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

Abstract

Iodine deficiency with the resultant maternal hypothyroxinemia and the effects of endocrine disruptors can, individually or together, have a negative effect on embryonic and fetal brain development. This is the conclusion of a recent review by the authors which examined and critically discussed a total of 279 publications from the past 30 years on the effects of mild to moderate iodine deficiency, reduced maternal thyroxine levels, and the influence of endocrine disruptors on child brain development during pregnancy. Adequate iodine intake is important for all women of childbearing age to prevent negative psychological and social consequences for their children. An additional threat to the thyroid hormone system is the ubiquitous exposure to endocrine disruptors, which can increase the impact of maternal iodine deficiency on the neurocognitive development of their offspring. Ensuring an adequate iodine intake is therefore not only crucial for healthy fetal and neonatal development in general, but could also prevent the potential effects of endocrine disruptors. Due to the current deficient iodine status of women of childbearing age and of children and adolescents in Germany and most European countries, urgent measures are needed to improve the iodine intake of the population. Therefore, in the opinion of the AKJ, young women of childbearing age should be instructed to take iodine supplements continuously for at least 3 months before conception and during pregnancy. In addition, detailed strategies for detecting and reducing exposure to endocrine disruptors in accordance with the “precautionary principle” should be urgently developed.

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 population a				Pregnant women b
	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	voluntary f
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
Perchlorate 3 Thiocyanate 3 Nitrate 3 Phthalates 4	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) Genistein 5 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-PCBs 2 Polybrominated diphenyl ethers (PBDEs) 9 Phthalates 4 Genistein 5	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 Triclosan 10	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
Silymarin 11	Disorders of cellular transmembrane transporters (MCT8, MCT10 and OATP1C1) inhibit T3 uptake.	Undesirable effects on the TH axis 148
Erythrosine 12 6-n-propylthiouracil PCBs 2	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-PCBs 2 OH-BDEs 13 Bisphenols 14	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.