A Review of the Potential Interaction of Selenium and Iodine on Placental and Child Health

A healthy pregnancy is important for the growth and development of a baby. An adverse pregnancy outcome is associated with increased chronic disease risk for the mother and offspring. An optimal diet both before and during pregnancy is essential to support the health of the mother and offspring. A key mediator of the effect of maternal nutrition factors on pregnancy outcomes is the placenta. Complicated pregnancies are characterized by increased oxidative stress in the placenta. Selenium and iodine are micronutrients that are involved in oxidative stress in placental cells. To date, there has been no comprehensive review investigating the potential synergistic effect of iodine and selenium in the placenta and how maternal deficiencies may be associated with increased oxidative stress and hence adverse pregnancy outcomes. We undertook a hypothesis-generating review on selenium and iodine, to look at how they may relate to pregnancy complications through oxidative stress. We propose how they may work together to impact pregnancy and placental health and explore how deficiencies in these micronutrients during pregnancy may impact the future health of offspring.


Introduction
Pregnancy is characterized by a pro-inflammatory, hyperlipidemic and hyperinsulinemic state [1]. A normal healthy pregnancy is important for the growth and development of the baby and for the lifelong health of the mother and offspring [2]. To provide a suitable condition for the developing fetus, the maternal body undergoes major biochemical, physiological and anatomic adaptations [3], which typically revert back to the condition they were in prior to pregnancy [4].
Human pregnancy is also associated with an increase in oxidative stress markers, due to increased placental mitochondrial activity and the production of reactive oxygen species, which have pronounced effects on placental function [5]. The placenta is the interface between the mother and baby. It mediates nutrient and waste exchange to support a healthy pregnancy. Factors such as poor maternal diet or obesity impact placental health and function, such as proliferation, invasion and apoptosis of trophoblast cells [6,7]. This can have a profound effect on fetal growth and development, and pregnancy success [6,7]. As such, a balance of antioxidant and oxidant status is key to a healthy placenta and hence a successful pregnancy outcome for mother and baby.
There is a clear role for an optimal diet both before and during pregnancy to support the health of the mother and offspring [8][9][10][11][12]. Higher dietary scores for a high-protein/fruit pattern before pregnancy, was associated with decreased likelihood of preterm birth (adjusted odds ratio; 95% confidence interval, OR: 0.31; 95% CI: 0.13, 0.72), whereas the reverse direction was apparent for the high-fat/sugar/takeaway pattern (adjusted OR: 1.54; 95% CI: 1.10, 2.15) [13]. Increasing dietary quality, calculated by the Alternative Healthy Eating Index 10 during pregnancy, was associated with a decrease in the likelihood of delivering a small-for-gestational-age (SGA) baby [14]. Supplementation with vitamins and minerals may also have a positive effect on infant birthweight [15]. Some micronutrients, such as selenium and iodine, are essential micronutrients because the body cannot produce them and the mother needs to obtain them from her diet or from supplemental intake. Deficiencies in iodine can lead to thyroid hormone deficiency, and therefore improper neurodevelopment and mental retardation in the fetus [16]. Selenium deficiency is associated with pregnancy-induced hypertensive disorders [17], miscarriage [18], preterm birth [19], and gestational diabetes [20,21].
Importantly, the key mediator of the effect of maternal nutrition factors on pregnancy outcomes is the placenta. However, such pregnancy outcomes do not just end after pregnancy, but can have lifelong consequences for a mother and her offspring. This is depicted by the developmental origins of health and disease (DOHaD) hypothesis, which emphasizes the importance of fetal life exposure to maternal factors, such as diet, in the development of chronic diseases later in life [22]. Yet, while maternal nutrition and the placenta are important factors regarding pregnancy success, there is a paucity of information examining multiple nutrients in combination, and the potential synergistic effect they may have in pregnancy.

Oxidative Stress and the Importance of Antioxidants
Oxidative stress occurs when free radicals are generated to a level higher than the physiological level and the antioxidant system cannot neutralize them [26,27]. Free radicals, namely reactive oxygen species (ROS), are unstable molecules that have unpaired electrons and can donate or accept an electron to be stabilized [28]. As a result, the new molecule is unstable and formation of free radicals continues. This chain reaction can cause oxidative damage to nucleic acids, lipids, carbohydrates and proteins, which results in the decaying of tissues and the disruption of homeostasis [27]. The production of ROS is a continuous phenomenon in cells and is essential for cell-signaling, however, excessive ROS levels are detrimental to cells [27,29].
To stop the accumulation and damage of ROS, free radicals need to be neutralized by pairing unpaired electrons. This is how the antioxidant system can protect the cell against oxidative damage [30]. Antioxidants typically work in three ways, including the prevention of ROS formation, the interception of a ROS chain reaction and the repairing of damaged molecules [31,32]. The antioxidant defense system is made up of enzymes and non-enzyme components. Glutathione peroxidase (GPx), catalase, superoxide dismutase and thioredoxin reductase (TRx) are some of the enzymes [33] but they need cofactors such as micronutrients to work properly. For example, superoxide dismutase requires manganese or copper and zinc, while GPx and TRx need selenium to function properly. Therefore, micronutrient deficiencies can reduce the ability of the antioxidant system to protect cells Adverse pregnancy outcomes are associated with increased oxidative stress in the placenta [23] and since selenium and iodine are involved in oxidative stress in placental cells [24], it is important to investigate the role of both micronutrients. To the best of our knowledge, no study has reviewed current evidence regarding the potential synergistic effect of iodine and selenium in the placenta. Our knowledge from other organs, such as the thyroid, highlights the importance of these two micronutrients and their combined impact on oxidative stress [25]. We identified studies that investigated the association between maternal selenium and iodine status with pregnancy complications using the following keywords: "maternal blood selenium concentration AND pregnancy complication" and "maternal urinary iodine concentration AND pregnancy complication" in PubMed. The last search was performed in July 2020. In addition, any relevant studies identified from the reference list of selected studies were also included. The exclusion criteria were: (1) review papers, (2) unavailable full text, (3) non-English language, (4) animal studies, and (5) taking any medication during pregnancy. Pregnancy outcomes were defined as healthy if there was no complication or complicated, if there was one of the following pregnancy complications: preeclampsia (PE), pregnancy-induced hypertension, miscarriage, gestational diabetes mellitus (GDM), preterm birth (PTB), intrauterine growth restriction (IUGR), or premature rupture of membrane (PROM). In this review we outline how selenium and iodine may relate to pregnancy complications through oxidative stress, and we propose how they may work together to impact pregnancy and placental health ( Figure 1). We also explore how deficiencies in these two micronutrients during pregnancy may impact on the future health of the offspring, which has not been previously reviewed as a combination.

Oxidative Stress and the Importance of Antioxidants
Oxidative stress occurs when free radicals are generated to a level higher than the physiological level and the antioxidant system cannot neutralize them [26,27]. Free radicals, namely reactive oxygen species (ROS), are unstable molecules that have unpaired electrons and can donate or accept an electron to be stabilized [28]. As a result, the new molecule is unstable and formation of free radicals continues. This chain reaction can cause oxidative damage to nucleic acids, lipids, carbohydrates and proteins, which results in the decaying of tissues and the disruption of homeostasis [27]. The production of ROS is a continuous phenomenon in cells and is essential for cell-signaling, however, excessive ROS levels are detrimental to cells [27,29].
To stop the accumulation and damage of ROS, free radicals need to be neutralized by pairing unpaired electrons. This is how the antioxidant system can protect the cell against oxidative damage [30]. Antioxidants typically work in three ways, including the prevention of ROS formation, the interception of a ROS chain reaction and the repairing of damaged molecules [31,32]. The antioxidant defense system is made up of enzymes and non-enzyme components. Glutathione peroxidase (GPx), catalase, superoxide dismutase and thioredoxin reductase (TRx) are some of the enzymes [33] but they need cofactors such as micronutrients to work properly. For example, superoxide dismutase requires manganese or copper and zinc, while GPx and TRx need selenium to function properly. Therefore, micronutrient deficiencies can reduce the ability of the antioxidant system to protect cells against free radicals [34]. Vitamin C, vitamin E and beta-carotene are other micronutrients involved in the antioxidant defense system [35,36].

Oxidative Stress and Pregnancy Complications
Pregnancy complications are adverse outcomes of pregnancy such as preeclampsia (PE), gestational diabetes mellitus (GDM), intrauterine growth restriction (IUGR), preterm birth (PTB), and premature rupture of membrane (PROM). They can increase morbidity and mortality rates for both the mother and her offspring [37][38][39][40].
Preeclampsia is a pregnancy-specific, multisystem disorder, presenting as hypertension with new onset of one or more of proteinuria or renal, liver, neurological or hematological complications, or uteroplacental dysfunction after 20 weeks' gestation [41]. Patients with a history of PE have around a 2-fold increased risk for vascular diseases such as hypertension and ischemic heart disease [42], stroke [42] and chronic kidney disease [43], at 10-15 years post-partum. Infants of mothers who had PE are also at an increased risk of small-for-gestational-age [44] and perinatal mortality [45]. Children exposed to preeclamptic pregnancies have increased hospitalizations due to infectious and parasitic, nutritional and metabolic diseases of the respiratory system, blood, and blood-forming organs at ages 1-13, 16, 18-21 and 24 years compared to unexposed children [46]. Moreover, women who experience PE in their first pregnancy have a higher risk of myocardial infarction and cardiovascular death compared to non-PE mothers [47]. Currently, delivery of the fetus and placenta is the only treatment [41,42,45,48,49].
The pathogenesis of PE involves improper placental development as a result of dysfunctional proliferation, migration, and invasion of placenta-derived extravillous cytotrophoblast cells into the uterine vasculature, along with maternal endothelial and vascular dysfunction [48]. This leads to placental hypoxia and subsequent reperfusion, resulting in oxidative stress and inflammation [50,51]. Similar to PE, oxidative stress also contributes to PTB, IUGR and PROM. IUGR refers to a fetus that is smaller than expected for their gestational age. One of the most common causes of IUGR is uteroplacental insufficiency in which the placenta is unable to provide the developing fetus with sufficient nutrients and oxygen. The growth-restricted offspring have a 2-6 fold increased risk of developing chronic diseases such as type 2 diabetes mellitus, coronary heart disease and chronic kidney disease later in life [52].
The same placental dysfunction seen in PE is also seen in IUGR with deficient spiral artery remodeling resulting in malperfusion [53]. The malperfusion results in oxidative stress within the placenta and overwhelms the antioxidant system. In addition, the enzymes which act as antioxidants require micronutrients to work and maternal diets deficient in these micronutrients impact on the placenta's ability to combat oxidative stress [53].

Micronutrients and Pregnancy
To compensate for the higher demand of growing maternal tissues and fetus and also for hemodilution that occurs in pregnancy, a higher dietary intake of many micronutrients and trace elements are recommended [4,54]. In developed countries, despite the availability of suitable nutritional foods, many pregnant women have an imbalanced diet that puts them at risk of an inadequate intake of micronutrients like folate, vitamin D, vitamin B12, iron and iodine [55,56]. There is considerable evidence that shows that deficiency of micronutrients such as iodine, selenium, zinc, vitamin E, folate and iron, adversely impacts maternal and fetal health, and pregnancy outcome [19,[57][58][59][60][61][62][63][64][65][66][67][68][69]. One of the reasons for this association may be the bio-functionality of vitamins and minerals in pregnancy, besides their classical roles in health and disease in the general population [56]. Although maternal micronutrient intake through the entire gestational period can affect fetal growth and development, the peri-implantation stage and placental development are critical windows for programming a healthy birth and future life [70,71].

Selenium
Selenium is an essential trace element that plays a pivotal role in the antioxidant defense system, cell cycle, and immune function, because of its contribution to selenoproteins [72]. Selenoproteins such as glutathione peroxidases (I, II, III, IV, and VI); thioredoxin reductases (I, II, and III); and selenoprotein H, P, and W, have antioxidant properties and are involved in managing ROS production. Selonoproteins also possess a vast range of functions such as protein folding, signaling, lipid biosynthesis, cell cycle, and calcium regulation [73][74][75][76][77][78][79].
Selenium is found in a broad range of foods including brazil nuts, wholegrain foods and cereals, fish, beef, eggs, and some fortified ready-to-eat breakfast cereals. The recommended dietary intake of selenium has been calculated by the amount of selenium needed to maximize the synthesis of glutathione peroxidase (GPx) [80]. During pregnancy, it is 60 micrograms per day in European countries [81] and 65 micrograms per day in Australia and New Zealand [82]. The requirement for selenium is higher during pregnancy, up to 4 micrograms per day, due to fetal requirements [83].
Globally, up to one in seven people have a low selenium dietary intake [84]. Selenium levels can be influenced by multiple factors including drinking water, soil, plant and animal tissue content of selenium [84], as well as different intakes in different regions. For example, the average intake of selenium in Eastern Europe is lower than that of Western Europe [85]. In addition, in New Zealand [85] and most areas of China [86], selenium deficiency is evident. In the Middle East, selenium intake is dependent on socio-economic status [85].
While studies across different countries report various levels of selenium during pregnancy (Table 1), using the data reviewed by Mariath et al. (2011) [87], Perkins and Vanderlelie (2016) proposed that selenium levels below 45 micrograms per litre can be dangerous and can be associated with adverse birth outcomes. They further concluded that selenium levels above 95 micrograms per litre can be considered as seleno-sufficient because the majority of selenoproteins can be maximally expressed at this level [57]. In addition to the measurement of maternal selenium levels, markers of functional effects of selenium may provide additional information. For instance, assessment of selenoproteins such as GPX3 and SEPP1 are suitable to investigate the functional effects of selenium such as antioxidant activity, nutritional selenium deficiency, and evaluating responses of deficient individuals to selenium supplementation [88]. However, more studies would be needed to determine whether these selenoproteins provide additional information for interpreting clinical outcomes in addition to, or instead of, maternal selenium levels. The time point of selenium assessment can also affect the interpretation of the data, since pregnant women that were selenium sufficient in the first trimester have been shown to become selenium deficient later in pregnancy [89].
This supports that selenium deficiency may contribute to higher oxidative stress levels, inflammation, and subsequent pregnancy complications (Table 2).

Iodine
Iodine is a vital trace element required for thyroid hormone synthesis and plays a fundamental role in fetal brain development [109,110]. Maternal iodine deficiency during pregnancy is associated with insufficient neurodevelopment, and defective intellectual skills such as poorer school performance and language delay as well as attention-deficit/hyperactivity disorder in offspring later in life [111,112]. While iodine deficiency is described as the most common cause of a child's central nervous system maldevelopment [113], mandatory iodine fortification programs such as salt iodization have helped address this common health issue among women of child-bearing age globally [114][115][116][117]. In Australia, although this preventive program seems to be successful among the general population, 16-44 year old pregnant women's median urinary iodine concentrations (MUIC: 116 micrograms per litre) still indicate insufficient iodine intake [118]. In New Zealand, MUIC of 68 micrograms per litre indicates a mild iodine deficiency in 18-44 year old women post-mandatory iodine fortification [118]. A similar situation has been reported in other countries with iodine fortification such as Austria, Croatia, Egypt, and Iran, all reporting that pregnant women's iodine status was insufficient [119]. Pregnancy iodine status should be at an optimal level to avoid the potentially harmful consequences of iodine deficiency [120].
Iodine intake during pregnancy should cover the needs of both the mother and her developing fetus. Thus, it is recommended that dietary intake increases from 150 micrograms perday for a non-pregnant woman to 220 micrograms per day during pregnancy [82]. The World Health Organization recommends a daily iodine supplement of 250 micrograms per day during pregnancy, or an annual dose of iodized oil supplement of 400 milligrams per year [121]. While maternal dietary intake of iodine can impact placental iodine content, and therefore control the effect of iodine on fetal thyroid gland activity [122], placental iodine accumulation plays a significant role in iodine availability to the fetus [123].
In thyroid hormone production, I _ oxidation occurs to form iodine (I 2 ). This reaction uses H 2 O 2 and thyroid peroxidase and inhibits H 2 O 2 accumulation or its decomposition to a hydroxyl radical [25,124]. A normal level of thyroid hormone exerts a negative feedback on thyroid-stimulating hormone (TSH). Iodine deficiency is associated with several health issues including a reduction in thyroid hormone production [125], which results in the absence of the negative feedback on TSH. Therefore, a cascade of signals and reactions, including increasing TSH secretion, occurs [126]. TSH stimulates H 2 O 2 generation for I − oxidation but in severe iodine deficiency this process does not occur, resulting in thyroid hormone insufficiency [125,126]. Therefore, TSH continues to increase H 2 O 2 generation, which can be higher than the antioxidant capacity of GPx; H 2 O 2 will accumulate and more ROS is produced, resulting in oxidative stress and apoptosis [126].
Iodide is the ionic state of iodine, occurring when iodine forms a salt with another element, such as potassium. Iodide may have an ancestral antioxidant function in various iodide-concentrating cells not only similar to thyroid cells where iodine consumes H 2 O 2 , but also because iodide can reduce the lipid peroxidation rate by reacting with double bonds of the cell membrane polyunsaturated fatty acids and make iodolipids that will be less reactive to ROS [127].

Iodine and Pregnancy Complications
There is limited but supporting evidence that iodine contributes to the antioxidant system. In a small sample of 74 women, there was decreased total antioxidant status and superoxide dismutase activity in women with mild iodine deficiency in the 2nd and 3rd trimesters of pregnancy compared to pregnant women with optimal iodine levels [138]. Iodine sufficient pregnant women, as indicated by more than 150 micrograms per litre urinary iodine concentration, had higher superoxide dismutase enzyme activity compared to iodine-deficient pregnant women [66]. In vitro studies support this and have shown that iodine supplementation reduces ROS production in a dose-dependent manner [139]. While to date there is no study about the potential antioxidant effect of iodine in the placenta, studies have shown a role for iodine in the antioxidant system of other organs such as thyroid, breast, stomach and eye [25,[140][141][142][143]. We have recently shown in a placental cell line that treatment with iodine resulted in a lower lipid peroxidation compared to control upon induction of oxidative stress [24], further supporting a potential role of iodine as an antioxidant in the placenta.
Importantly, several studies have shown that iodine-deficient pregnant women are at an increased risk of pregnancy complications such as maternal high blood pressure, PE, IUGR and PTB [64][65][66]138,144,145] (Table 3). Iodine assessment methods can significantly impact the iodine measurement [146]. Iodine intake can be assessed indirectly by thyroid hormone level, urine spot or 24 h urinary samples [146]. Although spot urinary samples in population studies with more than 500 people is a more feasible approach and provides a good estimate of iodine status, it is not a valid measure for individual iodine status; 24 h urine analysis is a more appropriate assessment among individuals or in studies with smaller sample sizes [146]. Adjusting for urinary creatinine to avoid the influence of fluid intake also improves the reliability of the measurement of iodine status [146,147]. However, regardless of the assays used to measure iodine, it is clear that iodine deficiency is associated with pregnancy complications (Table 3). Because complications in pregnancy are exacerbated by increased oxidative stress, the role of iodine as an antioxidant may positively impact pregnant complications.

Potential Synergistic Effects of Selenium and Iodine
To date, most studies have investigated the impact of micronutrients on oxidative stress in the placenta, separately. Unfortunately, this is unlikely to provide more information on potential interactions or synergistic effects than if they were assessed in combination. In particular, selenium and iodine are essential micronutrients that may affect oxidative stress synergistically. Deiodinases are selenocysteine-containing enzymes that can regulate thyroid hormone bioavailability by removing iodide from different positions on the tyrosine ring. There are various deiodinases in different tissues (deiodinase I, II, III), however type III is dominant in the placenta. It inactivates the T3 (triiodothyronine) and T4 (thyroxine) hormones by removing an inorganic iodine from their inner ring and converting them to T2 (diiodothyronine) and reverse T3 (rT3), respectively [148,149]. Deiodinase type II can produce T3 from T4, and increase the bioavailability of T3 [150]. Thus, the activity of both deiodinase II and deiodinase III leads to the release of iodine in the placenta [151].
Selenoprotein expression in endocrine tissues is precisely controlled to be maintained, even in Se deficiency, and deiodinases seem to be higher than GPxs hierarchically in some tissues [152]. It is also unclear whether there are similar protective mechanisms for deiodinase in the placenta because of the lack of systematic investigation of the placental deiodinases and other selenoproteins. Only one study has reported that placental deiodinase III mRNA expression and its enzyme activity were correlated in PE but not in normotensive pregnant women [135]. In this study, maternal selenium levels were significantly lower in PE compared to normotensive women. This suggests that in normotensive pregnant women where selenium level is optimal, translation of deiodinase III is conserved, while in PE women with low selenium levels, deiodinase III enzyme regulation is altered; therefore iodine metabolism may be affected [135]. However, further studies are required and in larger sample sizes. This will help identify whether and how fetal adaptations occur, in order to maximize iodide uptake.

Impact of Maternal Selenium and Iodine, via Oxidative Stress, on Child Health
Maternal deficiencies in selenium or iodine may result in oxidative stress in the placenta, which may impact on future offspring health through developmental origins of health and disease [158][159][160][161]. Numerous studies support that an adverse in utero environment contributes to future chronic disease risk in adult offspring (reviewed in [162]) and that this may be mediated by the placenta [159,163].
It is known that during a healthy pregnancy there is a large amount of oxidative stress, especially since the placenta initially develops in a hypoxic environment with maternal blood flow established at approximately 10 weeks of gestation [164]. During this time, reactive oxygen species are produced and the antioxidant system combats this, however, if there are deficiencies in micronutrients involved in this antioxidant system, then it is likely that oxidative stress will occur which will lead to damaged placenta and potentially pregnancy complications. These pregnancy complications are associated with future chronic disease risk in the offspring. Several animal studies have shown that the use of maternal antioxidant supplementation can prevent placental oxidative stress and the associated programming of cardiovascular disease risk to the offspring (reviewed in [165]). Human randomized controlled trials with antioxidants have not shown improvements in pregnancy complications and some have in fact been associated with an increased risk (reviewed in [166]). However, what needs to be considered is the micronutrient status of the mother as deficiencies in elements such as selenium and iodine, which are required for antioxidant enzymes, may diminish the effectiveness of simply adding antioxidant supplements to the maternal diet.

Conclusions
This is the first comprehensive review examining the potential synergistic effects of selenium and iodine ( Figure 2). In addition, we have discussed whether the association between maternal selenium and iodine status as measured in biological specimens is associated with pregnancy complications due to their roles in oxidative stress. In future, studies that assess maternal dietary intake of selenium and iodine should also be examined. Iodothyronine deiodinases are selenoenzymes involved in thyroid hormone metabolism. The incorporation of selenium into deiodinases causes it to play an essential role in the metabolism of thyroid hormones and in the release of iodide. In addition, iodine deficiencies result in greater production of H 2 O 2 , which requires the selenoenzyme GPx to remove the excess H 2 O 2 . Thus, selenium and iodine may have some combined effects that should be investigated. Maternal diet is essential for the health of the placenta and baby, and deficiencies in micronutrients impact placental health potentially via oxidative stress pathways. This in turn not only increases the risk of an adverse pregnancy outcome, but is associated with poor future health outcomes for mother and offspring. Supplementation with antioxidants is not necessarily the key if the underlying selenium and iodine levels are low, as antioxidants require these and other micronutrients for optimal activity. Therefore, to address adverse pregnancy outcomes and the impact they have on future offspring health, a better understanding of the role of each micronutrient, alone and in combination, in placental development and hence pregnancy success is needed.