Velasco Ines ¹, Bath Sarah C.², Rayman Margaret P.^2
1Pediatrics, Obstetrics and Gynecology Unit, Hospital de Riotinto, Avda La Esquila 5, 21660 Minas de Riotinto, Huelva, Spain
²Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK

Article received: Jan 11, 2018. Accepted for publication: Feb 27, 2018. Published: Mar 01, 2018.
Nutrients 2018, 10(3), 290; https://doi.org/10.3390/nu10030290
^©2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Iodine is an essential micronutrient incorporated into thyroid hormones. Although iodine deficiency can lead to a broad spectrum of disorders throughout life, it is most critical in the early stages of development, as the foetal brain is extremely dependent on iodine supply. During the last two decades, our understanding of thyroid physiology during gestation has substantially improved. Furthermore, thyroid hormone receptors have been identified and characterized in placental and embryonic tissues, allowing us to elucidate the maternal-foetal transfer of thyroid hormones. Experimental studies have demonstrated that the cyto-architecture of the cerebral cortex can be irreversibly disturbed in iodine deficiency causing abnormal neuron migratory patterns which are associated with cognitive impairment in children. In this context, the role of iodine as key factor in the programming of foetal and infant neurodevelopment, needs to be revisited with a special focus on areas of mild to moderate iodine deficiency.
Purpose — to summarize the available evidence from both animals and human studies, for the effect of iodine deficiency (particularly, of maternal hypothyroxinemia) on brain development and neurological or behavioural disorders, such as lower intelligence quotient (IQ) or attention deficit hyperactivity disorder.
No conflict of interest was declared by the authors.
Key words: iodine, deficiency, neurodevelopment, behavioural disorders, foetal programming.

REFERENCES

1. Springer, D.; Jiskra, J.; Limanova, Z.; Zima, T.; Potlukova, E. Thyroid in pregnancy: From physiology to screening. Crit. Rev. Clin. Lab. Sci. 2017, 54, 102–116. [CrossRef] [PubMed]

2. Forhead, A.J.; Fowden, A.L. Thyroid hormones in fetal growth and prepartum maturation. J. Endocrinol. 2014, 221, R87-R103. [CrossRef] [PubMed]

3. Pearce, E.N.; Lazarus, J.H.; Moreno-Reyes, R.; Zimmermann, M.B. Consequences of iodine deficiency and excess in pregnant women: An overview of current knowns and unknowns. Am. J. Clin. Nutr. 2016, 104, 918S-923S. [CrossRef] [PubMed]

4. Niwattisaiwong, S.; Burman, K.D.; Li-Ng, M. Iodine deficiency: Clinical implications. Cleve Clin. J. Med. 2017, 84, 236–244. [CrossRef] [PubMed]

5. Zimmermann, M.B.; Gizak, M.; Abbott, K.; Andersson, M.; Lazarus, J.H. Iodine deficiency in pregnant women in Europe. Lancet Diabetes Endocrinol. 2015, 3, 672–674. [CrossRef]

6. Vanderpump, M.P. Epidemiology of iodine deficiency. Minerva Med. 2017, 108, 116–123. [CrossRef] [PubMed]

7. Hetzel, B.S. Iodine deficiency disorders (IDD) and their eradication. Lancet 1983, 2, 1126–1129. [CrossRef]

8. Trumpff, C.; De Schepper, J.; Tafforeau, J.; Van Oyen, H.; Vanderfaeillie, J.; Vandevijvere, S. 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. [CrossRef] [PubMed]

9. Rayman, M.P.; Bath, S.C. The new emergence of iodine deficiency in the UK: Consequences for child neurodevelopment. Ann. Clin. Biochem. 2015, 52, 705–708. [CrossRef] [PubMed]

10. Lane, R.H. Fetal programming, epigenetics, and adult onset disease. Clin. Perinatol. 2014, 41, 815–831. [CrossRef] [PubMed]

11. Baye, K.; Faber, M.Windows of opportunity for setting the critical path for healthy growth. Public Health Nutr. 2015, 18, 1715–1717. [CrossRef] [PubMed]

12. Moleti, M.; Trimarchi, F.; Vermiglio, F. Thyroid physiology in pregnancy. Endocr. Pract. 2014, 20, 589–596. [CrossRef] [PubMed]

13. Bernal, J.; Guadano-Ferraz, A.; Morte, B. Thyroid hormone transporters-functions and clinical implications. Nat. Rev. Endocrinol. 2015, 11, 406–417. [CrossRef] [PubMed]

14. Rovet, J.F. The role of thyroid hormones for brain development and cognitive function. Endocr. Dev. 2014, 26, 26–43. [CrossRef] [PubMed]

15. Obregon, M.J.; Calvo, R.M.; Del Rey, F.E.; de Escobar, G.M. Ontogenesis of thyroid function and interactions with maternal function. Endocr. Dev. 2007, 10, 86–98. [PubMed]

16. Tingi, E.; Syed, A.A.; Kyriacou, A.; Mastorakos, G.; Kyriacou, A. Benign thyroid disease in pregnancy: A state of the art review. J. Clin. Transl. Endocrinol. 2016, 6, 37–49. [CrossRef] [PubMed]

17. Oguz Kutlu, A.; Kara, C. Iodine deficiency in pregnant women in the apparently iodine-sufficient capital city of Turkey. Clin. Endocrinol. 2012, 77, 615–620. [CrossRef] [PubMed]

18. Bath, S.C.; Pop, V.J.; Furmidge-Owen, V.L.; Broeren, M.A.; Rayman, M.P. Thyroglobulin as a Functional Biomarker of Iodine Status in a Cohort Study of Pregnant Women in the United Kingdom. Thyroid 2016, 27, 426–433. [CrossRef] [PubMed]

19. Pharoah, P.O.; Buttfield, I.H.; Hetzel, B.S. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1971, 1, 308–310. [CrossRef]

20. Thilly, C.H.; Delange, F.; Lagasse, R.; Bourdoux, P.; Ramioul, L.; Berquist, H.; Ermans, A.M. Fetal hypothyroidism and maternal thyroid status in severe endemic goiter. J. Clin. Endocrinol. Metab. 1978, 47, 354–360. [CrossRef] [PubMed]

21. Lavado-Autric, R.; Auso, E.; Garcia-Velasco, J.V.; Arufe Mdel, C.; Escobar del Rey, F.; Berbel, P.; Morreale de Escobar, G. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J. Clin. Investig. 2003, 111, 1073–1082. [CrossRef] [PubMed]

22. Auso, E.; Lavado-Autric, R.; Cuevas, E.; Del Rey, F.E.; Morreale De Escobar, G.; Berbel, P. A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 2004, 145, 4037–4047. [CrossRef] [PubMed]

23. Opazo, M.C.; Gianini, A.; Pancetti, F.; Azkcona, G.; Alarcon, L.; Lizana, R.; Noches, V.; Gonzalez, P.A.; Porto, M.; Mora, S.; et al. Maternal hypothyroxinemia impairs spatial learning and synaptic nature and function in the offspring. Endocrinology 2008, 149, 5097–5106. [CrossRef] [PubMed]

24. Babu, S.; Sinha, R.A.; Mohan, V.; Rao, G.; Pal, A.; Pathak, A.; Singh, M.; Godbole, M.M. Effect of hypothyroxinemia on thyroid hormone responsiveness and action during rat postnatal neocortical development. Exp. Neurol. 2011, 228, 91–98. [CrossRef] [PubMed]

25. Pinazo-Duran, M.D.; Pons-Vazquez, S.; Gallego-Pinazo, R.; Galbis Estrada, C.; Zanon-Moreno, V.; Vila Bou, V.; Sanz Solana, P. Thyroid hormone deficiency disrupts rat eye neurodevelopment. Brain Res. 2011, 1392, 16–26. [CrossRef] [PubMed]

26. Wei, W.; Wang, Y.; Wang, Y.; Dong, J.; Min, H.; Song, B.; Teng, W.; Xi, Q.; Chen, J. Developmental hypothyroxinaemia induced by maternal mild iodine deficiency delays hippocampal axonal growth in the rat offspring. J. Neuroendocrinol. 2013, 25, 852–862. [CrossRef] [PubMed]

27. Gilbert, M.E.; Ramos, R.L.; McCloskey, D.P.; Goodman, J.H. Subcortical band heterotopia in rat offspring following maternal hypothyroxinaemia: Structural and functional characteristics. J. Neuroendocrinol. 2014, 26, 528–541. [CrossRef] [PubMed]

28. Wang, Y.;Wang, Y.; Dong, J.;Wei,W.; Song, B.; Min, H.; Yu, Y.; Lei, X.; Zhao, M.; Teng,W.; et al. Developmental hypothyroxinemia and hypothyroidism reduce proliferation of cerebellar granule neuron precursors in rat offspring by downregulation of the sonic hedgehog signaling pathway. Mol. Neurobiol. 2014, 49, 1143–1152. [CrossRef] [PubMed]

29. Cisternas, P.; Louveau, A.; Bueno, S.M.; Kalergis, A.M.; Boudin, H.; Riedel, C.A. Gestational Hypothyroxinemia Affects Glutamatergic Synaptic ProteinDistribution and Neuronal Plasticity Through Neuron-Astrocyte Interplay. Mol. Neurobiol. 2016, 53, 7158–7169. [CrossRef] [PubMed]

30. Gilbert, M.E.; Sanchez-Huerta, K.; Wood, C. Mild Thyroid Hormone Insufficiency during Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 2016, 157, 774–787. [CrossRef] [PubMed]

31. Opazo, M.C.; Gonzalez, P.A.; Flores, B.D.; Venegas, L.F.; Albornoz, E.A.; Cisternas, P.; Bohmwald, K.; Nieto, P.A.; Bueno, S.M.; Kalergis, A.M.; et al. Gestational Hypothyroxinemia Imprints a Switch in the Capacity of Astrocytes and Microglial Cells of the Offspring to React in Inflammation. Mol. Neurobiol. 2017. [CrossRef] [PubMed]

32. Bleichrodt, N.; Born, M.P. A meta-analysis of research on iodine and its relationship to cognitive development. In The Damaged Brain of Iodine Deficiency: Cognitive, Behavioral, Neuromotor and Educative Aspects; Standbury, J.B., Ed.; Cognizant Communication Corporation: New York, NY, USA, 1994; pp. 195–200.

33. Verhoef, H.; West, C.E.; Bleichrodt, N.; Dekker, P.H.; Born, M.P. Effects of micronutrients during pregnancy and early infancy on mental and psychomotor development. In Micronutrient Deficiencies in the First Months of Life; Delange, F.,West, J.K.P., Eds.; S. Karger AG: Basel, Switzerland, 2003; pp. 327–357.

34. Qian, M.;Wang, D.;Watkins,W.E.; Gebski, V.; Yan, Y.Q.; Li, M.; Chen, Z.P. The effects of iodine on intelligence on children: A meta-analysis of studies conducted in China. Asia Pac. J. Clin. Nutr. 2005, 14, 32–42. [PubMed]

35. Melse-Boonstra, A.; Jaiswal, N. Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Pract. Res. Clin. Endocrinol. Metab. 2010, 24, 29–38. [CrossRef] [PubMed]

36. Skeaff, S.A. Iodine deficiency in pregnancy: The effect on neurodevelopment in the child. Nutrients 2011, 3, 265–273. [CrossRef] [PubMed]

37. Bougma, K.; Aboud, F.E.; Harding, K.B.; Marquis, G.S. Iodine and mental development of children 5 years old and under: A systematic review and meta-analysis. Nutrients 2013, 5, 1384–1416. [CrossRef] [PubMed]

38. Zhou, S.J.; Anderson, A.J.; Gibson, R.A.; Makrides, M. Effect of iodine supplementation in pregnancy on child development and other clinical outcomes: A systematic review of randomized controlled trials. Am. J. Clin. Nutr. 2013, 98, 1241–1254. [CrossRef] [PubMed]

39. Taylor, P.N.; Okosieme, O.E.; Dayan, C.M.; Lazarus, J.H. Therapy of endocrine disease: Impact of iodine supplementation in mild-to-moderate iodine deficiency: Systematic review and meta-analysis. Eur. J. Endocrinol. 2014, 170, R1-R15. [CrossRef] [PubMed]

40. Lam, L.F.; Lawlis, T.R. Feeding the brain-The effects of micronutrient interventions on cognitive performance among school-aged children: A systematic review of randomized controlled trials. Clin. Nutr. 2017, 36, 1007–1014. [CrossRef] [PubMed]

41. Taylor, R.M.; Fealy, S.M.; Bisquera, A.; Smith, R.; Collins, C.E.; Evans, T.J.; Hure, A.J. Effects of Nutritional Interventions during Pregnancy on Infant and Child Cognitive Outcomes: A Systematic Review and Meta-Analysis. Nutrients 2017, 9, 1265. [CrossRef] [PubMed]

42. Haddow, J.E.; Palomaki, G.E.; Allan,W.C.;Williams, J.R.; Knight, G.J.; Gagnon, J.; O'Heir, C.E.; Mitchell, M.L.; Hermos, R.J.; Waisbren, S.E.; et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N. Engl. J. Med. 1999, 341, 549–555. [CrossRef] [PubMed]

43. De Escobar, G.M.; Obregon, M.J.; del Rey, F.E. Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutr. 2007, 10, 1554–1570. [CrossRef] [PubMed]

44. Min, H.; Dong, J.; Wang, Y.; Wang, Y.; Teng, W.; Xi, Q.; Chen, J. Maternal Hypothyroxinemia-Induced Neurodevelopmental Impairments in the Progeny. Mol. Neurobiol. 2016, 53, 1613–1624. [CrossRef] [PubMed]

45. Furnica, R.M.; Lazarus, J.H.; Gruson, D.; Daumerie, C. Update on a new controversy in endocrinology: Isolated maternal hypothyroxinemia. J. Endocrinol. Investig. 2015, 38, 117–123. [CrossRef] [PubMed]

46. Akturk, M.; Oruc, A.S.; Danisman, N.; Erkek, S.; Buyukkagnici, U.; Unlu, E.; Tazebay, U.H. Na+/I- symporter and type 3 iodothyronine deiodinase gene expression in amniotic membrane and placenta and its relationship to maternal thyroid hormones. Biol. Trace Elem. Res. 2013, 154, 338–344. [CrossRef] [PubMed]

47. Calvo, R.M.; Jauniaux, E.; Gulbis, B.; Asuncion, M.; Gervy, C.; Contempre, B.; Morreale de Escobar, G. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J. Clin. Endocrinol. Metab. 2002, 87, 1768–1777. [CrossRef] [PubMed]

48. Kester, M.H.; Martinez de Mena, R.; Obregon, M.J.; Marinkovic, D.; Howatson, A.; Visser, T.J.; Hume, R.; Morreale de Escobar, G. Iodothyronine levels in the human developing brain: Major regulatory roles of iodothyronine deiodinases in different areas. J. Clin. Endocrinol. Metab. 2004, 89, 3117–3128. [CrossRef] [PubMed]

49. Maia, A.L.; Goemann, I.M.; Meyer, E.L.; Wajner, S.M. Deiodinases: The balance of thyroid hormone: Type 1 iodothyronine deiodinase in human physiology and disease. J. Endocrinol. 2011, 209, 283–297. [CrossRef] [PubMed]

50. Strich, D.; Karavani, G.; Edri, S.; Gillis, D. TSH enhancement of FT4 to FT3 conversion is age dependent. Eur. J. Endocrinol. 2016, 175, 49–54. [CrossRef] [PubMed]

51. Dosiou, C.; Medici, M. Management of endocrine disease: Isolated maternal hypothyroxinemia during pregnancy: Knowns and unknowns. Eur. J. Endocrinol. 2017, 176, R21-R38. [CrossRef] [PubMed]

52. Henrichs, J.; Ghassabian, A.; Peeters, R.P.; Tiemeier, H. Maternal hypothyroxinemia and effects on cognitive functioning in childhood: How and why? Clin. Endocrinol. 2013, 79, 152–162. [CrossRef] [PubMed]

53. Hynes, K.L.; Otahal, P.; Hay, I.; Burgess, J.R. Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. J. Clin. Endocrinol. Metab. 2013, 98, 1954–1962. [CrossRef] [PubMed]

54. Abel, M.H.; Caspersen, I.H.; Meltzer, H.M.; Haugen, M.; Brandlistuen, R.E.; Aase, H.; Alexander, J.; Torheim, L.E.; Brantsaeter, A.L. Suboptimal Maternal Iodine Intake Is Associated with Impaired Child Neurodevelopment at 3 Years of Age in the Norwegian Mother and Child Cohort Study. J. Nutr. 2017, 147, 1314–1324. [CrossRef] [PubMed]

55. Zoeller, R.T.; Rovet, J. Timing of thyroid hormone action in the developing brain: Clinical observations and experimental findings. J. Neuroendocrinol. 2004, 16, 809–818. [CrossRef] [PubMed]

56. Stenzel, D.; Huttner,W.B. Role of maternal thyroid hormones in the developing neocortex and during human evolution. Front. Neuroanat. 2013, 7, 1–9. [CrossRef] [PubMed]

57. Moog, N.K.; Entringer, S.; Heim, C.;Wadhwa, P.D.; Kathmann, N.; Buss, C. Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience 2017, 342, 68–100. [CrossRef] [PubMed]

58. Mohan, V.; Sinha, R.A.; Pathak, A.; Rastogi, L.; Kumar, P.; Pal, A.; Godbole, M.M. 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. [CrossRef] [PubMed]

59. Kohwi, M.; Doe, C.Q. Temporal fate specification and neural progenitor competence during development. Nat. Rev. Neurosci. 2013, 14, 823–838. [CrossRef] [PubMed]

60. Williams, G.R. Neurodevelopmental and Neurophysiological actions of thyroid hormone. J. Neuroendocrinol. 2009, 20, 784–794. [CrossRef] [PubMed]

61. Berbel, P.; Navarro, D.; Roman, G.C. An evo-devo approach to thyroid hormones in cerebral and cerebellar cortical development: Etiological implications for autism. Front. Endocrinol. (Lausanne) 2014, 5, 146. [CrossRef] [PubMed]

62. Valdes Hernandez, M.C.; Wilson, K.L.; Combet, E.;Wardlaw, J.M. Brain Findings Associated with Iodine Deficiency identified by Magnetic Resonance Methods: A Systematic Review. Open J. Radiol. 2013, 3, 180–195. [CrossRef]

63. Li, M.; Eastman, C.J. The changing epidemiology of iodine deficiency. Nat. Rev. Endocrinol. 2012, 8, 434–440. [CrossRef] [PubMed]

64. Moleti, M.; Sturniolo, G.; Trimarchi, F.; Vermiglio, F. The changing phenotype of iodine deficiency disorders: A review of thirty-five years of research in north-eastern Sicily. Ann. lst. Super. Sanita 2016, 52, 550–557. [CrossRef]

65. Gowachirapant, S.; Jaiswal, N.; Melse-Boonstra, A.; Galetti, V.; Stinca, S.; Mackenzie, I.; Thomas, S.; Thomas, T.;Winichagoon, P.; Srinivasan, K.; et al. Effect of iodine supplementation in pregnant women on child neurodevelopment: A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017, 5, 853–863. [CrossRef]

66. Bath, S.C. Iodine supplementation in pregnancy in mildly deficient regions. Lancet Diabetes Endocrinol. 2017, 5, 840–841. [CrossRef]

67. Bath, S.C.; Steer, C.D.; Golding, J.; Emmett, P.; Rayman, M.P. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: Results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet 2013, 382, 331–337. [CrossRef]

68. Hynes, K.L.; Otahal, P.; Burgess, J.R.; Oddy, W.H.; Hay, I. Reduced Educational Outcomes Persist into Adolescence Following Mild Iodine Deficiency in Utero, Despite Adequacy in Childhood: 15-Year Follow-Up of the Gestational Iodine Cohort Investigating Auditory Processing Speed and Working Memory. Nutrients 2017, 9, 1354. [CrossRef] [PubMed]

69. Ghassabian, A.; Steenweg-de Graaff, J.; Peeters, R.P.; Ross, H.A.; Jaddoe, V.W.; Hofman, A.; Verhulst, F.C.; White, T.; Tiemeier, H. Maternal urinary iodine concentration in pregnancy and children's cognition: Results from a population-based birth cohort in an iodine-sufficient area. BMJ Open 2014, 4, e005520. [CrossRef] [PubMed]

70. Fetene, D.M.; Betts, K.S.; Alati, R. Mechanisms in Endocrinology: Maternal thyroid dysfunction during pregnancy and behavioural and psychiatric disorders of children: A systematic review. Eur. J. Endocrinol. 2017, 177, R261-R273. [CrossRef] [PubMed]

71. Andersen, S.L.; Laurberg, P.;Wu, C.S.; Olsen, J. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: A Danish nationwide cohort study. BJOG 2014, 121, 1365–1374. [CrossRef] [PubMed]

72. Vermiglio, F.; Lo Presti, V.P.; Moleti, M.; Sidoti, M.; Tortorella, G.; Scaffidi, G.; Castagna, M.G.; Mattina, F.; Violi, M.A.; Crisa, A.; et al. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: A possible novel iodine deficiency disorder in developed countries. J. Clin. Endocrinol. Metab. 2004, 89, 6054–6060. [CrossRef] [PubMed]

73. Oostenbroek, M.H.W.; Kersten, R.H.J.; Tros, B.; Kunst, A.E.; Vrijkotte, T.G.M.; Finken, M.J.J. Maternal hypothyroxinaemia in early pregnancy and problem behavior in 5-year-old offspring. Psychoneuroendocrinology 2017, 81, 29–35. [CrossRef] [PubMed]

74. Modesto, T.; Tiemeier, H.; Peeters, R.P.; Jaddoe, V.W.; Hofman, A.; Verhulst, F.C.; Ghassabian, A. Maternal Mild Thyroid Hormone Insufficiency in Early Pregnancy and Attention-Deficit/Hyperactivity Disorder Symptoms in Children. JAMA Pediatr. 2015, 169, 838–845. [CrossRef] [PubMed]

75. Abel, M.H.; Ystrom, E.; Caspersen, I.H.; Meltzer, H.M.; Aase, H.; Torheim, L.E.; Askeland, R.B.; Reichborn-Kjennerud, T.; Brantsaeter, A.L. Maternal Iodine Intake and Offspring Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study. Nutrients 2017, 9, 1239. [CrossRef] [PubMed]

76. Moleti, M.; Trimarchi, F.; Tortorella, G.; Candia Longo, A.; Giorgianni, G.; Sturniolo, G.; Alibrandi, A.; Vermiglio, F. Effects of Maternal Iodine Nutrition and Thyroid Status on Cognitive Development in Offspring: A Pilot Study. Thyroid 2016, 26, 296–305. [CrossRef] [PubMed]

77. Roman, G.C.; Ghassabian, A.; Bongers-Schokking, J.J.; Jaddoe, V.W.; Hofman, A.; de Rijke, Y.B.; Verhulst, F.C.; Tiemeier, H. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann. Neurol. 2013, 74, 733–742. [CrossRef] [PubMed]

78. Van Mil, N.H.; Tiemeier, H.; Bongers-Schokking, J.J.; Ghassabian, A.; Hofman, A.; Hooijkaas, H.; Jaddoe, V.W.; de Muinck Keizer-Schrama, S.M.; Steegers, E.A.; Visser, T.J.; et al. Low urinary iodine excretion during early pregnancy is associated with alterations in executive functioning in children. J. Nutr. 2012, 142, 2167–2174. [CrossRef] [PubMed]

79. O'Donnell, K.J.; Meaney, M.J. Fetal Origins of Mental Health: The Developmental Origins of Health and Disease Hypothesis. Am. J. Psychiatry. 2017, 174, 319–328. [CrossRef] [PubMed]

80. Dong, H.; You, S.H.; Williams, A.; Wade, M.G.; Yauk, C.L.; Thomas Zoeller, R. Transient Maternal Hypothyroxinemia Potentiates the Transcriptional Response to Exogenous Thyroid Hormone in the Fetal Cerebral Cortex Before the Onset of Fetal Thyroid Function: A Messenger and MicroRNA Profiling Study. Cereb. Cortex 2015, 25, 1735–1745. [CrossRef] [PubMed]

81. Black, M.M.; Walker, S.P.; Fernald, L.C.H.; Andersen, C.T.; DiGirolamo, A.M.; Lu, C.; McCoy, D.C.; Fink, G.; Shawar, Y.R.; Shiffman, J.; et al. Early childhood development coming of age: Science through the life course. Lancet 2017, 389, 77–90. [CrossRef]

82. John, C.C.; Black, M.M.; Nelson, C.A., 3rd. Neurodevelopment: The Impact of Nutrition and Inflammation during Early to Middle Childhood in Low-Resource Settings. Pediatrics 2017, 139, S59-S71. [CrossRef] [PubMed]

83. Bath, S.C. Direct or indirect iodine supplementation of infants? Lancet Diabetes Endocrinol. 2014, 2, 184–185. [CrossRef]

84. Hess, S.Y. The impact of common micronutrient deficiencies on iodine and thyroid metabolism: The evidence from human studies. Best Pract. Res. Clin. Endocrinol. Metab. 2010, 24, 117–132. [CrossRef] [PubMed]

85. Bouhouch, R.R.; Bouhouch, S.; Cherkaoui, M.; Aboussad, A.; Stinca, S.; Haldimann, M.; Andersson, M.; Zimmermann, M.B. Direct iodine supplementation of infants versus supplementation of their breastfeeding mothers: A double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014, 2, 197–209. [CrossRef]

86. Britto, P.R.; Lye, S.J.; Proulx, K.; Yousafzai, A.K.; Matthews, S.G.; Vaivada, T.; Perez-Escamilla, R.; Rao, N.; Ip, P.; Fernald, L.C.H.; et al. Nurturing care: Promoting early childhood development. Lancet 2017, 389, 91–102. [CrossRef]

87. Daelmans, B.; Darmstadt, G.L.; Lombardi, J.; Black, M.M.; Britto, P.R.; Lye, S.; Dua, T.; Bhutta, Z.A.; Richter, L.M.; Lancet Early Childhood Development Series Steering Committee. Early childhood development: The foundation of sustainable development. Lancet 2017, 389, 9–11. [CrossRef]