working memory and auditory processing speed and may negatively affect fetal neurodevelopment such as reduced IQ, school performance, language delay, and behavior problems. This concept has been examined in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Children of women with a MUIC less than 150 μg/L were more likely to have scores in the lowest quartile for verbal IQ, reading accuracy, and reading comprehension than were those of mothers with MUIC 150 μg/L or more [79]. Similar indings have been observed by Hynes, et al. in Tasmania [80]. Mild gestational iodine de iciency also has subtle negative impacts on language skills. Abel, et al. in Norwegian Mother and Child Cohort Study (MoBa), have shown the language delay and poorer school performance in children of mothers with inadequate iodine intake during pregnancy [81]. In another study, Markhus, et al concluded that an insuf icient iodine intake in pregnancy was associated with lower infant language skills up to 18 months [82]. Although a causal relation has not con irmed in a RCT by Gowachirapant, et al. [10].

Interventional studies
Nowadays, severe iodine de iciency is rare, but mildto-moderate iodine de iciency, particularly in pregnant women, is prevalent [83]. Many studies on the effect of iodine supplementation on maternal and newborn thyroid functions, neurodevelopment of infants and schoolchildren cognitive performance have been performed in the last three decades [84][85][86]. These studies have not shown constant association between iodine supplementation and pregnancy outcomes [87]. Numerous experimental, epidemiologic and animal studies have demonstrated the association between maternal thyroid function in pregnancy and cognition and psychomotor development of offsprings. In a study Chaouki, et al. treated Algerian pregnant women with oral iodized oil just before conception or during the irst trimester. This intervention signi icantly increased placental and birth weights in a region of endemic goiter area [88]. The same study reported that in the treated group the rates of abortion (0% vs. 14.0%), prematurity (10.8% vs. 14.3%) and stillbirth (9.0% vs. 20.4%) were signi icantly lower than in the untreated group. In a study by Velasco, et al. the psychological development of infants was evaluated at aged 3 to 18 months whose mothers had received 300 μg of potassium iodide during the irst trimester of their pregnancy and compared with infants of control mothers with no iodine supplementation. Children of iodine supplemented group had a more favorable psychometric assessment than control group [86]. This study highlighted that dietary iodine supplements not only have no harmful effect on the neurodevelopment of the children, they may even be bene icial. In another study Qian, et al. in a meta-analysis of 37 studies involving 12292 children, have shown that those children whom mothers were supplemented with iodine before and during pregnancy, had more Intelligent Quotient (IQ) than those without iodine supplementation [89]. In a randomized placebo-controlled trial by Simona Censi, et al. it has been shown that initial iodine supplementation of 225 μg/day in pregnant women from the irst trimester helps to prevent thyroid derangement and may avoid detrimental impact of mild-to-moderate iodine de iciency on fetal neurodevelopment [90]. A systematic review of nine randomized controlled trials (RCTs) by Taylor, et al. [91] has shown that in seven RCTs iodine treatment was associated with a signi icant increase in maternal urinary iodine excretion. Rebagliato, et al. in their observational study of mildly iodine de icient women, found that iodine supplementation with at least 150 μg/day, did not improve psychomotor or mental development of their offspring [92]. Recently in a RCT by Mohammed, et al. from Ethiopia, it has been shown that iodized salt intervention improved the iodine status of pregnant women and their children [93]. The last available systemic review and metaanalysis of 37 publications -10 RCTs, 4 non-RCT intervention and 23 observational studies-has assessed the available evidence on the effects of iodine supplementation on thyroid function and child neurodevelopment in mildly-to-moderately iodine-de icient pregnant women [94]. Most of these studies showed no effect on maternal or infant TSH or FT4. Overall there was a lack of data on child cognitive outcomes. In metaanalysis of two RCTs no effect on child cognitive or motor scores was demonstrated. This review and meta-analysis provides insuf icient good-quality evidence to support current recommendations for iodine supplementation of pregnant women in areas of mild-to-moderate iodine de iciency.
In conclusion, available data have shown that correction of maternal mild-moderate iodine de iciency may improve neurological development of offspring. It is noteworthy that there exist a lack of randomized, controlled trials in this area. Due to the lack of data from any RCTs, several medical and public health advisory groups recommendations to initiate iodine supplementation for pregnant and lactating women or those who are planning a pregnancy have not been widely adopted to date in most regions.

Risks of iodine supplementation
Thyroid of human fetus attain the ability to fully scape from the acute Wolff-Chaikoff effect only at 32 weeks of gestation. Therefore, fetal hypothyroidism may develop after large iodine exposure, even no alterations in maternal thyroid function is observed [95]. It has been recommended to keep oral iodine replacement to less than 500 μg daily during pregnancy [96]. A study showed that the odds of subclinical hypothyroidism is increased in pregnant women with UIC of 250-499 μg/L, compare to those with UIC of 150 -250 μg/L [97]. This rose to an odds ratio of 2.17 in pregnant women with a UIC > 500 μg/L. Furthermore, individuals with a UIC > 500 μg/L also had a 2.85 fold increase in odds of isolated hypothyroxinemia. Data from the INMA cohort (N = 1519) showed that children of mothers who consumed 150 μg /day or more of iodine had higher odds of lower psychomotor scores (OR = 1.5; 95% CI 0.8, 2.9) and an IQ score less than 85 (OR = 1.7; 95% CI 0.9, 3.0). This study also indicates that supplementary iodine intake in excess of 200 μg/day was associated with higher TSH compared with those supplemented with less than 200 μg/day [84]. Another study demonstrated that a sudden increase in iodine intake of pregnant women may temporary inhibit thyroid hormone production and cause lower availability of T4 to the fetus [88].
The Institute of Medicine recommends an iodine upper limit of 1100 μg/day during pregnancy [98]. The data from a cross-sectional study conducted in China [96] suggest that the Institute of Medicine's recommended 1100μg/day upper limit is too high, therefore the WHO more conservatively recommends an upper limit of 500 μg/day [99]. Different clinical trials on iodine supplementation of pregnant women around the worlds, indicate that daily iodine supplementation with 50 to 300 μg iodine among pregnant women with moderate iodine de iciency was not associated with any adverse outcomes [100][101][102][103][104]. Ideally, women should have adequate intra-thyroidal iodine stores before conception, which should be assured by universal salt iodization (UIC) programs. In 2006 American Thyroid Association (ATA) recommended that all pregnant women should receive at least 150 μg iodine daily as dietary supplement [105]. But WHO [106], UNICEF [107] and ICCIDD (recently named Iodine Global Network =IGN) [108] underline that strategies to control iodine de iciency in pregnant and lactating women should be modulated according to the iodine nutritional status of the population. These organizations do not recommend iodine-containing supplements in pregnant women living in areas where universal salt iodization has been effective for at least two years. According to new guidelines of both the ATA [109], and Endocrine Society [110], all pregnant women should ingest 250 μg iodine daily and, to achieve this optimal intake, women who are planning pregnancy or currently pregnant should supplement their diet with a daily oral supplement that contains 150 μg of iodine. Both WHO and scienti ic societies agree on a daily iodine intake during pregnancy of 250 μg/day, but due to lack of randomized controlled trials in this area, there is no consensus on universal iodine supplementation in pregnancy. The discordance in guidance from different authorities most likely re lects the lack of data to properly indicate when and which dosage of iodine to recommend in pregnancy.

Conclusion
The physiological adaptation of maternal thyroid occurs in the irst trimester to compensate the increased thyroid hormone requirement during pregnancy. Association between maternal hypothyroidism with poor pregnancy outcomes and impaired cognitive and psychomotor in offspring are well documented. In addition, subclinical hypothyroidism may also be associated with gestational hypertension, preeclampsia, abortion, fetal growth retardation, neonatal morbidity and perinatal mortality. Adequate iodine nutrition during pregnancy and lactation is vital for thyroid hormone synthesis. Therefore, all women during pregnancy and lactation need optimal iodine intake. Iodine prophylaxis and prevention of iodine de iciency during pregnancy and lactation may decrease the rates of fetal death, endemic cretinism, neurocognitive impairment and prevent mental retardation of children. There are also many studies and systematic reviews that indicate even mild to moderate iodine de iciency may disturb thyroid function in pregnancy and it also may affects working memory and auditory processing speed and may negatively affect fetal neurodevelopment such as reduced IQ, school performance, language delay, and behavior problems. The bene its of correcting mild-to-moderate iodine de iciency are unclear and demand further controlled trial. Many international organization recommend that supplementation in pregnancy should be used in countries with mild-to-moderate iodine de iciency, although other organizations recommend that all pregnant and breastfeeding women should take at least 150 μg iodine supplementation, not only in iodine de icient regions but also in iodine suf icient areas. With referring to the lack of universal consensus and existing controversy regarding the adverse effects of mild-to moderate iodine de iciency during pregnancy on mother and sibling wellbeing and outcomes, we recommend to perform further prospective randomized controlled trials in this ield.

Ethical statement
The manuscript is currently being considered for publication has not been published in whole or in part in another journals.