Damaged Reproduction: The Most Important Consequence of Iodine Deficiency

John T. Dunn1 and Francois Delange1

Department of Medicine (J.T.D.), University of Virginia, Charlottesville, Virginia 22908; and University of Brussels (F.D.), B1170 Brussels, Belgium

Address correspondence and requests for reprints to: John T. Dunn, M.D., Department of Medicine, University of Virginia, Health Sciences Center, Box 800414, Charlottesville, Virginia 22908.

In 1998, over one third of the world’s population lived in areas of iodine deficiency (1). Most countries, including many in western Europe, are involved. Iodine is an essential component of thyroid hormones, and its importance stems from that role.

The most obvious consequence of iodine deficiency is goiter. This adaptive response, mediated principally by TSH, attempts to cope with a shortage of the raw material (iodine) needed for hormone synthesis. If the iodine deficiency is not too severe and the response is adequate, the affected individual has no apparent consequence, except an enlarged thyroid. In the past, the disease entity was labeled "endemic goiter," and although recognized as a significant public health issue, it received much less attention than other pressing needs, such as infectious diseases. Cretinism was known to be associated with endemic goiter, but the existence of a continuum from mild mental retardation to gross neurological impairment has only been widely appreciated in the last several decades (review in Ref. 2).

The term "iodine deficiency disorders" serves to emphasize the many other consequences of iodine deficiency (3). Of these, damage to reproductive function and to the developing fetus and infant is the most severe and is the focus of this commentary. Aspects of this topic have been reviewed in detail elsewhere (4, 5, 6), and Smallridge et al. (7) discuss the related issue of hypothyroidism in pregnancy in this issue of the journal.

Need for iodine during pregnancy

International organizations, including the United States Institute of Medicine (IOM) of the National Academy of Sciences, the World Health Organization (WHO), the United Nations Children’s Fund (UNICEF), and the International Council for Control of Iodine Deficiency Disorders (ICCIDD), recommend a daily intake of 150 µg iodine for nonpregnant adults (8, 9). This number is based on studies of iodine accumulation and turnover, the T4 dose required to maintain euthyroidism in athyreotics, T4 disposal rates, and the amounts of iodine necessary to prevent goiter in populations (10). Pregnant women need more than this baseline requirement, to cover the iodine needs of the developing fetus and to compensate for increased renal iodine losses. Renal clearance of iodine increases during pregnancy (11); in one study, the concentration of iodine in urine was 60% higher during pregnancy in women from a mildly iodine-deficient area (12). An older balance study estimated an average iodine requirement of 160 µg/day during pregnancy (13). Several reports from iodine-deficient areas in Europe indicated that a total daily iodine intake of about 200 µg prevents pregnancy-associated goiter (14, 15). The most recent IOM methodology defines an estimated average requirement (EAR) for a nutrient as the amount that will be sufficient for 50% of the population, and from this calculates a recommended daily allowance (RDA); the EAR for iodine in pregnancy is 160 µg/day, and the RDA is 220 µg/day (8).

During lactation, the mother must obtain enough iodine for her own thyroid plus that of her growing infant. Calculations from the EAR for nonpregnant adult women (95 µg/day) and from an average loss in human breast milk (about 114 µg/day) lead to an EAR during lactation of 209 µg iodine/day and a RDA of 290 µg/day. The IOM report also includes "adequate intake" (AI) estimates (used when an EAR cannot be calculated) and RDAs for other population groups (8). The AI is less exact and, therefore, reaches higher levels than those derived by the EAR/RDA methodology, which is based largely on balance studies. The IOM sets the AI at 110 µg iodine/day for infants 0–6 months old and at 130 µg/day for those 7–12 months old; the RDA is 90 µg/day for children 1–8 yr old, 120 µg/day for those 9–13 yr, and 150 µg/day for older ages. These values correspond fairly closely to those recommended by WHO, ICCIDD, and other groups and provide a reasonable target in considering iodine nutrition for mother and child. Positive iodine balance for the neonate and young infant, which is required to accommodate the increasing stores of the thyroid, is achieved only when the iodine intake is at least 15 µg/kg·day in full term and 30 µg/kg·day in preterm infants (10). This corresponds to an iodine intake of approximately 90 µg/day and is the present recommendation by WHO/UNICEF/ICCIDD for infants and children aged 0–59 months (9).

Effects of iodine deficiency on the mother

Hypothyroxinemia, elevated serum TSH, enlargement of the thyroid (by 10–50%), and goiter are the most obvious consequences for the pregnant woman. They can be prevented by adequate iodine supplementation (14, 15). Because the increased demands for iodine continue during lactation, an iodine-deficient woman may face several years of exaggerated iodine loss and consequent goiter. Even after she stops lactation and the iodine demand decreases, her thyroid may not return to its previous size and she risks multinodular goiter and hyperthyroidism later. In iodine-sufficient countries like the United States, goiter is rarely found in pregnancy and unlikely to be related to iodine.

Iodine deficiency poses additional reproductive risks, including overt hypothyroidism, infertility, and increased abortions. Hypothyroidism causes anovulation, infertility, gestational hypertension, increased first trimester abortions, and stillbirths; all are common in iodine deficiency. Lack of iodine also has cultural and socioeconomic consequences for the mother. Infertility and fetal wastage may compromise her quality of life and her role in the family and community. If she produces a defective child, she will most likely be responsible for its long-term care, diverting her time and resources from other needs.

Effects of maternal iodine deficiency on the fetus and neonate

Iodine deficiency increases neonatal mortality. We emphasize this statement so that iodine deficiency can take its proper place among the disorders that kill children; "child survival" is something of a buzzword in international aid circles, and showing its relation to iodine deficiency helps direct resources toward its correction. Here, we briefly cite supporting evidence.

In one study, DeLong et al. (16) added KIO3 to irrigation water in western China over several years. In three treated villages, infant mortality decreased to half the average of the previous 5 years (e.g. from 58.2 to 28.7 per 1000 for one village). In comparison with untreated villages, the odds of neonatal death were reduced by about 65%. An investigation from an iodine-deficient region of Indonesia found the mortality in infants treated at 6–10 weeks with oral iodized oil to be only half that of an untreated group (17). In Congo, women with a median pregnancy stage of 28 weeks received iodized oil im; their offspring had lower neonatal mortality and higher birth weights than those from untreated controls (18). A long-range follow-up of women treated with im iodized oil in an iodine-deficient area of Papua, New Guinea, showed that their offspring had a significantly greater 15-yr survival than those from an untreated control group (19). Investigations from several other countries support these conclusions. In addition, a large older literature documents the adverse effects of iodine deficiency on reproduction in farm animals, especially abortions and neonatal mortality. As just one example, "hairless pig malady" from iodine deficiency killed one million pigs annually in Montana in the early part of the 20th century (20).

The epidemiologic studies in humans do not directly address the causes of the increased mortality. Undoubtedly, many factors are at play, and other nutritional and health problems usually accompany iodine deficiency in most of its geographic and sociocultural settings. Infectious diseases are the usual immediate cause of childhood death. Iodine deficiency may impair the immune response and, thus, lower the child’s defense against infection (21). More generally, the iodine-deficient child is poorly equipped to deal with his harsh environment and its many threats. Birth weights are lower, and development is less advanced. Whatever the roles of other factors, the available data clearly show that correction of iodine deficiency per se substantially decreases neonatal and infant mortality.

The most vulnerable target for iodine deficiency is the developing brain. Iodine is critical to maturation of the central nervous system, particularly its myelination. DeLong et al. (22) have carefully examined the effects at different stages of pregnancy. Correction of iodine deficiency during the second trimester reduced neurological abnormalities, increased head growth, and improved the development quotient in a severely iodine-deficient area of western China. Correction at a later period did not improve neurological development, although there was a trend toward slightly larger mean head circumference and higher development quotients than in untreated individuals. The principal effects of T4 are on somatogenesis, neuronal differentiation, and formation of neural processes, particularly active for the cerebral cortex, cochlea, and basal ganglia during the second trimester; brain growth and differentiation are more active in the third trimester (22, 23, 24). In iodine deficiency, maternal T4, which must cover fetal needs during the first trimester before the fetal thyroid makes its own, is low, so the fetus is exposed to inadequate T4 throughout gestation.

The most extreme clinical result is cretinism, defined by severe mental retardation, associated defects (e.g. deaf mutism, spasticity, and stunted growth), and iodine deficiency as the causal agent. Historically, cretins were separated phenotypically into neurological and myxedematous types, but the division is not rigid and the entity is better described as a spectrum. The neurological type typically has the features mentioned above, whereas the myxedematous has, in addition, hypothyroidism, attributed to thyroid exhaustion in the third trimester and early postnatal period (2).

Mental retardation from iodine deficiency is not limited to the extreme form of cretinism, but instead extends over a broad continuum to mild intellectual blunting that may go unrecognized unless carefully investigated. Thus, iodine deficiency puts virtually everyone in the affected population at some risk for brain damage. Many studies have compared performance of iodine-deficient children with that of iodine-sufficient peers on standardized intelligence tests. A meta-analysis of 18 such studies, comprising 2214 subjects, concluded that iodine deficiency lowered a mean intelligence quotient by 13.5 points (25). In view of the many people living in iodine-deficient areas and their vulnerability to its effects on the developing brain, these numbers indicate a staggering public health problem. This and neonatal mortality, rather than goiter, have become the main reasons for advocating urgent correction of iodine deficiency.

Screening for congenital hypothyroidism offers a useful index of community iodine nutrition and of the risk of brain damage in the developing infant (26). Neonates are more sensitive than children and adults to the effects of iodine deficiency because they have a very small intrathyroidal iodine pool with markedly accelerated turnover. Iodine deficiency, even of a degree that does not affect adult thyroid function, elevates neonatal TSH values so that more than 5% (the upper limit of the normal distribution in iodine sufficiency) exceed the critical cutoff point of 5 mU/L. This shift can increase the number of neonates recalled for suspected congenital hypothyroidism in areas of moderate to severe iodine deficiency and increase the appearance of overt, although transient, hypothyroidism. The long-term effects of transient neonatal hypothyroidism are not established, but the potential for damage should be respected, and every effort made to ensure adequate iodine (27). Screening programs are already in place in most developed countries, and the results should be regularly examined to detect signs of iodine deficiency.

Current efforts to correct iodine deficiency

The history of iodine deficiency offers an instructive example of transferring medical knowledge to public health. Physicians have known for over a century that endemic goiter and endemic cretinism are associated with low iodine intake. For decades, they have recognized that a large fraction of the iodine-deficient population risks varying degrees of brain damage. Yet before the 1980s, iodine deficiency held a low priority among the public health needs of developing countries because attention was focused on goiter rather than on the more deadly consequences.

In 1985, the ICCIDD was formed for the express purpose of achieving sustainable optimal iodine nutrition worldwide. Emphasis on iodine deficiency’s damage to reproductive outcome, rather than only on goiter, caught the interest of organizations dedicated to children, particularly UNICEF. The WHO already had a longstanding interest in iodine deficiency. Together, these three organizations have worked closely toward eliminating global iodine deficiency. The effort accelerated markedly in 1990 following the World Summit for Children’s pledge to virtually eliminate iodine deficiency by 2000. Iodized salt has been the principal vehicle. A 1999 review reported the following figures: 1) 2.2 billion people (38% of the world’s population), at risk for iodine deficiency; 2) 130 of the world’s 191 countries affected by iodine deficiency; 3) 13% of the world’s population (740 million people) with goiter; 4) 105 countries with national coordinating bodies to fight iodine deficiency; 5) 102 countries with an action plan; 6) 98 countries with iodized salt legislation; and 7) 68% of the at-risk population using iodized salt at the household level (1).2

Conclusions

The mother and fetus must have adequate iodine throughout the pregnancy. Screening for maternal hypothyroidism during pregnancy should be strongly considered, particularly in areas of iodine deficiency, even if borderline (see Ref. 6 for algorithm). The presence of iodized salt in an iodine-deficient community does not always protect reproductive outcome. Usual medical practice decreases salt intake during pregnancy, precisely the time when the mother needs more iodine, so iodized salt alone may not provide enough for her child’s proper development. If this possibility seems likely, the mother should be supplemented from other sources. Potassium iodide tablets, alone or as part of prenatal vitamin preparations, are usually the best alternative because they provide an appropriate daily ration. Oral iodized oil offers another choice; its single dose is easier to administer, although it does not provide constant blood iodine levels, and it is safe (28). Pregnancies in areas of iodine deficiency that are not satisfactorily covered with iodized salt should always be supplemented with iodine in another appropriate form. Best, of course, is to provide adequate iodine before conception takes place.

Iodized salt should be viewed as a means to an end—adequate iodine nutrition—rather than as an end in itself. Monitoring of people is essential. We have previously cited examples where initially successful programs later deteriorated, usually because of insufficient attention to monitoring (e.g. Guatemala, Mexico, Thailand; Ref. 29). Even in Australia and the United States, recent data show marked decreases in population iodine nutrition over past decades. Some other countries now receive excess dietary iodine, usually from improperly iodized salt; they risk iodine-induced hyperthyroidism (30), autoimmune thyroid disease, and possibly papillary cancer. The solution to these problems is regular effective assessment of iodine nutrition.

Summary

Over one third of the world’s population risk the consequences of iodine deficiency. The worst of these are on reproductive function and outcome and include more neonatal deaths, increased abortions, and defective progeny. Great progress has been made in the past decade toward the sustainable elimination of iodine deficiency, principally from the widespread introduction of iodized salt. However, availability of iodized salt does not guarantee optimal iodine nutrition, and populations must be adequately monitored to protect their reproductive health.

Footnotes

1 Member of the International Council for Control of Iodine Deficiency Disorders. Back

2 Details on countries and other supporting information appear on the web sites of the ICCIDD (www.iccidd.org) and WHO (www.who.int.nut). Back

Received February 6, 2001.

Revised March 12, 2001.

Accepted March 19, 2001.

References

  1. WHO, UNICEF, and ICCIDD. 1999 Progress towards the elimination of iodine deficiency disorders (IDD). Geneva: WHO.
  2. Delange F. 2000 Endemic cretinism. In: Braverman LE, Utiger RD, eds. The thyroid. A fundamental and clinical text. Philadelphia: Lippincott; 743–754.
  3. Hetzel BS. 1983 Iodine deficiency disorders (IDD) and their eradication. Lancet. ii:1126–1129.
  4. McMichael AJ, Potter JD, Hetzel BS. 1980 Iodine deficiency: thyroid function and reproductive failure. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. Iodine nutrition in health and disease. New York: John Wiley; 445–460.
  5. Lazarus JH, Kokandi A. 2000 Thyroid disease in relation to pregnancy: a decade of change. Clin Endocrinol. 53:265–278.[CrossRef][Medline]
  6. Glinoer D, Delange F. 2000 The potential repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny. Thyroid. 10:871–887.[Medline]
  7. Smallridge RC, Ladenson PW. 2001 Commentary: hypothyroidism in pregnancy—consequences to neonatal health. J Clin Endocrinol Metab. 86:2349–2353.[Free Full Text]
  8. Panel on Micronutrients, Food and Nutrition Board, Institute of Medicine. 2001 Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press. In press.
  9. WHO, UNICEF, and ICCIDD. 2001 Assessment of the iodine deficiency disorders and monitoring their elimination. Geneva: WHO. In press.
  10. Delange F. 1993 Requirements of iodine in humans. In: Delange F, Dunn JT, Glinoer D, eds. Iodine deficiency in Europe. A continuing concern. New York: Plenum Press; 5–16.
  11. Aboul-Khair SA, Crooks J, Turnbull AC, Hytten FE. 1964 The physiological changes in thyroid function during pregnancy. Clin Sci. 27:195–207.
  12. Smyth PPA, Hetherton AMT, Smith DF, Radcliff M, O’Herlihy C. 1997 Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal iodine intake. J Clin Endocrinol Metab. 82:2840–2843.[Abstract/Free Full Text]
  13. Dworkin HJ, Jacquez JA, Beierwaltes WH. 1966 Relationship of iodine ingestion to iodine excretion in pregnancy. J Clin Endocrinol Metab. 26:1329–1342.[Medline]
  14. Glinoer D, Nayer PD, Delange F, et al. 1995 A randomized trial for the treatment of excessive thyroid stimulation in pregnancy: maternal and neonatal effects. J Clin Endocrinol Metab. 80:258–269.[Abstract]
  15. Berghout A, Wiersinga WM. 1998 Thyroid size and thyroid function during pregnancy. In: Stanbury JB, Delange F, Dunn JT, Pandav CS, eds. Iodine in pregnancy. Delhi: Oxford University Press; 35–53.
  16. DeLong GR, Leslie PW, Wang S-H, et al. 1997 Effect on infant mortality of iodination of irrigation water in a severely iodine-deficient area of China. Lancet. 350:771–773.[CrossRef][Medline]
  17. Cobra C, Muhilal, Rusmil K, et al. 1997 Infant survival is improved by oral iodine supplementation. J Nutr. 127:574–578.[Abstract/Free Full Text]
  18. Thilly CH, Lagasse R, Roger G, Bourdoux P, Ermans AM. 1980 Impaired fetal and postnatal development and high perinatal death-rate in a severe iodine deficient area. In: Stockigt JR, Nagataki S, Meldrum E, Barlow JW, Harding PE, eds. Thyroid research VIII. Canberra: Australian Academy of Science; 20–23.
  19. Pharoah POD, Connolly KJ. 1994 Iodine deficiency in Papua, New Guinea. In: Stanbury JB, ed. The damaged brain of iodine deficiency. New York: Cognizant Communication; 299–305.
  20. Iodine Educational Bureau. 1949 Hairless pig malady. Iodine facts #382. London: The Iodine Educational Bureau.
  21. Marani L, Venturi S, Masala R. 1985 Role of iodine in delayed immune response. Isr J Med Sci. 21:864.[Medline]
  22. DeLong GR, Xue-Yi C, Xin-Min J, et al. 1998 Iodine supplementation of a cross-section of iodine-deficient pregnant women: does the human fetal brain undergo metamorphosis? In: Stanbury JB, Delange F, Dunn JT, Pandav CS, eds. Iodine in pregnancy. Delhi: Oxford University Press; 55–78.
  23. Chan S, Kilby MD. 2000 Thyroid hormone and central nervous system development. J Endocrinol. 165:1–8.[Free Full Text]
  24. Koibuchi N, Chin WW. 2000 Thyroid hormone action and brain development. Trends Endocrinol Metab. 4:123–128.
  25. Bleichrodt N, Born MP. 1994 A metaanalysis of research on iodine and its relationship to cognitive development. In: Stanbury JB, ed. The damaged brain of iodine deficiency. New York: Cognizant Communication; 195–200.
  26. Delange F. 1998 Screening for congenital hypothyroidism used as an indicator of the degree of iodine deficiency and of its control. Thyroid. 8:1185–1192.[Medline]
  27. Calaciura F, Mendorla G, Distefano M, et al. 1995 Childhood IQ measurements in infants with transient congenital hypothyroidism. Clin Endocrinol. 43:473–477.[Medline]
  28. Delange FD. 1996 Administration of iodized oil during pregnancy: a summary of the published evidence. Bull WHO. 74:101–108.[Medline]
  29. Dunn JT. 2000 Complacency: the most dangerous enemy in the war against iodine deficiency. Thyroid. 10:681–683.[CrossRef][Medline]
  30. Delange F, de Benoist B, Alnwick D, et al. 1999 Risks of iodine-induced hyperthyroidism following correction of iodine deficiency by iodized salt. Thyroid. 9:545–556.[Medline]