Iodine and Foetal Programming

INTRODUCTION

Until birth mother is the source of all the molecular elements that help to regulate growth and development of the embryo and foetus.¹Musumeci G, Castrogiovanni P, Trovato FM, et al. Pregnancy, embryo-fetal development and nutrition: physiology around fetal programming. J Histol Histopathol. 2015; 2:1. http://dx.doi.org/10.7243/2055-091X-2-1   Pregnancy is a time which provides a unique opportunity to influence the long term health of the infant and mother.²Luton D, Alberti C, Vuillard E, et al. Iodine Deficiency in Northern Paris Area: Impact on Fetal Thyroid Mensuration. PLoS ONE. 2011; 6(2): e14707. https://doi.org/10.1371/journal.pone.0014707

The growth and potential development of the foetus depends on maternal nutrition at conception and during pregnancy which contributes to the maturity of a healthy baby. Nutrition during pregnancy effects not only foetal development, but also the risk of chronic diseases for that infant in adulthood.³Institute of Obstetricians and Gynaecologists, Royal College of Physicians of Ireland. Clinical Practice Guideline Nutrition for Pregnancy. Revised in 2016;27

Therefore, for the improvement of the pregnancy outcomes, the promotion of healthy growth and development, the reduction of the risk of chronic diseases and the slowing down of the metabolic decline associated with aging, it is necessary to develop dietary strategies to optimise the nutrition not only during the pregnancy, but at the time in which it is planned, through the intake of adequate micronutrients.¹Musumeci G, Castrogiovanni P, Trovato FM, et al. Pregnancy, embryo-fetal development and nutrition: physiology around fetal programming. J Histol Histopathol. 2015; 2:1. http://dx.doi.org/10.7243/2055-091X-2-1

IODINE

Importance of Iodine and Iodine Requirements

Pregnancy has a profound impact on the thyroid gland and its function.⁴Alexander 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(3): 315-389. doi:10.1089/thy.2016.0457.   For normal foetal and neonatal development iodine is an essential micronutrient.2

Iodine is required for the biosynthesis of thyroid hormones thyroxine (T4) and triiodothyronine (T3), which are responsible for regulating growth, develop-ment and metabolism (Figure 1).⁵Sharma JB, Toshyan V. Iodine Deficiency in Pregnancy. Indian Obstetrics & Gynaecology. 2017;7(1);8-9.

The World Health Organization (WHO), the International Council for Control of Iodine Deficiency Disorders (ICCIDD) and the United Nations Children’s Fund (UNICEF) has recommended nutrient intake for iodine of 150 µg/day for non-pregnant women.⁶Zimmermann MB. Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009;89(suppl):668S–72S.   Recently WHO/UNICEF increased the Recommended Nutrient Intake (RNI) for iodine during pregnancy and lactation to 220-250μg/day.⁵Sharma JB, Toshyan V. Iodine Deficiency in Pregnancy. Indian Obstetrics & Gynaecology. 2017;7(1);8-9.   ⁶Zimmermann MB. Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009;89(suppl):668S–72S.

Increase Iodine Requirement during Pregnancy and Lactation

The iodine requirement during pregnancy is sharply elevated because of an increase by approximately 50% in maternal thyroxine (T4) production to maintain maternal euthyroidism and to transfer thyroid hormone to the foetus; because iodine needs to be transferred to the foetus for foetal thyroid hormone production, particularly in later gestation; and because of a probable increase in renal iodine clearance (RIC).⁶Zimmermann MB. Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009;89(suppl):668S–72S.

Classification of Iodine Status

Based upon the median urinary iodine (UI) concentration in a population iodine status is classified.⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]

• Iodine sufficiency is defined as a median UI concen-tration of:
  • 100 to 299 μg/L for children and non-pregnant adults
  • 150 to 249 μg/L for pregnant women

• Iodine deficiency is defined by the following median UI concentrations:
  • Mild iodine deficiency: 50 to 99 μg/L
  • Moderate deficiency: 20 to 49 μg/L
  • Severe deficiency: <20 μg/L

Consequences of Iodine Deficiency

The term “iodine deficiency disorders” refers to all of the consequences of iodine deficiency, which depend on its severity and the age of the affected subject. Optimal iodine nutrition in the pregnant woman is required for full development of the foetus. For the first 12 weeks of gestation, the foetus is completely dependent upon maternal T4.

During the 10th to 12^thweek of gestation, foetal TSH appears, and the foetal thyroid is capable of concentrating iodine and synthesising iodothyronines. Small amount of hormone synthesis occurs until the 18^th to 20^th week. Thereafter, foetal thyroid secretion increases gradually.⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]

Severe iodine deficiency in pregnant women has been associated with increased rates of pregnancy loss, stillbirth, and increased perinatal and infant mortality.⁸Delange FM, Dunn JT. Iodine deficiency. In: Braverman LE, Utiger RD (eds) Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 9th edition. Lippincott, Williams and Wilkins, Philadelphi., 2005:264–288.

Children whose mothers were severely iodine deficient during pregnancy may exhibit cretinism, characterised by profound intellectual impairment, deaf-mutism, and motor rigidity.

Iodine deficiency is the leading cause of preventable intellectual deficits worldwide.⁹World Health Organization/International Council for the Control of the Iodine Deficiency Disorders/United Nations Children’s Fund (WHO/ ICCIDD/UNICEF) 2007 Assessment of the iodine deficiency disorders and monitoring their elimination. World Health Organization, Geneva   A meta-analysis of 18 studies concluded that maternal iodine deficiency lowered offspring IQ score by 13.5 points.¹⁰Bleichrodt N, Born MP. A meta-analysis of research on iodine and its relationship to cognitive development. In: Stanbury JB, editor. The damaged brain of iodine deficiency: cognitive, behavioral, neuromotor, educative aspects. New York: Cognizant Communication. 1994:195-200   Women with mild to moderate iodine deficiency during pregnancy are at increased risk for the development of goiter¹¹Berghout A, Wiersinga W. Thyroid size and thyroid function during pregnancy: an analysis. Eur J Endocrinol. 1998;138:536–542   and thyroid disorders.¹²Moreno-Reyes R, Glinoer D, Van Oyen H, et al. High prevalence of thyroid disorders in pregnant women in a mildly iodine-deficient country: a population-based study. J Clin Endocrinol Metab. 2013;98(9):3694-3701   Mild to moderate maternal iodine deficiency has also been associated with attention deficit and hyperactivity disorders in children¹³Vermiglio F, Lo Presti VP, Moleti M, 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   as well as impaired cognitive outcomes.¹⁴Bath SC, Steer CD, Golding J, et al. 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(9889):331-337

Impact of Iodine Supplementation

In areas of severe iodine deficiency, iodine supple-mentation of mothers prior to conception or in early pregnancy results in children with improved cognitive performance relative to children of mothers given a placebo.

The prevalence of cretinism and other severe neurological abnormalities is significantly reduced. Maternal iodine supplementation in severely iodine-deficient areas also decreases rates of stillbirth and neonatal and infant mortality.¹⁵Alexander 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(3):315-389. doi:10.1089/thy.2016.0457.

ASSESSMENT OF IODINE NUTRITION

At the community level iodine nutrition is best assessedby measurements of: ⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]

• Urinary Iodine Excretion: Median urinary iodine concentrations can be used to assess the iodine status of populations, but single spot or 24-hour urine iodine concentrations are not a valid marker for the iodine nutritional status of individual patients
• Thyroid Size: Size of the thyroid is a sensitive marker for iodine deficiency because goiter, although not the most severe consequence of iodine deficiency, is the most clinically evident
• Neonatal Serum Thyroid Stimulating Hormone (TSH) Screening for Hypothyroidism: In regions of iodine deficiency, the frequency of supranormal TSH concentrations (>5 mU/L) in blood spots collected as part of neonatal screening programs is higher than in iodine sufficient areas and roughly correlates with the severity of iodine deficiency. WHO has established that the results of neonatal blood TSH screening can be used as convenient indicators for iodine intake.
• Serum Thyroglobulin Concentration: It is a sensitive measure of thyroid activity and hyperplasia.
• Other Tests: Other tests like serum T4, T3, and TSH concentrations determine iodine nutrition.

THYROID HORMONES AND FOETAL NEUROLOGICAL DEVELOPMENT

Thyroid hormones primarily regulate genes involved in myelination and neuronalglial cell differentiation. Foetal thyroid function development depends on the embryogenesis, differentiation and maturation of the thyroid gland. Regulation of thyroid hormone action, production, and secretion is resulted due to evolution of the hypothalamic–pituitary–thyroid axis and thyroid hormone metabolism.

For normal early foetal neurogenesis there is a steady supply of maternal thyroxine (T4) from 4-weeks post-implantation.During gestation due to metabolism via placental and foetal deiodinase type 3, triiodothyronine concentrations remain very low. T4 concentrations are highly regulated to maintain low concentrations, essential for protecting the foetus and reaching key neurological sites such as the cerebral cortex at specific developmental stages.¹⁶Patel J, Landers K, Li H, et al. Thyroid hormones and fetal neurological development. Journal of Endocrinology. 2011;209:1–8. DOI: 10.1530/JOE-10-0444

FOETAL PROGRAMMING BY MATERNAL THYROID DISEASE

Nutritional or/and hormonal changes in the embryo-foetal microenvironment, can alter the foetal genomic expre-ssion and exert permanent effects on a wide range of physiological processes. This phenomenon is known as “foetal programming”(Figure 2)¹Musumeci G, Castrogiovanni P, Trovato FM, et al. Pregnancy, embryo-fetal development and nutrition: physiology around fetal programming. J Histol Histopathol. 2015; 2:1. http://dx.doi.org/10.7243/2055-091X-2-1

Thyroid hormones play a crucial role in early brain development. Maternal and foetal thyroid hormones are essential in regulating the development of the foetal brain and nervous system including the creation and growth of nerve cells, the formation of synapses, which are required for communication between nerve cells, and myelination.⁵Sharma JB, Toshyan V. Iodine Deficiency in Pregnancy. Indian Obstetrics & Gynaecology. 2017;7(1);8-9.

Maternal thyroid dysfunction in pregnancy may lead to structural and/or functional changes during foetal brain development. Such an effect could later predispose the offspring to an increased risk of neurologic or psychiatric disease.

Studies have also shown that children born to mothers with thyroid dysfunction had an increased risk of developing seizure disorders, autism spectrum disorders, attention-deficit hyperactivity disorders and psychiatric disease in adolescence and young adulthood.¹⁷Andersen SL, Olsen J, Laurberg P. Foetal programming by maternal thyroid disease. Clin Endocrinol (Oxf). 2015;83(6):7518. doi: 10.1111/cen.12744.Epub 2015 Mar 13.

PSYCHIATRIC DISORDERS IN CHILDHOOD, ADOLESCENCE AND YOUNG ADULTHOOD

Autism spectrum disorders are characterised by impairments in multiple functions and onset of symptoms is before the age of 3-years. It impairs the social, behav-ioural and communicative skills. Later in childhood asperger disorder is diagnosed which is characterised by impairments in social and behavioural skills, but not in cognitive skills and language development. Affective disorders and schizophrenia are examples of psychiatric disorders with a typical onset in adolescence and early adulthood, and anxiety disorders are also common either alone or co-morbid to depression.¹⁷Andersen SL, Olsen J, Laurberg P. Foetal programming by maternal thyroid disease. Clin Endocrinol (Oxf). 2015;83(6):7518. doi: 10.1111/cen.12744.Epub 2015 Mar 13.

PROPHYLAXIS AND TREATMENT

Community

• Iodisation of Salt: Salt being a dietary necessity, it is the preferred method of increasing iodine intake in a community. Adding iodine during the packaging or processing of salt is an efficient means for distributing iodine on a mass basis. The usual “dose” is between 10 and 50 mg of iodine/kg salt (sodium chloride) as potassium iodide or iodate.⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]

Other Options: Iodised oil, iodised water, and iodine tablets or drops are other alternative effective options.⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]

Individual

• Non-pregnant: For non-pregnant women daily iodine fortified foods is sufficient. Iodine supplementation is not necessary.⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]
• During Pregnancy and Lactation: International Federation of Gynecology and Obstetrics (FIGO)-2015 states that even with use of iodized salt and eating seafood 2-3 days per week, a woman’s daily iodine intake would be approximately half the amount recently recommended during pregnancy and lactation.18 From an implementation perspective, pregnant and postpartum women often have contact with the healthcare system, which generally provides or recommends prenatal and sometimes postnatal micronutrient supplementation – usually iron and folic acid. Similarly, iodine supplementation could be integrated into routine antenatal and postnatal care. To reach women prior to pregnancy, existing contacts with the healthcare system or other platforms could be used to provide or recommend iodine supple-mentation for those planning on becoming pregnant and/or to all women of reproductive age because pregnancies are often unplanned (as is done with folic acid supplementation recommendations in many settings).¹⁸Hanson MA, Bardsley A, De-Regil LM, et al. The International Federationof Gynecology and Obstetrics (FIGO) recommendations on adolescent, preconception, and maternal nutrition: “Think Nutrition First”. Int J Gynaecol Obstet. 2015;131 Suppl 4:S213-53. doi: 10.1016/S00207292 (15)30023-0.

Sustaining Iodine Sufficiency

For sustaining iodine sufficiency regular monitoring of iodine nutrition is essential. Decrease in salt intake, a reduction in the use of iodine salts and undoubtedly other unidentified commercial and environmental factor are some the factors responsible for iodine deficiency.⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]

RECOMMENDATION BY SCIENTIFIC BODIES (ON DAILY IODINE SUPPLEMENTATION DURING PREGNANCY AND LACTATION)

Iodine dosing guidelines by scientific bodies are as follows:⁷Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]

• WHO :250 μg daily during pregnancy and lactation
• United States Institute of Medicine (IOM): 220 μg daily for pregnant women and 290 μg daily for lactating women
• American Thyroid Association (ATA):150 μg potassium iodide daily for pregnant and lactating women.

CONCLUSION

Maternal dietary iodine deficiency results in impaired maternal and foetal thyroid hormone synthesis. The key relationship between thyroid hormone and brain development is significant. Thyroid disorders are common in women of reproductive age, and careful management of pregnant women suffering from thyroid disease is important considering the crucial role of thyroid hormones during early brain development. Due to maternal thyroid dysfunction in pregnancy may lead to structural and/or functional changes during foetal brain development.

Such an effect could later predispose the offspring to an increased risk of neurologic or psychiatric disease. Recently, it was observed that children born to mothers with thyroid dysfunction had an increased risk of developing seizure disorders, autism spectrum disorders, attention deficit hyperactivity disorders and psychiatric disease in adolescence and young adulthood. Foetal programming is an upcoming concept that links exposures during early life with the risk of developing disease later in life. Programming of the foetus results from adaptations invoked when the materno-placental nutrient supply fails to match the foetal nutrient demand. Recently, WHO has increased their recommended iodine intake during pregnancy from 200 to 250 μg/day and suggested that a median UI concentration of 150–249 μg/L indicates adeq-uate iodine intake in pregnant women.

REFERENCES

1. Musumeci G, Castrogiovanni P, Trovato FM, et al. Pregnancy, embryo-fetal development and nutrition: physiology around fetal programming. J Histol Histopathol. 2015; 2:1. http://dx.doi.org/10.7243/2055-091X-2-1
2. Luton D, Alberti C, Vuillard E, et al. Iodine Deficiency in Northern Paris Area: Impact on Fetal Thyroid Mensuration. PLoS ONE. 2011; 6(2): e14707. https://doi.org/10.1371/journal.pone.0014707
3. Institute of Obstetricians and Gynaecologists, Royal College of Physicians of Ireland. Clinical Practice Guideline Nutrition for Pregnancy. Revised in 2016;27
4. 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(3): 315-389. doi:10.1089/thy.2016.0457.
5. Sharma JB, Toshyan V. Iodine Deficiency in Pregnancy. Indian Obstetrics & Gynaecology. 2017;7(1);8-9.
6. Zimmermann MB. Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009;89(suppl):668S–72S.
7. Vitti P. Iodine deficiency disorders. Available from: https://www.uptodate.com/contents/iodine-deficiency-disorders [Accessed on 02nd June 2017]
8. Delange FM, Dunn JT. Iodine deficiency. In: Braverman LE, Utiger RD (eds) Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 9th edition. Lippincott, Williams and Wilkins, Philadelphi., 2005:264–288.
9. World Health Organization/International Council for the Control of the Iodine Deficiency Disorders/United Nations Children’s Fund (WHO/ ICCIDD/UNICEF) 2007 Assessment of the iodine deficiency disorders and monitoring their elimination. World Health Organization, Geneva
10. Bleichrodt N, Born MP. A meta-analysis of research on iodine and its relationship to cognitive development. In: Stanbury JB, editor. The damaged brain of iodine deficiency: cognitive, behavioral, neuromotor, educative aspects. New York: Cognizant Communication. 1994:195-200
11. Berghout A, Wiersinga W. Thyroid size and thyroid function during pregnancy: an analysis. Eur J Endocrinol. 1998;138:536–542
12. Moreno-Reyes R, Glinoer D, Van Oyen H, et al. High prevalence of thyroid disorders in pregnant women in a mildly iodine-deficient country: a population-based study. J Clin Endocrinol Metab. 2013;98(9):3694-3701
13. Vermiglio F, Lo Presti VP, Moleti M, 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
14. Bath SC, Steer CD, Golding J, et al. 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(9889):331-337
15. 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(3):315-389. doi:10.1089/thy.2016.0457.
16. Patel J, Landers K, Li H, et al. Thyroid hormones and fetal neurological development. Journal of Endocrinology. 2011;209:1–8. DOI: 10.1530/JOE-10-0444
17. Andersen SL, Olsen J, Laurberg P. Foetal programming by maternal thyroid disease. Clin Endocrinol (Oxf). 2015;83(6):7518. doi: 10.1111/cen.12744.Epub 2015 Mar 13.
18. Hanson MA, Bardsley A, De-Regil LM, et al. The International Federationof Gynecology and Obstetrics (FIGO) recommendations on adolescent, preconception, and maternal nutrition: “Think Nutrition First”. Int J Gynaecol Obstet. 2015;131 Suppl 4:S213-53. doi: 10.1016/S00207292 (15)30023-0.