Key Messages of the Iodine Deficiency Working Group (AKJ): Maternal Hypothyroxinemia Due to Iodine Deficiency and Endocrine Disruptors as Risks for Child Neurocognitive Development

Keywords

iodine deficiency - pregnancy - hypothyroxinemia - neurocognitive development - endocrine disruptors

Introduction

Thyroid hormones are especially important for embryonic/fetal and early postnatal neurocognitive development. Depending on the severity, duration and time of iodine deficiency in certain stages of life, iodine-deficiency disorders are associated with physical, neurological and mental deficiencies in humans. Severe iodine deficiency during pregnancy can have a number of negative impacts on the health of mother and child, including hypothyroidism, goiter, stillbirths, increased perinatal mortality, neurological damage and mental disability [1] [2].

In addition, exposure to endocrine-disrupting chemicals (EDCs) is increasing worldwide [3] [4] [5]. These endocrine disruptors are substances which are either present in nature or are produced artificially and released into the environment. The majority of EDCs specifically interfere with the thyroid metabolism and are therefore known as thyroid-disrupting chemicals (TDCs) [6] [7] [8]. The placenta is especially sensitive to EDCs because of its abundance of hormone receptors [9]. Exposure to these chemicals combined with an inadequate iodine intake can additionally harm the development, growth, differentiation and metabolic processes of the embryonic/fetal and neonatal brain [6] [7] [8] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22].

Both iodine deficiency and exposure to TDCs have a negative impact on general health and the socioeconomic system. The estimated annual cost of the seven EDC categories with the highest causation amounts to 33.1 billion Euros in Europe. The largest share of these costs relate to the loss of IQ and the increase in neurocognitive disorders [23] [24] [25] [26] [27]. In addition, a growing body of evidence suggests that exposure to TDCs, including through air pollution, not only affects brain function [13] [28] [29] [30] [31] but also has an impact on the outcomes of pregnancy and birth [32] [33] [34] [35] [36].

“Endemic goiter” has been synonymous with iodine deficiency for years and the aim has always been to prevent enlargement and overt dysfunction of the thyroid gland. However, there has been a paradigm shift in recent decades [37], ever since the focus has moved to examining the consequences of mild to moderate iodine deficiency on the cognitive development of the embryo ([Fig. 1]).

Fig. 1 The paradigm shift relating to iodine deficiency (Fig. is based on data from [24]).

Epidemiological and experimental studies on mild to moderate iodine deficiency carried out in the last two decades have shown that embryonic/fetal brain development can be affected not only in the infants of mothers with overt hypothyroidism but also those born to mothers with hypothyroxinemia in the early stages of pregnancy [38] [39] [40] [41] [42]. Low FT4, also known as hypothyroxinemia, is an indication of individual iodine deficiency. As FT4, but not FT3, is transported almost exclusively via the placenta in the first three months of pregnancy, slight changes in fetal brain development can be observed even if maternal thyroid hormone levels are low but still within reference ranges. The fetus is able to produce thyroid hormones from week 12–14 of gestation and is then dependent on iodine which is transported via the placenta, and no longer on maternal FT4 of which lower levels cross the placenta to reach the fetus from the 12th week of pregnancy.

Because of methodological issues with the definition, findings may not be homogeneous. Moreover, too little attention has been paid to isolated maternal hypothyroxinemia (IMH) because of some uncertainty regarding treatment. But IMH is clearly an indication of maternal iodine deficiency not reflected by elevated TSH levels, as the iodine-depleted thyroid gland reacts more sensitively to TSH [43] [44] [45].

The pollution of our environment, with EDCs found in the air, the water, food, and sanitary products, is increasing worldwide and has reached potentially hazardous levels. Generally speaking, EDCs can affect the normal functioning of the endocrine system of humans and animals. They especially affect the thyroid hormone system, with negative impacts on fetal and neonatal brain development, growth, differentiation, and metabolic processes [6] [7].

The aim of a recently published review article was to highlight the importance of IMH caused by mild iodine deficiency and additional environmental factors such as EDCs and air pollution on the cognitive and psychosocial development of children and to identify measures for the prevention and treatment of IMH.

Method

The basis for compiling this opinion was a joint review article published in the international peer-reviewed journal Nutrients in 2023 [2]. We also carried a search of the recent literature, focusing on relevant articles published between 2022 and September 2024 in PubMed, Medline, Cochrane, Web of Science, and Google Scholar using the search terms Iodine, Pregnancy, Thyroid Hormone, Thyroid Diseases, Endocrine Disruptors, Hypothyroxinemia, and Subclinical Hypothyroidism, which were searched for in combination using the operators AND and OR. The drafted key statements were voted on by the scientific advisory board of the Iodine Deficiency Working Group (Arbeitskreis Jodmangel e. V., AKJ).

Thyroid Function in Pregnancy

In pregnancy, the functions of the maternal thyroid are dynamically adapted to the thyroid hormone needs of the mother and embryo/fetus ([Fig. 2] a). Pregnant women need about 50% more iodine because of their increased production of thyroid hormones, increased renal iodide clearance and the transplacental transfer of iodine to the fetus [46] [47]. The average iodine supplementation recommendation during pregnancy is therefore 250 µg/day [48].

Fig. 2 Changes in thyroid physiology during pregnancy (a) and the relationship between thyroid hormone activity and brain development (b) (Fig. is based on data from [49] [50]). See text for further explanations (based on data from [2]).

Median urine iodine concentrations (UIC) are used to assess iodine intake of the general population in the context of epidemiological studies. According to the criteria of the WHO, they should be over 100 µg/l, and over 150 µg/l during pregnancy and lactation [51].

We know from recent epidemiological studies that the standard iodine intake is below the mean of what is required in about 30% of adults, 48% of women of childbearing age, and 44% of children and adolescents in Germany [52] [53] [54]. This is also the case in more than 70% (n = 21) of 29 European countries ([Table 1]) [52] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68]. A mean UIC figure of > 150 μg/l was only found in a few EU countries with mandatory universal salt iodization programs such as Bulgaria or Romania (see [Table 1]). Studies in other countries have shown that only mandatory universal salt iodization of more than 25 mg/kg can ensure sufficient iodine intake through nutrition across all sections of the population including pregnant women who have higher requirements [51] [69]. Young women who are vegan or vegetarian and do not take iodine supplements are most at risk of low iodine status, iodine deficiency, and insufficient iodine intake.

Table 1 Iodine intake for the general population and for pregnant women in Europe (data from [2]).

Country	General populationa				Pregnant womenb
	Median (UIC) (μg/l)	Date of survey (N, S)	Population	Iodine intake of the population	Median (UIC) (μg/l)	Date of survey (N, S)	Iodine intake	Legal status (year)e
Abbreviations: SAC = school-age children (normally aged 6–12 years); UIC = urine iodine concentration; USI = universal salt iodization; N = national representative data; S = only subnational data; Dates from a [68], b [55], c [70], d [56], e [62], f [63] [64]
Austria	111	2012 (N)	SAC (7–14)	adequate	87	2009–2011 (S)	inadequate	obligatory (1999)
Belgium	113	2010/2011 (N)	SAC (6–12)	adequate	124	2010 (N)	inadequate	voluntary (2009)
Bulgaria	182	2008 (N)	SAC (7–11)	adequate	165	2003 (N)	adequate	obligatory (2001)
Croatia	248	2009 (N)	SAC (7–11)	adequate	140	2009, 2015 (S)	inadequate	obligatory (1996)
Denmark	145	2015 (S)	SAC	adequate	101	2012 (S)	inadequate	obligatory (2000)f
Finland	96	2017 (N)	adults (25–74)	inadequate	115	2013–2017 (S)f	inadequate	voluntaryf
France	136	2006–2007 (N)	adults (18–74)	adequate	65	2006–2009 (S)	inadequate	voluntary
Germany	89	2014–2017 (N)	SAC, adolescents (6–12)	inadequate	54	2008–2011 (N)c	inadequate	voluntary
Greece	132	2018 (N)	adults	adequate	127	2008–2015 (S)	inadequate	voluntary
Hungary	228	2005 (S)	SAC (10–14)	adequate	128	2018 (S)d	inadequate	obligatory (2013)
Ireland	111	2014–2015 (N)	adolescent girls (14–15)	adequate	107	2008–2010 (S)	inadequate	voluntary
Italy	118	2015–2019 (S)	SAC	adequate	72	2002–2013 (S)	inadequate	obligatory (2005)
Netherlands	130	2006 (S)	adults (50–72)	adequate	223	2002–2006 (S)	adequate	voluntary
Poland	112	2009–2011 (S)	SAC (6–12)	adequate	113	2007–2008 (S)	inadequate	obligatory (2010)
Portugal	106	2010 (N)	SAC	adequate	85	2005–2007 (N)	inadequate	voluntary
Romania	255	2015–16 (N)	SAC (6–11)	adequate	206	2016 (S)	adequate	obligatory (2009)
Spain	173	2011–12 (N)	SAC	adequate	120	2002–2011 (S)	inadequate	voluntary
Sweden	125	2006–07 (N)	SAC (6–12)	adequate	98	2006–2007; 2010–2012 (S)	inadequate	voluntary (1936)f
Switzerland	137	2015 (N)	SAC (6–12)	adequate	136	2015 (N)	inadequate	voluntary
United Kingdom	166	2015–2016 (N)	SAC, adolescents (4–18)	adequate	99	2002–2011 (S)	inadequate	no USI program

As thyroxine-binding globulin (TBG) increases in pregnancy, determination of FT4 is imprecise as routine measurement of FT4 values is false resulting in figures that are either too low or too high because measurement methods depend on measuring TBG values.

In practice, this means that to ensure correct values, the mean normal FT4 range must be assumed to ensure that pregnant women have an adequate iodine intake. Additional supplementation with iodide tablets is necessary and is a useful preventive measure for all women wanting to have children [71] [72] [73].

Impact of Mild Iodine Deficiency and Maternal Hypothyroxinemia on Prenatal Brain Development

A time frame (s. [Fig. 2] b, between the two red dotted lines) has been identified in which a decrease in maternal thyroid hormones (FT4) has a particularly strong impact on neuronal proliferation and on the migration and development of the inner ear. Recognizing this early critical phase can have a direct clinical impact on the assessment of risk and the time frame for treatment options [74] [75]. A lower fT4 transfer to the maternal placenta in this critical developmental stage probably has the greatest impact on the neurological development of the child [76] [77] [78] [79] [80] [81] and also manifests in the form of permanent structural and functional anomalies [38] [82] [83] [84] [85] [86].

IMH ([Table 2]) probably occurs much more often than subclinical hypothyroidism, [40] [42] [44] [87] [88] [89] [90]. IMH prevalence is assumed to be higher in countries with iodine deficiency [43] [91]. Trimester-specific reference ranges for serum TSH and fT4 levels in an euthyroid pregnant population would have to be established as the gold standard for diagnosis [92] [93]. Unfortunately, reference ranges are currently only available for TSH levels.

Table 2 Definition and prevalence of maternal thyroid disorders (data from [82]).

Isolated maternal hypothyroxinemia (1.5–25%) Serum fT4 concentration in the lower 5th or 10th percentile of the reference range with normal TSH concentrations

Overt hypothyroidism (0.3–0.5%) Elevated serum TSH levels together with decreased fT4 concentrations

Subclinical hypothyroidism (2–2.5%) Elevated serum TSH levels and normal fT4 concentrations

Autoimmune thyroid disease (10–20%) Presence of TPO and/or TG antibodies in serum with or without changes to TSH and fT4 concentrations

In observational studies on the impairment of cognitive development and behavioral disorders in the context of mild iodine deficiency, maternal blood samples were usually taken between the 9th and the 13th week of gestation ([Table 3]). The neurological examinations of the offspring were carried out between the ages of 6 months and 16 years [81]. The general study designs varied considerably. The differences relate to the criteria used to select mother-child pairs, the reference values and ranges used to determine the different levels of maternal hypothyroidism or hypothyroxinemia, and the different tests used to evaluate neurological development (s. [Table 3]).

Table 3 Observational studies on the negative impact on cognitive development and behavioral disorders in connection with mild iodine deficiency – characteristics of all studies included in the systematic evaluation (data from [94]) (“sister articles” were combined).

Author, Year [Reference]	Total number of tested participants	Country	Maternal thyroid disorder	Pregnancy week at TFT	Criteria for thyroid function disorder	Age of child at evaluation	Tests used to evaluate neurological development
Abbreviations: Co = continuous; HR = hypothyroxinemia; OH = overt hypothyroidism; SH = subclinical hypothyroidism; TFT = thyroid function test; TSH = thyroid-stimulating hormone; WISC = Wechsler Intelligence Scale for Children
Pop et al. 1999 [95]	220	Netherlands	HR	12 and 32 weeks	10th percentile for fT4 (< 10.4 pmol/l) and 5th percentile for fT4 (< 9.8 pmol/l)	10 months	Bayley Scales of Infant Development
Pop et al. 2003 [96]	125	Netherlands	HR	12, 24 and 32 weeks	fT4 < 10th percentile (12.10 pmol/l)	1–2 years	Bayley Scales of Infant Development
Kasatkina et al. 2006 [81]	35	Russia	HR	1st and 3rd trimester	fT4 < 12.0 pmol/l	6, 9 and 12 months	Gnome method, especially the Coefficient of Mental Development
Li et al. 2010 [97]	213	China	SH and HR	16 to 20 weeks	SH = TSH > 97.5 percentile (4.21 mU/l), HR = tT4 < 2.5 percentile (101.79 nmol/l)	25–30 months	Bayley Scales of Infant Development
Henrichs et al. 2010 [98]	3659	Netherlands	HR and Co TSH	13,3 weeks	HR = fT4 10th percentile (< 11.76 pmol/l) and 5th percentile (< 10.96 pmol/l), Co TSH = TSH reference range 0.03–2.50 mU/l	18 and 30 months	MacArthur-Bates Communication Development Inventories after 18 months, review of speech development after 30 months
Suárez-Rodríguez et al. 2012 [80]	70	Spain	HR	37 weeks	fT4 < 10th percentile (9.5 pmol/l)	38 months and 5 years	McCarthy Scales of Children’s Abilities
Williams et al. 2012 [99]	166	United Kingdom	SH and HR	+ 1 hour after delivery	SH = TSH > 3.0 mU/l, HR = fT4 ≤ 10th percentile (11.6 pmol/l) or tT4 ≤ 10th percentile (108.4 nmol/l)	5.5 years	McCarthy Scales of Children’s Abilities
Craig et al. 2012 [100]	196	USA	HR	2nd trimester	fT4 < 3rd percentile (11.84 pmol/l)	2 years	Bayley Scale of Infant Development III
Ghassabian et al. 2014 [79]/Korevaar et al. 2016 [83]	3737/5647	Netherlands	HR and SH	13.5/13.2 weeks	HR = fT4 < 5th percentile (10.99 pmol/l), SH = TSH > 2.50 mU/l	6 years	Snijders-Oomen Non-verbal Intelligence Test, revision (mosaic patterns and categories)
Päkkilä et al. 2015 [101]	5295	Finland	HR, SH and OH	Average 10.7 weeks	HR = fT4 < 11.4–11.09 pmol/l depending on the trimester, SH = TSH > 3.10–3.50 mU/l, depending on the trimester	8 and 16 years	Severe and mild ADHD symptoms and normal behavior; teachers reported on the standard of the schoolwork of the child; self-report by the adolescent and WISC-reviewed
Grau et al. 2015 [102]	455	Spain	HR	1st and 2nd trimester	< 10th percentile (13.7–11.5 pmol/l depending on the trimester)	1 and 6–8 years	Brunet-Lézine Scale and WISC-IV

All studies, with the exception of the one by Grau et al. [102] which investigated the effects of low maternal fT4 levels at the end of the first trimester of pregnancy, report impairment of cognitive and motor development in exposed children [40] [44] [77] [79] [92] [96] [97] [98] [103] [104]. The correlation gradually decreased with advancing pregnancy and disappeared by late pregnancy [42] [101] [105].

Overall, none of the systematic reviews and meta-analyses showed clear threshold values for high TSH and/or low fT4 values in the serum of pregnant women which would clearly indicate an increased risk of neurological developmental disorders in their offspring. Such threshold values could not be determined because the epidemiological studies were not designed to show quantitative thresholds (s. [Table 3]).

Impact of Endocrine Disruptors (TDCs) on Thyroid Hormone System and the Role of Adequate Iodine Intake

TDCs do not just have a direct effect on pregnancy by acting as hormone agonists or antagonists but also have indirect effects by impairing maternal, placental, and fetal homeostasis. It is thought that the adverse health effects of TDCs including air pollution on offspring may be the result of two mechanisms: the first mechanism directly affects the placenta and therefore passes into the fetal circulation, and/or the second mechanism has an indirect impact through oxidative stress on the placenta which induces inflammation and epigenetic changes in the placenta and offspring [13] [106] [107] [108] [109] [110] [111].

In view of the many different effects of all EDCs, such as low-dose effects, possible non-linear dose responses, cumulative effects which are often expected in cases of combined exposure, and cross-generational effects with different impacts during critical windows of exposure, it is currently unlikely that it is possible to define safe EDC contamination levels [26] [84] [112] [113] [114] [115].

Iodine deficiency is clearly able to promote adverse effects [116]. The urgency of the problem is due to the concurrence of the widely prevalent inadequate iodine intake and the continuously increasing exposure of humans to TDCs [6] [32] [117] [118] [119]. The studies on maternal hypothyroxinemia caused by mild to moderately severe iodine deficiency carried out to date have not taken additional prenatal exposure to TDCs into account (s. [Table 4], right-hand column).

Table 4 Potential thyroid-disrupting chemicals (TDCs) which target the signaling pathways of thyroid hormones (data from [2]).

Examples of chemicals	Target of TDC activities and outcomes	Changes in neurological development
1 OCPs – are predominantly used in agriculture to protect crops, but they have been banned or their use has been greatly reduced in recent decades because of their environmental persistence and neurotoxicity. 2 PCBs – banned compounds used to produce electrical devices such as transformers and used in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers. 3 Perchlorates, thiocyanate, and nitrate – exposure to these harmful substances occurs through foodstuffs or from other sources (e.g., thiocyanate in cigarette smoke or rocket fuels and perchlorate and nitrate in fertilizers). 4 Phthalates – are used to make plastics more flexible. They are also present in some food packaging, cosmetics, children’s toys, and medical devices. 5 Genistein – a substance which occurs naturally in plants with hormone-like activity found in soya products such as tofu or soya milk. 6 4NP – is used in the production of antioxidants, lubricant oil additives, detergents and washing-up liquids, emulsifiers, and solubilizers. 7 BP2 – is no longer approved for use as a UV filter in sun creams in the European Union. However, it is still contained in plastic materials and many cosmetics to prevent UV-related degradation. 8 Amitrole – is used as an herbicide. 9 PBDEs – are used in the production of flame retardants in household items such as upholstery foam and carpets. Although most PBDEs have been banned or are being gradually phased out, they persist in the environment. 10 Triclosan – may be present in some antimicrobial products and personal care products such as body washes. 11 Silymarin – a flavonoid compound which is a purified extract of the milk thistle plant. 12 Erythrosine, also known as Red Dye No. 3 – is an organo-iodine compound. It is a reddish-pink dye mainly used for food coloring. 13 Hydroxylated PBDEs (OH-BDEs) are abiotic and biotic transformation products of PBDEs which also occur naturally in marine systems. 14 Bisphenols, especially bisphenol A (BPA) – are used in the production of polycarbonate plastics and epoxy resins and are contained in many plastic products such as water bottles, food containers, CDs, DVDs, safety equipment, thermal paper, and medical devices.
Organochlorine pesticides (OCPs)1 Polychlorinated biphenyl compounds (PCB)2	TSH-receptor signaling and reduced stimulation of thyroid follicular cells [120]	Impairs cognitive, motor, and communication development [121] [122] [123] [124] [125] Impairs cognitive and motor development and play activity [126] Lower IQ [120] Development of ADHD-associated behavior [127]
Perchlorate3 Thiocyanate3 Nitrate3 Phthalates4	Na+/I symporter (NIS) and inhibition of TH biosynthesis	Impairs cognitive development [128] Pre- and postnatal exposure to tobacco can affect neurocognitive development [129] Gender-specific effects on cognitive, psychomotor and behavioral development [116] [130] [131] Lower nonverbal and verbal IQ scores in offspring [132] [133]
Propylthiouracil (PTU) Methimazole (MMI) Genistein5 4-nonylphenol (NP)6 Benzophenone-2 (BP2)7 Herbicide (amitrole)8	Inhibition of thyroid peroxidase (TPO) leads to lower TH synthesis and a subsequent reduction in circulating TH concentrations.	Increased risk of periventricular heterotopia [134] TH insufficiency leads to brain malformations and learning impairment [135] Lower cognitive function [136]
OH-PCBs2 Polybrominated diphenyl ethers (PBDEs)9 Phthalates4 Genistein5	TH distributor proteins: Displacement of T4 and T3 by the thyroid serum-binding protein transthyretin (TTR) and/or thyroid-binding globulin (TBG) disturbs TH homeostasis and decreases TH plasma levels.	Impairs cognitive, behavioral, and motor development [137] [138] [139] [140] [141] Delayed neurological development [142]
Polychlorinated biphenyls (PCBs, OH-PCBs)2 Triclosan10	Upregulation of thyroid hormone catabolism through activation of key hepatic receptors leads to decrease of circulating TH levels [111] [143].	Impairs early motor development [144] Hearing loss [145] Changes thyroid hormone levels in serum [146] [147]
Silymarin11	Disorders of cellular transmembrane transporters (MCT8, MCT10 and OATP1C1) inhibit T3 uptake.	Undesirable effects on the TH axis [148]
Erythrosine12 6-n-propylthiouracil PCBs2	Modification of deiodinase enzyme activities (DIO2, DIO3) through competitive inhibition of the enzyme or through interaction with its sulfhydryl cofactor.	With the exception of FD&C Red No. 3 which causes thyroid tumors in rats, no studies have shown yet that chemicals which affect DIO expression and/or activity directly lead to undesirable outcomes [18].
OH-PCBs2 OH-BDEs13 Bisphenols14	Binding and transactivation of thyroid hormone receptor (TR) (TRα, TRβ) by some chemicals which bind TRs as antagonists and/or change the transcription; interactions with these TRs disrupt normal thyroid homeostasis which may possibly lead to anomalies in brain development [11] [18] [149] [150].	Impairs mental and motor development [149] Hearing loss [145] Impairs neurogenesis and synaptic plasticity [150]

There are public health concerns about pregnant women with mild iodine deficiency who are exposed to perchlorate, thiocyanate, nitrate and other environmental “thyreostatic substances” [5] [8] [12] [26] [143] [151] [152] [153] [154] [155] [156]. A dose-effect model which investigated iodide and perchlorate exposure in foodstuffs showed that a low iodine intake of 75 μg/day and a daily perchlorate dose of 4.2 μg/kg would be sufficient to induce hypothyroxinemia, whereas a higher daily dose of perchlorate of about 34 µg/kg would be required if the iodine intake was sufficient (approx. 250 µg/day) [157]. Iodine deficiency can therefore worsen the effects of exposure to TDC, especially in pregnancy [5] [8] [12] [17] [18] [26].

[Table 4] summarizes the well-characterized effects of TDCs on TH metabolism and the infant brain [116] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [144] [145] [146] [147] [148] [149] [150] [158]. Air pollution is the main risk factor for the global disease burden, but the negative effects of exposure to airborne fine particulate matter measuring < 2.5 µm (PM_2.5) in pregnancy were previously not taken into account [159] [160] [161]. The available evidence suggests that intrauterine PM_2.5 exposure can change prenatal brain development through oxidative stress and systemic inflammation and lead to chronic neuroinflammation, microglial activation, and neuronal micturition disorders [28] [162] [163]. It was shown that exposure to fine particulate matter was associated with structural changes to the cerebral cortex of the child as well as impairment of core executive functions such as inhibitory control [164] [165] [166] [167].

Prevention and Treatment of IMH

As studies on the impact of IMH on the cognitive and motor development and the risk of neuropsychiatric disorders in children have shown a clear connection to early pregnancy, the key clinical question is whether these complications could be prevented at an early stage by iodine or levothyroxine substitution [39] [43] [89]. Treatment of IMH or subclinical hypothyroidism by administering levothyroxine in early pregnancy did not have any benefit on the neurological development of children based on evaluations when they were aged 6 and 9 years. However, levothyroxine supplementation was initiated, on average, in the 12th week of gestation, which is too late [168] [169]. This is why the ATA guidelines do not recommend supplementation with levothyroxine [92]. However, based on new epidemiological data, the ETA guidelines suggest that levothyroxine supplementation should be carried out in the first trimester of pregnancy rather than during later stages of pregnancy [93]. The results of a recent study showed that early levothyroxine supplementation in women with TSH values of > 2.5 mU/l and fT4 < 7.5 pg/ml in or before the ninth week of gestation is safe and improves the course of pregnancy. Whether it also improves the neurological development of affected offspring has not yet been investigated. The data supports the recommendation to adopt threshold values for levothyroxine supplementation and start supplementation as early as possible, ideally before the end of the first trimester of pregnancy. TSH suppression must be avoided [170].

A positive association has been demonstrated between maternal iodine intake starting even before conception and cognitive functions of her offspring at the age of 6–7 years [171], but not if iodine substitution was only initiated in pregnancy [105] [172] [173] [174] [175] [176]. Well designed, randomized controlled studies to study the neuropsychological development of children are currently in progress, which will investigate the impact of daily supplementation with 150–200 µg iodine in the period prior to preconception, during pregnancy and during lactation [177] [178] [179] [180].

The Krakow Declaration on Iodine, published by the Euthyroid Consortium and other organizations, raises important points on how iodine deficiency in Europe could be efficiently eliminated. The demands include

1. harmonizing universal salt iodization in all European countries,

2. carrying out regular monitoring and evaluation studies to continuously measure the benefit and potential damage of iodine enrichment programs, and

3. necessary social engagement to ensure that programs to prevent iodine deficiency disorders (IDD) are sustained [181] [182].

Conclusions for Clinical Practice

1. Iodine deficiency means that less FT4 and more FT3 is produced; rather than being elevated, TSH concentrations are decreased. Individual levels of iodine deficiency can be best determined based on hypothyroxinemia.

2. In clinical practice when dealing with women who want to have children this means that improving iodine intake should already start prior to conception. A low FT4 level is a useful supporting argument.

3. Some of the numerous endocrine-disrupting chemicals (EDCs) in the environment can negatively affect thyroid hormone metabolism and may even amplify the effects of iodine deficiency. These chemicals are also referred to as TDCs. As such TDCs may be below the detection limits in individuals, FT4 can serve as a marker for adequate iodine intake, especially in the first three months of pregnancy.

4. Of course, it is the responsibility of policy makers to persuade industry to reduce the prevalence of EDCs. But every one of us can also contribute to reducing the extent of EDCs released into the environment.

• References/Literatur

• 1 Eastman CJ, Zimmermann MB. The iodine deficiency disorders. In: Feingold KR, Anawalt B, Boyce A. et al. , ed. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. Accessed February 06, 2018 at: https://www.ncbi.nlm.nih.gov/books/NBK285556/
• 2 Grossklaus R, Liesenkötter K-P, Doubek K. et al. Iodine Deficiency, Maternal Hypothyroxinemia and Endocrine Disrupters Affecting Fetal Brain Development: A Scoping Review. Nutrients 2023; 15: 2249
• 3 American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice. Reducing Prenatal Exposure to Toxic Environmental Agents: ACOG Committee Opinion, Number 832. Obstet Gynecol 2021; 138: e40-e54
• 4 Yilmaz B, Terekeci H, Sandal S. et al. Endocrine disrupting chemicals: exposure, effects on human health, mechanism of action, models for testing and strategies for prevention. Rev Endocr Metab Disord 2020; 21: 127-147
• 5 Ghassabian A, Trasande L. Disruption in Thyroid Signaling Pathway: A Mechanism for the Effect of Endocrine-Disrupting Chemicals on Child Neurodevelopment. Front Endocrinol (Lausanne) 2018; 9: 204
• 6 Köhrle J, Frädrich C. Thyroid hormone system disrupting chemicals. Best Pract Res Clin Endocrinol Metab 2021; 35: 101562
• 7 Demeneix BA. Evidence for Prenatal Exposure to Thyroid Disruptors and Adverse Effects on Brain Development. Eur Thyroid J 2019; 8: 283-292
• 8 Mughal BB, Fini JB, Demeneix BA. Thyroid-disrupting chemicals and brain development: an update. Endocr Connect 2018; 7: R160-R186
• 9 Yan Y, Guo F, Liu K. et al. The effect of endocrine-disrupting chemicals on placental development. Front Endocrinol (Lausanne) 2023; 14: 1059854
• 10 Gómez-Roig D, Pascal R, Cahuana MJ. et al. Environmental Exposure during Pregnancy: Influence on Prenatal Development and Early Life: A Comprehensive Review. Fetal Diagn Ther 2021; 48: 245-257
• 11 Hamers T, Kortenkamp A, Scholze M. et al. Transthyretin-Binding Activity of Complex Mixtures Representing the Composition of Thyroid-Hormone Disrupting Contaminants in House Dust and Human Serum. Environ Health Perspect 2020; 128: 17015
• 12 Lisco G, De Tullio, AGiagulli VA. et al. Interference on iodine uptake and human thyroid function by perchlorate-contaminated water and food. Nutrients 2020; 12: 1669
• 13 Ghassabian A, Pierotti L, Basterrechea M. et al. Association of Exposure to Ambient Air Pollution With Thyroid Function During Pregnancy. JAMA Netw Open 2019; 2: e1912902
• 14 Lanphear BP. The impact of toxins on the developing brain. Annu Rev Public Health 2015; 36: 211-230
• 15 Boas M, Feldt-Rasmussen U, Main KM. Thyroid effects of endocrine disrupting chemicals. Mol Cell Endocrinol 2012; 355: 240-248
• 16 Jugan ML, Levi Y, Blondeau JP. Endocrine disruptors and thyroid hormone physiology. Biochem Pharmacol 2010; 79: 939-947
• 17 Hartoft-Nielsen ML, Boas M, Bliddal S. et al. Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy?. J Thyroid Res 2011; 2011: 342189
• 18 Noyes PD, Friedman KP, Browne P. et al. Evaluating Chemicals for Thyroid Disruption: Opportunities and Challenges with in Vitro Testing and Adverse Outcome Pathway Approaches. Environ Health Perspect 2019; 127: 95001
• 19 Calsolaro V, Pasqualetti G, Niccolai F. et al. Thyroid Disrupting Chemicals. Int J Mol Sci 2017; 18: 2583
• 20 Duntas LH, Stathatos N. Toxic chemicals and thyroid function: hard facts and lateral thinking. Rev Endocr Metab Disord 2015; 16: 311-318
• 21 Gilbert ME, Rovet J, Chen Z. et al. Developmental thyroid hormone disruption: prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology 2012; 33: 842-852
• 22 Cediel-Ulloa A, Lupu DL, Johansson Y. et al. Impact of endocrine disrupting chemicals on neurodevelopment: the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity. Expert Rev Endocrinol Metab 2022; 17: 131-141
• 23 Hetzel BS. The development of a global program for the elimination of brain damage due to iodine deficiency. Asia Pac J Clin Nutr 2012; 21: 164-170
• 24 Monahan M, Boelaert K, Jolly K. et al. Costs and benefits of iodine supplementation for pregnant women in a mildly to moderately iodine-deficient population: a modelling analysis. Lancet Diabetes Endocrinol 2015; 3: 715-722
• 25 Großklaus R. Nutzen und Risiken der Jodprophylaxe. Einfluss von Jodsalz auf Schilddrüsenkrankheiten und die Gesundheit des Menschen. Präv Gesundheitsf 2007; 2: 158-166
• 26 Demeneix B, Slama R. Endocrine Disruptors: From Scientific Evidence to Human Health Protection. In Report Commissioned by the PETI Committee of the European Parliament; Policy Department for Citizen’s Rights and Constitutional Affairs. 2019 Accessed October 09, 2021 at: http://www.europarl.europa.eu/RegData/etudes/STUD/2019/608866/IPOL_STU(2019)608866_EN.pdf
• 27 Trasande L, Zoeller RT, Hass U. et al. Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis. Andrology 2016; 4: 565-572
• 28 Costa LG, Cole TB, Dao K. et al. Developmental impact of air pollution on brain function. Neurochem Int 2019; 131: 104580
• 29 Rivas I, Basagaña X, Cirach M. et al. Association between Early Life Exposure to Air Pollution and Working Memory and Attention. Environ Health Perspect 2019; 127: 57002
• 30 D’Angiulli A. Severe Urban Outdoor Air Pollution and Children’s Structural and Functional Brain Development, From Evidence to Precautionary Strategic Action. Front Public Health 2018; 6: 95
• 31 Suades-González E, Gascon M, Guxens M. et al. Air Pollution and Neuropsychological Development: A Review of the Latest Evidence. Endocrinology 2015; 156: 3473-3482
• 32 Padmanabhan V, Song W, Puttabyatappa M. Praegnatio Perturbatio-Impact of Endocrine-Disrupting Chemicals. Endocr Rev 2021; 42: 295-353
• 33 Inoue K, Yan Q, Arah OA. et al. Air Pollution and Adverse Pregnancy and Birth Outcomes: Mediation Analysis Using Metabolomic Profiles. Curr Environ Health Rep 2020; 7: 231-242
• 34 Pergialiotis V, Kotrogianni P, Christopoulos-Timogiannakis E. et al. Bisphenol A and adverse pregnancy outcomes: a systematic review of the literature. J Matern Fetal Neonatal Med 2018; 31: 3320-3327
• 35 Janssen BG, Saenen ND, Roels HA. et al. Fetal Thyroid Function, Birth Weight, and in Utero Exposure to Fine Particle Air Pollution: A Birth Cohort Study. Environ Health Perspect 2017; 125: 699-705
• 36 Zhao X, Peng S, Xiang Y. et al. Correlation between Prenatal Exposure to Polybrominated Diphenyl Ethers (PBDEs) and Infant Birth Outcomes: A Meta-Analysis and an Experimental Study. Int J Environ Res Public Health 2017; 14: 268
• 37 Li M, Eastman CJ. The changing epidemiology of iodine deficiency. Nat Rev Endocrinol 2012; 8: 434-440
• 38 Velasco I, Bath SC, Rayman MP. Iodine as Essential Nutrient during the First 1000 Days of Life. Nutrients 2018; 10: 290
• 39 Bath C. The effect of iodine deficiency during pregnancy on child development. Proc Nutr Soc 2019; 78: 150-160
• 40 Min H, Dong J, Wang Y. et al. Maternal Hypothyroxinemia-Induced Neurodevelopmental Impairments in the Progeny. Mol Neurobiol 2016; 53: 1613-1624
• 41 de Escobar GM, Obregón MJ, del Rey FE. Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutr 2007; 10: 1554-1570
• 42 Chen Y, Xue F. The impact of gestational hypothyroxinemia on the cognitive and motor development of offspring. J Matern Fetal Neonatal Med 2020; 33: 1940-1945
• 43 Dosiou C, Medici M. Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns. Eur J Endocrinol 2017; 176: R21-R38
• 44 Henrichs J, Ghassabian A, Peeters RP. et al. Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why?. Clin Endocrinol (Oxf) 2013; 79: 152-162
• 45 Moleti M, Trimarchi F, Vermiglio F. Doubts and Concerns about Isolated Maternal Hypothyroxinemia. J Thyroid Res 2011; 2011: 463029
• 46 Glinoer D. The regulation of thyroid function during normal pregnancy: importance of the iodine nutrition status. Best Pract Res Clin Endocrinol Metab 2004; 18: 133-152
• 47 Mégier C, Dumery G, Luton D. Iodine and Thyroid Maternal and Fetal Metabolism during Pregnancy. Metabolites 2023; 13: 633
• 48 EFSA NDA Panel (EFSA Panel on Panel on Dietetic Products Nutrition and Allergies). Scientific Opinion on Dietary Reference Values for iodine. EFSA Journal 2014; 12: 3660
• 49 Korevaar TIM, Medici M, Visser TJ. et al. Thyroid disease in pregnancy: new insights in diagnosis and clinical management. Nat Rev Endocrinol 2017; 13: 610-622
• 50 Williams GR. Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol 2008; 20: 784-794
• 51 World Health Organization. Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers. 3. Geneva: World Health Organization; 2007. Accessed December 04, 2012 at: https://apps.who.int/iris/handle/10665/43781
• 52 The Iodine Global Network. Global scorecard of iodine nutrition in 2020 in the general population based on school-age children (SAC). Ottawa, Canada: IGN; 2020. Accessed October 20, 2020 at: https://www.ign.org/cm_data/Global-Scorecard-2020-3-June-2020.pdf
• 53 Hey I, Thamm M. Monitoring der Jod- und Natriumversorgung bei Kindern und Jugendlichen im Rahmen der Studie des Robert Koch-Instituts zur Gesundheit von Kindern und Jugendlichen in Deutschland (KiGGS Welle 2). Abschlussbericht. Berlin: Robert Koch-Institut; 2019. Accessed May 14, 2020 at: https://service.ble.de/ptdb/index2.php?detail_id=47144&site_key=145&zeilenzahl_zaehler=592&NextRow=330
• 54 Bundesinstitut für Risikobewertung (BfR). Jodversorgung in Deutschland wieder rückläufig – Tipps für eine gute Jodversorgung. Fragen und Antworten zur Jodversorgung und zur Jodmangelvorsorge. FAQ des BfR vom 20. Februar 2020 (aktualisiert 9. Februar 2021). Accessed October 20, 2023 at: https://www.bfr.bund.de/cm/343/jodversorgung-in-deutschland-wieder-ruecklaeufig-tipps-fuer-eine-gute-jodversorgung.pdf
• 55 The Iodine Global Network. Global Scorecard of Iodine Nutrition in 2017 in the general population and in pregnant women (PW). Zurich, Switzerland: IGN; Accessed June 09, 2017 at: https://www.ign.org/cm_data/IGN_Global_Scorecard_AllPop_and_PW_May2017.pdf
• 56 Katko M, Gazso AA, Hircsu I. et al. Thyroglobulin level at week 16 of pregnancy is superior to urinary iodine concentration in revealing preconceptual and first trimester iodine supply. Matern Child Nutr 2018; 14: e12470
• 57 Candido AC, Morais NS, Dutra LV. et al. Insufficient iodine intake in pregnant women in different regions of the world: a systematic review. Arch Endocrinol Metab 2019; 63: 306-311
• 58 Baldini E, Virili C, D’Armiento E. et al. Iodine Status in Schoolchildren and Pregnant Women of Lazio, a Central Region of Italy. Nutrients 2019; 11: 1647
• 59 Medici M, Ghassabian A, Visser W. et al. Women with high early pregnancy urinary iodine levels have an increased risk of hyperthyroid newborns: the population-based Generation R Study. Clin Endocrinol (Oxf) 2014; 80: 598-606
• 60 Vandevijvere S, Amsalkhir S, Mourri AB. et al. Iodine deficiency among Belgian pregnant women not fully corrected by iodine-containing multivitamins: a national cross-sectional survey. Br J Nutr 2013; 109: 2276-2284
• 61 Andersen SL, Sørensen LK, Krejbjerg A. et al. Iodine deficiency in Danish pregnant women. Dan Med J 2013; 60: A4657
• 62 Global Fortification Data Exchange. Global Fortification Coverage Data. 2021 Accessed March 17, 2025 at: https://www.gfdx.org
• 63 Nyström HF, Brantsæter AL, Erlund I. et al. Iodine status in the Nordic countries – past and present. Food Nutr Res 2016; 60: 31969
• 64 Miles EA, Vahlberg T, Calder PC. et al. Iodine status in pregnant women and infants in Finland. Eur J Nutr 2022; 61: 2919-2927
• 65 Nazeri P, Mirmiran P, Shiva N. et al. Iodine nutrition status in lactating mothers residing in countries with mandatory and voluntary iodine fortification programs: an updated systematic review. Thyroid 2015; 25: 611-620
• 66 Manousou S, Andersson M, Eggertsen R. et al. Iodine deficiency in pregnant women in Sweden: a national cross-sectional study. Eur J Nutr 2020; 59: 2535-2545
• 67 Lindorfer H, Krebs M, Kautzky-Willer A. et al. Iodine deficiency in pregnant women in Austria. Eur J Clin Nutr 2015; 69: 349-354
• 68 Johner SA, Thamm M, Schmitz R. et al. Examination of iodine status in the German population: an example for methodological pitfalls of the current approach of iodine status assessment. Eur J Nutr 2016; 55: 1275-1282
• 69 Dold S, Zimmermann MB, Jukic T. et al. Universal salt iodization provides sufficient dietary iodine to achieve adequate iodine nutrition during the first 1000 days: A cross-sectional multicenter study. J Nutr 2018; 148: 587-598
• 70 Ittermann T, Albrecht D, Arohonka P. et al. Standardized Map of Iodine Status in Europe. Thyroid 2020; 30: 1346-1354
• 71 Eastman CJ, Ma G, Li M. Optimal Assessment and Quantification of Iodine Nutrition in Pregnancy and Lactation: Laboratory and Clinical Methods, Controversies and Future Directions. Nutrients 2019; 11: 2378
• 72 Trumpff C, De Schepper J, Tafforeau J. et al. Mild iodine deficiency in pregnancy in Europe and its consequences for cognitive and psychomotor development of children: a review. J Trace Elem Med Biol 2013; 27: 174-183
• 73 Zimmermann M, Delange F. Iodine supplementation of pregnant women in Europe: a review and recommendations. Eur J Clin Nutr 2004; 58: 979-984
• 74 Chan S, Boelaert K. Optimal management of hypothyroidism, hypothyroxinemia and euthyroid TPO antibody positivity preconception and in pregnancy. Clin Endocrinol (Oxf) 2015; 82: 313-326
• 75 Dhillon-Smith RK, Boelaert K. Preconception Counseling and Care for Pregnant Women with Thyroid Disease. Endocrinol Metab Clin North Am 2022; 51: 417-436
• 76 Miranda A, Sousa N. Maternal hormonal milieu influence on fetal brain development. Brain Behav 2018; 8: e00920
• 77 Costeira MJ, Oliveira P, Santos NC. et al. Psychomotor development of children from an iodine-deficient region. J Pediatr 2011; 159: 447-453
• 78 Kawahori K, Hashimoto K, Yuan X. et al. Mild Maternal Hypothyroxinemia During Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring. Thyroid 2018; 28: 395-406
• 79 Ghassabian A, El Marroun H, Peeters RP. et al. Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children. J Clin Endocrinol Metab 2014; 99: 2383-2390
• 80 Suárez-Rodríguez M, Azcona-San Julián C, Alzina de Aguilar V. Hypothyroxinemia during pregnancy: the effect on neurodevelopment in the child. Int J Dev Neurosci 2012; 30: 435-438
• 81 Kasatkina EP, Samsonova LN, Ivakhnenko VN. et al. Gestational hypothyroxinemia and cognitive function in offspring. Neurosci Behav Physiol 2006; 36: 619-624
• 82 Moog NK, Entringer S, Heim C. et al. Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience 2017; 342: 68-100
• 83 Korevaar TI, Muetzel R, Medici M. et al. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol 2016; 4: 35-43
• 84 Préau L, Fini JB, Morvan-Dubois G. et al. Thyroid hormone signaling during early neurogenesis and its significance as a vulnerable window for endocrine disruption. Biochim Biophys Acta 2015; 1849: 112-121
• 85 Abel MH, Korevaar TIM, Erlund I. et al. Iodine Intake is Associated with Thyroid Function in Mild to Moderately Iodine Deficient Pregnant Women. Thyroid 2018; 28: 1359-1371
• 86 Alcaide Martin A, Mayerl S. Local Thyroid Hormone Action in Brain Development. Int J Mol Sci 2023; 24: 12352
• 87 Korevaar TI, Nieboer D, Bisschop PH. et al. Risk factors and a clinical prediction model for low maternal thyroid function during early pregnancy: two population-based prospective cohort studies. Clin Endocrinol (Oxf) 2016; 85: 902-909
• 88 Berbel P, Mestre JL, Santamaría A. et al. Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 2009; 19: 511-519
• 89 Mohan V, Sinha RA, Pathak A. et al. Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis. Exp Neurol 2012; 237: 477-488
• 90 Julvez J, Alvarez-Pedrerol M, Rebagliato M. et al. Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 2013; 24: 150-157
• 91 Elahi S, Nagra SA. Low maternal iodine intake and early pregnancy hypothyroxinemia: Possible repercussions for children. Indian J Endocrinol Metab 2014; 18: 526-530
• 92 Alexander EK, Pearce EN, Brent GA. et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017; 27: 315-389
• 93 Lazarus J, Brown RS, Daumerie C. et al. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014; 3: 76-94
• 94 Thompson W, Russell G, Baragwanath G. et al. Maternal thyroid hormone insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 2018; 88: 575-584
• 95 Pop VJ, Kuijpens JL, van Baar AL. et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999; 50: 149-155
• 96 Pop VJ, Brouwers EP, Vader HL. et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 2003; 59: 282-288
• 97 Li Y, Shan Z, Teng W. et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clin Endocrinol (Oxf) 2010; 72: 825-829
• 98 Henrichs J, Bongers-Schokking JJ, Schenk JJ. et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010; 95: 4227-4234
• 99 Williams F, Watson J, Ogston S. Scottish Preterm Thyroid Group. et al. Mild maternal thyroid dysfunction at delivery of infants born ≤ 34 weeks and neurodevelopmental outcome at 5.5 years. J Clin Endocrinol Metab 2012; 97: 1977-1985
• 100 Craig WY, Allan WC, Kloza EM. et al. Mid-gestational maternal free thyroxine concentration and offspring neurocognitive development at age two years. J Clin Endocrinol Metab 2012; 97: E22-E28
• 101 Päkkilä F, Männistö T, Hartikainen AL. et al. Maternal and Child’s Thyroid Function and Child’s Intellect and Scholastic Performance. Thyroid 2015; 25: 1363-1374
• 102 Grau G, Aguayo A, Vela A. et al. Normal intellectual development in children born from women with hypothyroxinemia during their pregnancy. J Trace Elem Med Biol 2015; 31: 18-24
• 103 Kampouri M, Margetaki K, Koutra K. et al. Maternal mild thyroid dysfunction and offspring cognitive and motor development from infancy to childhood: the Rhea mother-child cohort study in Crete, Greece. J Epidemiol Community Health 2021; 75: 29-35
• 104 Andersen SL, Andersen S, Liew Z. et al. Maternal Thyroid Function in Early Pregnancy and Neuropsychological Performance of the Child at 5 Years of Age. J Clin Endocrinol Metab 2018; 103: 660-670
• 105 Chevrier J, Harley KG, Kogut K. et al. Maternal Thyroid Function during the Second Half of Pregnancy and Child Neurodevelopment at 6, 12, 24, and 60 Months of Age. J Thyroid Res 2011; 2011: 426427
• 106 Chen H, Oliver BG, Pant A. et al. Particulate Matter, an Intrauterine Toxin Affecting Foetal Development and Beyond. Antioxidants (Basel) 2021; 10: 732
• 107 Johnson NM, Hoffmann AR, Behlen JC. et al. Air pollution and Children’s health-a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter. Environ Health Prev Med 2021; 26: 72
• 108 Costa LG, Cole TB, Dao K. et al. Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders. Pharmacol Ther 2020; 210: 107523
• 109 Ozaki K, Kato D, Ikegami A. et al. Maternal immune activation induces sustained changes in fetal microglia motility. Sci Rep 2020; 10: 21378
• 110 Street ME, Bernasconi S. Endocrine-Disrupting Chemicals in Human Fetal Growth. Int J Mol Sci 2020; 21: 1430
• 111 Genc S, Zadeoglulari Z, Fuss SH. et al. The adverse effects of air pollution on the nervous system. J Toxicol 2012; 2012: 782462
• 112 Bose S, Ross KR, Rosa MJ. et al. Prenatal particulate air pollution exposure and sleep disruption in preschoolers: Windows of susceptibility. Environ Int 2019; 124: 329-335
• 113 Vandenberg LN, Colborn T, Hayes TB. et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 2012; 33: 378-455
• 114 Dutta S, Haggerty DK, Rappolee DA. et al. Phthalate Exposure and Long-Term Epigenomic Consequences: A Review. Front Genet 2020; 11: 405
• 115 Xin F, Susiarjo M, Bartolomei MS. Multigenerational and transgenerational effects of endocrine disrupting chemicals: A role for altered epigenetic regulation?. Semin Cell Dev Biol 2015; 43: 66-75
• 116 Daniel S, Balalian AA, Insel BJ. et al. Prenatal and early childhood exposure to phthalates and childhood behavior at age 7 years. Environ Int 2020; 143: 105894
• 117 Neven KY, Cox B, Cosemans C. et al. Lower iodine storage in the placenta is associated with gestational diabetes mellitus. BMC Med 2021; 19: 47
• 118 Neven KY, Wang C, Janssen BG. et al. Ambient air pollution exposure during the late gestational period is linked with lower placental iodine load in a Belgian birth cohort. Environ Int 2021; 147: 106334
• 119 Neven KY, Cox B, Vrijens K. et al. Determinants of placental iodine concentrations in a mild-to-moderate iodine-deficient population: an ENVIRONAGE cohort study. J Transl Med 2020; 18: 426
• 120 Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med 1996; 335: 783-789
• 121 Bouchard MF, Chevrier J, Harley KG. et al. Prenatal exposure to organophosphate pesticides and IQ in 7-year-old children. Environ Health Perspect 2011; 119: 1189-1195
• 122 Eskenazi B, Kogut K, Huen K. et al. Organophosphate pesticide exposure, PON1, and neurodevelopment in school-age children from the CHAMACOS study. Environ Res 2014; 134: 149-157
• 123 Yamazaki K, Araki A, Nakajima S. et al. Association between prenatal exposure to organochlorine pesticides and the mental and psychomotor development of infants at ages 6 and 18 months: The Hokkaido Study on Environment and Children’s Health. Neurotoxicology 2018; 69: 201-208
• 124 Wang S, Hu C, Lu A. et al. Association between prenatal exposure to persistent organic pollutants and neurodevelopment in early life: A mother-child cohort (Shanghai, China). Ecotoxicol Environ Saf 2021; 208: 111479
• 125 Jeddy Z, Kordas K, Allen K. et al. Prenatal exposure to organochlorine pesticides and early childhood communication development in British girls. Neurotoxicology 2018; 69: 121-129
• 126 Vermeir G, Covaci A, Van Larebeke N. et al. Neurobehavioural and cognitive effects of prenatal exposure to organochlorine compounds in three year old children. BMC Pediatr 2021; 21: 99
• 127 Sagiv SK, Thurston SW, Bellinger DC. et al. Prenatal organochlorine exposure and behaviors associated with attention deficit hyperactivity disorder in school-aged children. Am J Epidemiol 2010; 171: 593-601
• 128 Taylor PN, Okosieme OE, Murphy R. et al. Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the Controlled Antenatal Thyroid Study. J Clin Endocrinol Metab 2014; 99: 4291-4298
• 129 Moore BF, Shapiro AL, Wilkening G. et al. Prenatal Exposure to Tobacco and Offspring Neurocognitive Development in the Healthy Start Study. J Pediatr 2020; 218: 28-34.e2
• 130 Zhang Q, Chen XZ, Huang X. et al. The association between prenatal exposure to phthalates and cognition and neurobehavior of children-evidence from birth cohorts. Neurotoxicology 2019; 73: 199-212
• 131 Engel SM, Miodovnik A, Canfield RL. et al. Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environ Health Perspect 2010; 118: 565-571
• 132 van den Dries MA, Guxens M, Spaan S. et al. Phthalate and Bisphenol Exposure during Pregnancy and Offspring Nonverbal IQ. Environ Health Perspect 2020; 128: 77009
• 133 Olesen TS, Bleses D, Andersen HR. et al. Prenatal phthalate exposure and language development in toddlers from the Odense Child Cohort. Neurotoxicol Teratol 2018; 65: 34-41
• 134 Ramhøj L, Frädrich C, Svingen T. et al. Testing for heterotopia formation in rats after developmental exposure to selected in vitro inhibitors of thyroperoxidase. Environ Pollut 2021; 283: 117135
• 135 O’Shaughnessy KL, Kosian PA, Ford JL. et al. Developmental Thyroid Hormone Insufficiency Induces a Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study. Toxicol Sci 2018; 163: 101-115
• 136 Crofton KM, Gilbert M, Friedman KP. et al. Adverse outcome pathway on inhibition of thyroperoxidase and subsequent adverse neurodevelopmental outcomes in mammals. In: OECD Series on Adverse Outcome Pathways, No. 13. Paris: OECD Publishing; 2019.
• 137 Gibson EA, Siegel EL, Eniola F. et al. Effects of Polybrominated Diphenyl Ethers on Child Cognitive, Behavioral, and Motor Development. Int J Environ Res Public Health 2018; 15: 1636
• 138 Lam J, Lanphear BP, Bellinger D. et al. Developmental PBDE Exposure and IQ/ADHD in Childhood: A Systematic Review and Meta-analysis. Environ Health Perspect 2017; 125: 086001
• 139 Vuong AM, Yolton K, Xie C. et al. Childhood polybrominated diphenyl ether (PBDE) exposure and neurobehavior in children at 8 years. Environ Res 2017; 158: 677-684
• 140 Herbstman JB, Mall JK. Developmental Exposure to Polybrominated Diphenyl Ethers and Neurodevelopment. Curr Environ Health Rep 2014; 1: 101-112
• 141 Roze E, Meijer L, Bakker A. et al. Prenatal exposure to organohalogens, including brominated flame retardants, influences motor, cognitive, and behavioral performance at school age. Environ Health Perspect 2009; 117: 1953-1958
• 142 Wang Y, Qian H. Phthalates and Their Impacts on Human Health. Healthcare (Basel) 2021; 9: 603
• 143 Charatcharoenwitthaya N, Ongphiphadhanakul B, Pearce EN. et al. The association between perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant Thai women. J Clin Endocrinol Metab 2014; 99: 2365-2371
• 144 Berghuis SA, Soechitram SD, Hitzert MM. et al. Prenatal exposure to polychlorinated biphenyls and their hydroxylated metabolites is associated with motor development of three-month-old infants. Neurotoxicology 2013; 38: 124-130
• 145 Crofton KM, Zoeller RT. Mode of action: neurotoxicity induced by thyroid hormone disruption during development--hearing loss resulting from exposure to PHAHs. Crit Rev Toxicol 2005; 35: 757-769
• 146 Paul KB, Hedge JM, Bansal R. et al. Developmental triclosan exposure decreases maternal, fetal, and early neonatal thyroxine: a dynamic and kinetic evaluation of a putative mode-of-action. Toxicology 2012; 300: 31-45
• 147 Wang X, Ouyang F, Feng L. et al. Maternal Urinary Triclosan Concentration in Relation to Maternal and Neonatal Thyroid Hormone Levels: A Prospective Study. Environ Health Perspect 2017; 125: 067017
• 148 Johannes J, Jayarama-Naidu R, Meyer F. et al. Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8. Endocrinology 2016; 157: 1694-1701
• 149 Ruel MVM, Bos AF, Soechitram SD. et al. Prenatal exposure to organohalogen compounds and Children’s mental and motor development at 18 and 30 months of age. Neurotoxicology 2019; 72: 6-14
• 150 Santoro A, Chianese R, Troisi J. et al. Neuro-toxic and Reproductive Effects of BPA. Curr Neuropharmacol 2019; 17: 1109-1132
• 151 Gaberšček S, Zaletel K. Epidemiological trends of iodine-related thyroid disorders: an example from Slovenia. Arh Hig Rada Toksikol 2016; 67: 93-98
• 152 Román GC. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. J Neurol Sci 2007; 262: 15-26
• 153 Lewandowski TA, Peterson MK, Charnley G. Iodine supplementation and drinking-water perchlorate mitigation. Food Chem Toxicol 2015; 80: 261-270
• 154 Leung AM, Pearce EN, Braverman LE. Environmental perchlorate exposure: potential adverse thyroid effects. Curr Opin Endocrinol Diabetes Obes 2014; 21: 372-376
• 155 Ozpinar A, Kelestimur F, Songur Y. et al. Iodine status in Turkish populations and exposure to iodide uptake inhibitors. PLoS One 2014; 9: e88206
• 156 Suh M, Abraham L, Hixon JG. et al. The effects of perchlorate, nitrate, and thiocyanate on free thyroxine for potentially sensitive subpopulations of the 2001–2002 and 2007–2008 National Health and Nutrition Examination Surveys. J Expo Sci Environ Epidemiol 2014; 24: 579-587
• 157 Lumen A, Mattie DR, Fisher JW. Evaluation of perturbations in serum thyroid hormones during human pregnancy due to dietary iodide and perchlorate exposure using a biologically based dose-response model. Toxicol Sci 2013; 133: 320-341
• 158 Kim MJ, Park YJ. Bisphenols and Thyroid Hormone. Endocrinol Metab (Seoul) 2019; 34: 340-348
• 159 World Health Organization. WHO global air quality guidelines: particulate matter (‎PM2.5 and PM10)‎, ozone, nitrogen dioxide, sulfur dioxide and carbon monoxide: executive summary. Geneva: World Health Organization; 2021. Accessed October 02, 2021 at: https://apps.who.int/iris/handle/10665/345334
• 160 World Health Organization. WHO Fact sheets Ambient (outdoor) air quality and health. 22.09.2021. Geneva, Switzerland: World Health Organization; Accessed September 30, 2021 at: https://www.who.int/en/news-room/fact-sheets/detail/ambient-(outdoor)-air-quality-and-health
• 161 Burnett R, Chen H, Szyszkowicz M. et al. Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter. Proc Natl Acad Sci U S A 2018; 115: 9592-9597
• 162 Chen H, Oliver BG, Pant A. et al. Particulate matter, an intrauterine toxin affecting foetal development and beyond. Antioxidants (Basel) 2021; 10: 732
• 163 Block ML, Elder A, Auten RL. et al. The outdoor air pollution and brain health workshop. Neurotoxicology 2012; 33: 972-984
• 164 Loftus CT, Ni Y, Szpiro AA. et al. Exposure to ambient air pollution and early childhood behavior: A longitudinal cohort study. Environ Res 2020; 183: 109075
• 165 Peterson BS, Rauh VA, Bansal R. et al. Effects of prenatal exposure to air pollutants (polycyclic aromatic hydrocarbons) on the development of brain white matter, cognition, and behavior in later childhood. JAMA Psychiatry 2015; 72: 531-540
• 166 Lubczyńska MJ, Muetzel RL, El Marroun H. et al. Exposure to Air Pollution during Pregnancy and Childhood, and White Matter Microstructure in Preadolescents. Environ Health Perspect 2020; 128: 27005
• 167 Guxens M, Lubczyńska MJ, Muetzel RL. et al. Air Pollution Exposure During Fetal Life, Brain Morphology, and Cognitive Function in School-Age Children. Biol Psychiatry 2018; 84: 295-303
• 168 Lee SY, Pearce EN. Testing, Monitoring, and Treatment of Thyroid Dysfunction in Pregnancy. J Clin Endocrinol Metab 2021; 106: 883-892
• 169 Leung AM. No Benefit of Levothyroxine Among Pregnant Hypothyroid and/or Hypothyroxinemic Women on Offspring IQ at Age 9 years. Clin Thyroidol 2018; 30: 100-103
• 170 Runkle I, de Miguel MP, Barabash A. et al. Early Levothyroxine Treatment for Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy: The St Carlos Gestational and Thyroid Protocol. Front Endocrinol (Lausanne) 2021; 12: 743057
• 171 Robinson SM, Crozier SR, Miles EA. et al. Preconception Maternal Iodine Status Is Positively Associated with IQ but Not with Measures of Executive Function in Childhood. J Nutr 2018; 148: 959-966
• 172 Dineva M, Fishpool H, Rayman MP. et al. Systematic review and meta-analysis of the effects of iodine supplementation on thyroid function and child neurodevelopment in mildly-to-moderately iodine-deficient pregnant women. Am J Clin Nutr 2020; 112: 389-412
• 173 Machamba AAL, Azevedo FM, Fracalossi KO. et al. Effect of iodine supplementation in pregnancy on neurocognitive development on offspring in iodine deficiency areas: a systematic review. Arch Endocrinol Metab 2021; 65: 352-367
• 174 Nazeri P, Shariat M, Azizi F. Effects of iodine supplementation during pregnancy on pregnant women and their offspring: a systematic review and meta-analysis of trials over the past 3 decades. Eur J Endocrinol 2021; 184: 91-106
• 175 Harding KB, Peña-Rosas JP, Webster AC. et al. Iodine supplementation for women during the preconception, pregnancy and postpartum period. Cochrane Database Syst Rev 2017; 3 (03) CD011761
• 176 Verhagen NJE, Gowachirapant S, Winichagoon P. et al. Iodine Supplementation in Mildly Iodine-Deficient Pregnant Women Does Not Improve Maternal Thyroid Function or Child Development: A Secondary Analysis of a Randomized Controlled Trial. Front Endocrinol (Lausanne) 2020; 11: 572984
• 177 Manousou S, Eggertsen R, Hulthén L. et al. A randomized, double-blind study of iodine supplementation during pregnancy in Sweden: pilot evaluation of maternal iodine status and thyroid function. Eur J Nutr 2021; 60: 3411-3422
• 178 Lopes-Pereira M, Roque S, Costa P. et al. Impact of iodine supplementation during preconception, pregnancy and lactation on maternal thyroid homeostasis and offspring psychomotor development: protocol of the IodineMinho prospective study. BMC Pregnancy Childbirth 2020; 20: 693
• 179 Bell MA, Ross AP, Goodman G. Assessing infant cognitive development after prenatal iodine supplementation. Am J Clin Nutr 2016; 104 (Suppl. 3) 928S-9234S
• 180 Troendle JF. Statistical design considerations applicable to clinical trials of iodine supplementation in pregnant women who may be mildly iodine deficient. Am J Clin Nutr 2016; 104 (Suppl. 3) 924S-927S
• 181 Schaffner M, Mühlberger N, Conrads-Frank A. et al. Benefits and Harms of a Prevention Program for Iodine Deficiency Disorders: Predictions of the Decision-Analytic EUthyroid Model. Thyroid 2021; 31: 494-508
• 182 Volzke H, Erlund I, Grunert I. et al. The Krakow Declaration on Iodine: Tasks and Responsibilities for Prevention Programs Targeting Iodine Deficiency Disorders. Eur Thyroid J 2018; 7: 201-204