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Int J Endocrinol Metab 2004; 2:1-12

REVIEW ARTICLE

Optimal Iodine Nutrition during Pregnancy, Lactation and the Neonatal Period
Delange F. International Council for Control of Iodine Deficiency Disorders (ICCIDD); Department of Pediatrics, University of Brussels, Brussels, Belgium
odine of maternal origin is required for brain development of the progeny during fetal and early postnatal life. Therefore, the iodine requirements of the mother are increased during pregnancy and lactation. This paper reevaluates the iodine requirements during pregnancy, lactation and the neonatal period and formulates original proposals for the median concentrations of urinary iodine indicating optimal iodine nutrition during these three critical periods of life. Based on an extensive and critical review of the literature on thyroid physiopathology during the perinatal period, the following proposals are made: the iodine requirements are 250-300 µg/day during pregnancy, 225-350 µg/day during lactation and 90 µg/day during the neonatal period. The median urinary iodine indicating optimal iodine nutrition during these three periods should be in the range 150-230 µg/L. These figures are higher than those recommended so far by international agencies.

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changes is the increased requirement of iodine in the mother due to the transfer of thyroxine (T4) and of iodide from mother to fetus during pregnancy and to the loss of iodide in breast milk during lactation. These two processes are required in order to ensure normal brain development and prevention of mental retardation in the offspring.5-10 The objectives of this paper are: 1. To review the data from the literature on the iodine requirements during pregnancy, lactation and the neonatal period. 2. To offer practical recommendations regarding the median concentrations of urinary iodine indicating optimal iodine nutrition during these critical periods of life.

Key Words: Iodine, Nutrition, Pregnancy, Lactation, Neonatal Period, Median urinary iodine

Requirement of Iodine During Pregnancy and Lactation
The requirement of iodine is increased during pregnancy because of at least three factors: 1) There is an increased requirement of T4 in order to maintain a normal global metabolism in the mother. 2) There is a transfer of T4 and iodide from the mother to the fetus and 3) There is supposed to be an increased loss of iodide through the kidney due to an increase in the renal clearance of iodide.

Introduction
The thyroid economy undergoes a series of metabolic changes during pregnancy and lactation.1-4 One of the factors involved in these
Correspondence: Professor François Delange, MD, PhD, 153, avenue de la Fauconnerie B-1170, Brussels, Belgium E-mail: fdelange@ulb.ac.be

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Because of these three factors, the recommended dietary intake of iodine during pregnancy is higher than the value of 150 µg/day recommended for non-pregnant adults and adolescents.11,12 Below this critical threshold of 150 µg/day, the iodine balance is negative during pregnancy.13 WHO/UNICEF/ICCIDD recommend an iodine intake of 200 µg/day for pregnant women,11 i.e. a percentage increase of 33% over non-pregnant women. The Institute of Medicine (IOM) of the US Academy of Sciences recommends a higher intake of 220 µg/day,12 i.e. an increase of some 47%, and other organizations recommend 175 to 230 µg/day.14,15 Increase in the T4 requirements The daily requirement of T4 in order to maintain euthyroidism in hypothyroid women increases by 10 to 150% during pregnancy with a median increment of 40-50%.16-18 This represents an additional dose of 75 to 150 µg T4/day, i.e. 50 to 100 µg iodine. Transfer of T4 and iodide from mother to fetus The transfer of T4 from mother to fetus, including before the onset of fetal thyroid function, is not quantified but it is has been estimated that up to 40% of the T4 measured on cord at birth is still of maternal origin.8 The transfer of iodide is also difficult to quantify but considering that the iodine content of the fetal thyroid increases progressively from less than 2 µg at 17 weeks of gestation19 up to 300 µg at term,20-23 that the T4 iodine at term probably averages 500 µg24 and that the substitutive dose of T4 in hypothyroid neonates is 50-75 µg/day,25,26 it can be estimated that the transfer of iodide from mother to fetus represents some 50 µg/day. It has been estimated at 75 µg/day by the IOM.12 Increased renal clearance of iodide It is often stated that the increase in iodine requirement during pregnancy is largely due to an increased loss of iodide through the

kidney because of an increased renal clearance of iodide. This should decrease the serum concentration of plasma inorganic iodide, PII.27-30 However, Liberman et al.31 showed on the contrary that there is no significant decline in the PII during pregnancy. In addition, as shown by the data collected in Table 1 and already by Dworkin et al.,13 almost all studies on urinary iodine during pregnancy showed that, in a given environment, the urinary excretion of iodide is almost similar in pregnant and non-pregnant women and in the general population, irrespective of the status of iodine nutrition in the population. Only the studies conducted by the group of Smyth et al.32,33 in Ireland, the United Kingdom and Sri Lanka, by Kung et al. in Hong Kong34 and perhaps by Hess et al. in Switzerland35 have shown a clear-cut increase in the urinary iodine excretion during pregnancy. The results reported for Switzerland by Brander et al.36 are difficult to interpret because of the surprisingly low value of the urinary iodine in the general population reported in this study as Switzerland is known to be iodine sufficient.37 On the contrary, some studies showed that urinary iodine decreases during gestation.38-40 It thus appears that the concept of systematically increased urinary loss of iodine during pregnancy is not firmly established. Finally, it has to be underlined that no data are available on the possible storage and loss of iodide in the placenta itself. Taking all these variables into consideration, it can be speculated that the additional requirement of iodine during pregnancy is at least 100-150 µg/day, i.e. an increment of almost 100% as compared to non-pregnant adults instead of the 33% proposed by WHO/UNICEF/ICCIDD.11 Consequently, the requirement of iodine during pregnancy is at least 250 µg/day, probably in the range of 250 to 300 µg/day. This figure is still higher than the figure of 220 µg/day proposed by the IOM,12 which did not take into account the increased requirement of T4 during pregnancy.

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Table 1. Comparison of the median or mean (in bold) urinary iodine (µg/L) in pregnant women and in the general population or in non-pregnant controls (publications 1990-2003)
Country General population or controls n S/C Pregnant women Trimester Urinary iodine UK33 Country General population or controls 73† n S/C Pregnant women Urinary iodine 1 125† 2 170 3 147 1 50† 3 54 1-2 50† 2-3 45 1 56† 2 50 3 50 2 51† 3 40 1 week PP 30 26 weeks 50 PP 52 weeks 58 PP 5 days PP 40‡ 3 38† 3 months PP 51 6 months 30 PP 9 months 63 PP Monthly 24-52* during pregnancy and 3, 6 and 12 months PP 1,2 74‡ 3 1 11 days PP 1,2,3 50* 55‡ 50 57‡ Trimester

Countries with no iodine deficiency Chile31 19 S

Iran43 Sweden77

193-312† -

Srilanka33

147†

USA78 Switzerland35 (2000) Scotland79 Switzerland36 (1992)

130 115† 138† 91‡

403 51 51 51 290 511 433 153 31 56 66 15 15 15

C S S S C C C C C C C C C C S S S C S

1 594* 2 469 3 786 3 months PP 459 1-3 186-338† 1 180* 2 170 3 145 1 181† 2 136 3 154 1-3 148 2,3 138† 1 1-3 1 2 3 1 2 3 3 1 2 3 6 weeks PP 3 months PP 1,2,3 1-3 1 2 3 6 weeks PP 137† 205* 267 206 172 325 166 183 124† 107† 116 124 105 104 33* 91* 135† 125 122 70

France40 Belgium38

50-80* 50-75*

Denmark83

50*

306 224 334 334 136 133 49 26 26 26 26 26

C C C S S C C C C C S S S S S C S S S S S

Denmark84 Sudan55

76†

47 47 47 47

Iodine deficient countries 98† 253 Singapore34,80 230 54,81 Sicily (Italy) 46* 10 85* 80 Turkey82 32,33 70† 38 Ireland 38 38 108

New Zealand

49

24-47*

35

S S S S S C

Italy85 (2002) Italy86 (1991) Germany87 Hungary88

Marginal ID Marginal ID Mild ID Mild ID

67 18 70 70 119

C C S S C

n: number of subjects; S/C: Sequential (S) or cross-sectional study(C); 1,2,3: Trimesters of pregnancy; PP: Postpartum; ID: Iodine deficiency; 100 µg/L = 0.78 µmol/L * µg/day; † µg/L; ‡ µg/g creatinine

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Table 2. Selective examples of the iodine content of breastmilk * Countries Medians or means (µg/L) No iodine deficiency Korea 892 Japan 661 33-385 USA 146 168 124 145 145 Sweden 93 90 70 Switzerland 78 Mild to moderate iodine deficiency Germany 93 15-150 Belgium 95 France 82 77 74 70 108 77 64 60 57 50 43 27 5-16 64 15

µg/day. Consequently, the iodine requirement during lactation is estimated at 225 to 350 µg/day. The slight difference, if any, as compared to the figure of 290 µg/day recommended by IOM12 results from more recent data on the iodine content of breast milk.41,42

Level of Urinary Iodine Indicating Optimal Iodine Nutrition During Pregnancy and Lactation
Considering that most (above 90%) of the iodine absorbed in the body eventually appears in the urine, urinary iodine excretion is a good marker of a very recent dietary iodine intake.11 Therefore, a median urinary iodine in the general population varying from 100 to 199 µg/L is considered as an indicator of an adequate iodine intake and an optimal status of iodine nutrition.11 As the iodine requirement is increased during pregnancy, the median urinary iodine during pregnancy indicating optimal iodine nutrition needs to be higher than 100 µg/L. Table 1 compares the data available in the literature on urinary iodine in pregnant women and in the general population. In this Table, the countries are arbitrarily listed on the basis of roughly decreasing iodine intake of the general population, starting with Chile31 which is exposed to iodine excess based on the 11 WHO/UNICEF/ICCIDD criteria, down to countries where different degrees of mild to moderate iodine deficiency have been documented. As indicated earlier, there is a striking similarity between the urinary iodine in pregnant women and in the global population except in the reports published by Smyth et al.32,33 in which the values during pregnancy are systematically markedly higher than in non-pregnant controls. Therefore, it appears difficult to derive a reference value for urinary iodine during pregnancy and lactation from the data collected in countries with no iodine deficiency as this value varies from 800 µg/L in Chile31 to 138 µg/L in Switzerland, where the median urinary iodine in the

Spain United Kingdom Hungary Guatemala Philippines Thailand Italy (Sicily) Severe iodine deficiency Marocco Ethiopia Congo

13
* Compiled from Semba-Delange 200141 and Dorea 2002,42 where detailed data and references are to be found.

During lactation, considering that the iodine content of breastmilk in conditions of iodine sufficiency is in the range of 150-180 µg/L41,42 (Table 2) and that the milk production is from 0.5 to 1.1 liter per day up to the age of 6 months, the daily loss of iodine in human milk is estimated at some 75 to 200

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general population is barely above the lower limit of normal.35 In Iran, where iodine deficiency has been successfully eliminated,43 the median urinary iodine in pregnant women in four different cities varies from 186 to 403 µg/L and is almost entirely similar to the values found in the general population in the same cities.44 The values during pregnancy are of the same order of magnitude as the 250-300 µg/day recommended as intake based on metabolic studies. And yet, in spite of these relatively elevated values, Azizi et al.44 underline that with such medians, some 8% of the values are still below the critical threshold of 100 µg/L for non-pregnant adults. They suggest that the recommended dietary intake of iodine during pregnancy should be still higher. It has to be recognized however, that this figure of 8% corresponds almost exactly to the percentage of values (7.2%) below the cut-off point of 50 µg/L indicating at least moderate iodine deficiency in a general population when the median is between 100 and 200 µg/L.45 This percentage is considered as acceptable45 considering the well documented day to day variability of urinary iodine, including during pregnancy.46-49 From these different considerations, it can be concluded that the recommended median value for urinary iodine during pregnancy and lactation has to be based on theoretical grounds. If, as in non-pregnant adults, the recommended median (100 to 200 µg/L) corresponds to the recommended intake (150 µg/day), the median urinary iodine during pregnancy and lactation should be in the range 225-350 µg/L. If, on the contrary, this recommended median was based on a recommended intake of 225-350 µg/day and a mean daily urinary volume of 1.5 L/day, it should be in the range of 150-230 µg/L, i.e. only slightly higher than the value recommended for non-pregnant adults. It has to be recognized that thyroid function and volume remained perfectly normal during pregnancy in Iran44 as well as in Chile31 for values still twice higher, which strongly suggests that these values are not excessive

and potential sources of side effects.50,51 On the contrary, in all countries submitted to some degree of iodine deficiency where the point has been investigated, thyroid function is critically impaired during pregnancy and in the neonate even when it remains normal in the general population.52-56 The anomalies include progressive decrease in free T4 and increase in serum Tg and thyroid volume. The alterations are usually still more marked in the neonates than in the mothers.52 They are at least partly corrected by iodine supplementation during pregnancy and lactation.57,58 In summary, it appears that the recommended dietary intake of iodine during pregnancy (250-300 µg/L) and lactation (225-350 µg/L) should be higher than what has been proposed earlier, especially by WHO/UNICEF/ICCIDD,11 and that a median urinary iodine indicating optimal iodine nutrition during pregnancy and lactation could be in the range 150-230 µg/L.

As underlined by the IOM,12 no functional criteria of iodine status have been demonstrated that reflect response to dietary intake in infants. Consequently, the recommended intake of iodine in neonates reflects the observed mean iodine intake of young infants exclusively fed human milk in iodine replete areas. Up to the late sixties, the iodine content of breast milk in such areas was usually around 50 µg/L.41,42,59 Considering a daily intake of breast milk of some 0.6 to 1 liter in the neonate and young infant, the assumption was that an infant may get 30 to 50 µg/day iodine in milk from an adequately fed mother.60 However, it is well established that the iodine content of breastmilk is critically influenced by the dietary intake of the pregnant and lactating mother and of the general population and that much higher figures have been recorded more recently.41,42 Thus, again on theoretical grounds, the requirement of io dine in neonates was evaluated from metabolic studies by determining the value which

Requirement of Iodine in Neonates

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Table 3. Median or mean (in bold) urinary iodine (UI) concentrations (µg/L) in neonates in iodine sufficiency and iodine deficiency Countries and locan Gestational tion age Japan 118 FT Breastfed Hokkaido 182 FT Bottlefed United States Boston ? PT≤ 36 weeks Torrance 50 FT Canada Toronto 81 FT The Netherlands Rotterdam 64 FT Amesterdam 36 FT Sweden Stockholm 39 FT Stockholm 61 FT Mild to moderate iodine deficiency Germany Nine towns 1983 461 FT Berlin West 1985 87 FT Kiel 1992 50 FT Frankfurt 1992 21 FT Berlin West 1994 177 FT Berlin East 1994 213 FT Gottingen 2000 22 FT Heidelberg 1999 32 FT Belgium Brussels 1983 103 PT+FT Brussels 1985 196 FT Brussels 2000 90 FT Italy Rome 1985 114 FT Catania 1985 14 FT ?towns 1995 195 FT Milano 1995 18 PT 30 weeks Torino 9 FT France Lille 1985 82 FT Toulouse 1985 37 FT Ireland Belfast 1993 ? FT Israel Tel Aviv 1996 55 PT 30-31 wks Czech Republic Prague 1998 50 FT Prisbram 1998 50 PT Hungary Budapest 2002 55 FT Gyor 2002 65 FT Miskole 2002 54 FT Nyiregyhaza 35 FT Severe iodine deficiency Gottingen 1985 81 FT Heidelberg 1985 39 FT Freiburg 1985 39 FT n: number; FT: Full-term, PT: Pre-term * Values are medians or means (bold). Urinary iodine (µg/L) * 736 521 148 921 148 162 150 112 96 12-29 28 33 37 31 44 50 95 35 48 86 47 71 56 123 67 58 29 100 55-100 79 78 35 57 59 75 15 13 11 10-150 Range Reference Harada et al. 199463 16-510 Brown et al. 199789 Delange et al. 198490 Delange et al. 198672 Delange et al. 198672 Bakker et al. 199991 Delange et al. 198672 Heidemann et al. 198465 Heidemann et al. 198465 Delange et al. 198672 Grebe et al 199392 Bohles et al. 199393 Grüters et al. 199594 Grüters et al. 199594 Roth et al. 200195 Klett et al. 199996 Delange et al. 198490 Delange et al. 198672 Ciardelli et al. 200197 Delange et al. 198672 Delange et al. 198672 Rapa er al. 199698 Parravicini et al. 199699 Bono et al 1998100 Delange et al. 198672 Delange et al. 198672 Barakat et al. 1994101 Linder et al. 1997102 Hnikova et al. 199970 Peter et al. 2003103

10-950 10-162

Delange et al. 198672 Delange et al. 198672 Delange et al. 198672

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resulted in a situation of positive iodine balance, which is required in order to insure a progressively increased intrathyroidal iodine pool in the growing young infant. Such iodine balance studies were conducted in healthy preterm and in fullterm infants aged approximately one month in Belgium, a country with mild iodine deficiency.61 These studies, reported extensively elsewhere,60 indicate that the iodine intake required in order to achieve a positive iodine balance is at least 15 µg/kg/day in fullterms and 30 µg/kg/day in preterms. This corresponds approximately to 90 µg/day and is consequently twice higher than the 1989 US recommendations of 40-50 µg/day62 but is still a bit lower than the present recommendation of 110 µg/day by the IOM.12

Level of Urinary Iodine Indicating Optimal Iodine Nutrition in Neonates
Table 3 summarizes the data from the literature on the median urinary iodine in neonates in countries or areas with iodine sufficiency and with different degrees of iodine deficiency. There is a large variability in the results even in iodine sufficient countries, where they vary from 736 µg/L in Hokkaido, Japan,63 which is submitted to an extremely high iodine intake64 to 96 µg/L in Stockholm.65 Therefore, again, the data from the literature do not help substantially in identifying the optimal urinary iodine level and this level has also to be defined on the basis of theoretical considerations. Based on an iodine requirement of 90 µg/day and a volume of urines in neonates of some 0.4 to 0.5 liter/day,66 the median urinary iodine indicating optimal iodine nutrition in neonates can be evaluated at some 180 to 225 µg/L when ignoring the fact that the iodine balance of the neonate should also be positive in order to constitute the iodine stores of the thyroid. This level, which is higher than the one recommended for schoolchildren and adults, is indeed observed when healthy young infants are supplemented with a daily

are supplemented with a daily physiological dose of 90 µg/day.67 It is also the value reported in some parts of the United States supposed to be iodine sufficient.68,69 On the other hand, studies reported in the literature in which urinary iodine has been determined simultaneously in mothers at delivery and in neonates during the first days of life39,70,71 indicate that these levels are almost similar in mothers and neonates. Therefore, based on the considerations on optimal urinary iodine in pregnant mothers, it can be extrapolated that the level in neonates should be around 150 to 230 µg/L, which is almost similar to the figure derived from the iodine requirements of the neonates. The data reported from neonates in conditions of mild, moderate and severe iodine deficiency are indeed much lower than normal, down to less than 20 µg/L in Germany72 before the partly successful implementation of a program of voluntary salt iodization.73 It is particularly interesting to observe that this level progressively increased with time in Germany and in Belgium for example following the implementation of programs of iodine supplementation73,74 and silent iodine prophylaxis, respectively.75 In summary, the recommended dietary intake of iodine in neonates is 90 µg/day and the median urinary iodine to be expected when this requirement is met is 180 to 225 µg/L, a value almost similar to the one recommended for pregnant women.

Conclusion
Pregnant and lactating women and neonates are the main targets to the effects of iodine deficiency because of the impact of maternal, fetal and neonatal hypothyroxinemia on brain development of the progeny.5-10 Therefore, any program of salt iodization in a population should pay special attention to these particular groups. And yet, no firm recommendations are presently available on the level of urinary iodine indicating optimal iodine nutrition in these groups. This paper constitutes an attempt

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to propose such normative values. It appears that an extensive review of the literature based in particular on the evaluation of urinary iodine in these groups in iodine replete populations does not offer clear answers to the questions because of the variability of individual results even in iodine sufficient countries. One first conclusion of this paper is thus that more accurate data should be collected in iodine sufficient countries, comparing systematically and at the same time the urinary iodine in the general population, in non-pregnant adults, schoolchildren, pregnant and lactating women and in neonates. However, based on the data from the literature and on metabolic considerations, it is proposed that the recommended dietary intake of iodine is 250-300 µg/day for pregnant women, 225-350 µg/day for lactating women and 90 µg/day for neonates and young infants. It is proposed that the median level of urinary iodine indicating optimal iodine nutrition during pregnancy and lactation is in the range 150-230 µg/L. Recommendations for neonates are still more difficult not only because of the lack of accurate data but also because the neonate is not in a steady state regarding iodine metabolism and that urinary iodine probably represents a relatively imprecise estimation of the iodine intake. How-

ever, based on the data from the literature and on theoretical considerations, it can be concluded that the median urinary iodine indicating optimal iodine nutrition in the neonate should be in the same range of 180-225 µg/L, almost similar to the value recommended for their mothers. It has to be emphasized again that these levels are higher than the ones recommended for the general population and are supposed to be potentially responsible for side effects in adolescents and non-pregnant adults.11 Therefore, special attention should be focused on iodine supplementation and monitoring urinary iodine during pregnancy and possibly during the neonatal period in addition to programs of Universal Salt Iodization in countries with iodine deficiency.58 This recommendation is particularly relevant considering that pregnant and lactating women and neonates have usually a limited access to salt in general and, consequently, to iodized salt, and that even in the United States, where the status of iodine nutrition is adequate in the general population (median urinary iodine of 145 µg/L), 6.7% of the pregnant women are still affected by moderate to severe iodine deficiency (urinary iodine below 50 µg/L).76

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maternal thyroid during pregnancy. J Clin Endocrinol Metab. 1990 Aug;71(2):276-87. Vermiglio F, Lo Presti VP, Finocchiaro MD, Battiato S, Grasso L, Ardita FV, et al. Enhanced iodine concentrating capacity by the mammary gland in iodine deficient lactating women of an endemic goiter region in Sicily. J Endocrinol Invest. 1992 Feb;15(2):137-42. Caron P, Hoff M, Bazzi S, Dufor A, Faure G, Ghandour I, et al. Urinary iodine excretion during normal pregnancy in healthy women living in the southwest of France: correlation with maternal thyroid parameters. Thyroid. 1997 Oct;7(5):74954. Semba RD, Delange F. Iodine in human milk: perspectives for infant health. Nutr Rev. 2001 Aug; 59(8 Pt 1):269-78. Dorea JG. Iodine nutrition and breast-feeding. J Trace Elem Med Biol. 2002;16(4):207-20. Azizi F, Sheikholeslam R, Hedayati M, Mirmiran P, Malekafzali H, Kimiagar M, et al. Sustainable control of iodinedeficiency in Iran: beneficial results of the implementation of the mandatory law on salt iodization. J Endocrinol Invest. 2002 May;25(5):409-13. Azizi F, Aminorroya A, Hedayati M, Rezvanian H, Amini M, Mirmiran P. Urinary iodine excretion in pregnant women residing in areas with adequate iodine intake. Public Health Nutr. 2003 Feb;6(1):95-8. Delange F, de Benoist B, Bürgi H. Median urinary iodine concentrations indicating adequate iodine intake at population level. Bull WHO 2002; 80:410-7. Rasmussen LB, Ovesen L, Christiansen E. Day-today and within-day variation in urinary iodine excretion. Eur J Clin Nutr. 1999 May;53(5):401-7. Als C, Helbling A, Peter K, Haldimann M, Zimmerli B, Gerber H. Urinary iodine concentration follows a circadian rhythm: a study with 3023 spot urine samples in adults and children. J Clin Endocrinol Metab. 2000 Apr;85(4):1367-9. Bürgi H, Bangerter B, Siebenhüner L. High dayto-day variability of urinary iodine excretion despite almost universal salt iodization in Switzerland. In: RM Geertman, editor. 8th World Salt Symposium. Amsterdam: Elsevier publishers; 2000: p.961-3. Thomson CD, Packer MA, Butler JA, Duffield AJ, O'Donaghue KL, Whanger PD. Urinary selenium and iodine during pregnancy and lactation. J Trace Elem Med Biol. 2001 Apr;14(4):210-7. Delange F, Lecomte P. Iodine supplementation: benefits outweigh risks. Drug Saf. 2000 Feb; 22(2):89-95. Braverman LE. Adequate iodine intake--the good far outweighs the bad. Eur J Endocrinol. 1998 Jul;139(1):14-5.

52. Glinoer D, Delange F, Laboureur I, de Nayer P, Lejeune B, Kinthaert J, et al. Maternal and neonatal thyroid function at birth in an area of marginally low iodine intake. J Clin Endocrinol Metab. 1992 Sep;75(3):800-5. 53. Berghout A, Endert E, Ross A, Hogerzeil HV, Smits NJ, Wiersinga WM. Thyroid function and thyroid size in normal pregnant women living in an iodine replete area. Clin Endocrinol (Oxf). 1994 Sep;41(3):375-9. 54. Vermiglio F, Lo Presti VP, Scaffidi Argentina G, Finocchiaro MD, Gullo D, Squatrito S, et al. Maternal hypothyroxinaemia during the first half of gestation in an iodine deficient area with endemic cretinism and related disorders. Clin Endocrinol (Oxf). 1995 Apr;42(4):409-15. 55. Eltom A, Eltom M, Elnagar B, Elbagir M, GebreMedhin M. Changes in iodine metabolism during late pregnancy and lactation: a longitudinal study among Sudanese women. Eur J Clin Nutr. 2000 May;54(5):429-33. 56. Rotondi M, Amato G, Biondi B, Mazziotti G, Del Buono A, Rotonda Nicchio M, et al. Parity as a thyroid size-determining factor in areas with moderate iodine deficiency. J Clin Endocrinol Metab. 2000 Dec;85(12):4534-7. 57. Chan S, Gittoes N, Franklyn J, Kilby M. Iodine intake in pregnancy. Lancet. 2001 Aug 18;358(9281):583-4. 58. Zimmermann M, Delange F. Iodine supplementation of pregnant women in Europe: a review and recommendation. Eur J Clin Nutr 2004 Jul; 58(7):979-84. 59. Delange F. Physiopathology of iodine nutrition. In: RK Chandra, editor. Trace Elements in nutrition of children. New York: Raven Press; 1985: p.291-9. 60. Delange F. Requirements of iodine in humans. In: Delange F, Dunn JT, Glinoer D, editors. Iodine Deficiency in Europe. A continuing concern. New York: Plenum Press; 1993: p.5-16. 61. Delange F. Iodine deficiency in Europe anno 2002. Thyroid International. 2002;5:1-19. 62. National Research Council, Food and Nutrition Board. Recommended Dietary Allowances. Washington DC: National Academy Press; 1989: p. 213-7 and Table p. 285. 63. Harada S, Ichihara N, Arai J, Honma H, Matsuura N, Fujieda K. Influence of iodine excess due to iodine-containing antiseptics on neonatal screening for congenital hypothyroidism in Hokkaido prefecture, Japan. Screening 1994;3:115-23. 64. Suzuki H, Higuchi T, Sawa K, Ohtaki S, Horiuchi Y. Endemic coast goitre in Hokkaido, Japan. Acta Endocrinol (Copenh). 1965 Oct;50(2):161-76. 65. Heidemann PH, Stubbe P, von Reuss K, Schurnbrand P, Larson A, von Petrykowski W. Iodine excretion and dietary iodine supply in newborn in-

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fants in iodine-deficient regions of West Germany Dtsch Med Wochenschr. 1984 May 18; 109(20):773-8. (German). Behrman RE, VC Vaughan, and Nelson WE. Nelson Textbook of Pediatrics, 13th Ed. Philadelphia: W.B. Saunders publishing; 1987. Delange F, Wolff P, Gnat D, Dramaix M, Pilchen M, Vertongen F. Iodine deficiency during infancy and early childhood in Belgium: does it pose a risk to brain development? Eur J Pediatr. 2001 Apr; 160(4):251-4. Bryant WP, Zimmerman D. Iodine-induced hyperthyroidism in a newborn. Pediatrics. 1995 Mar; 95(3):434-6. Gordon CM, Rowitch DH, Mitchell ML, Kohane IS. Topical iodine and neonatal hypothyroidism. Arch Pediatr Adolesc Med. 1995 Dec; 149(12):1336-9. Hnikova O, Hromadkova M, Wiererova O, Bilek R. Follow-up study of iodine status in neonates and their mothers in 2 regions of the Czech Republic after a 3-year intervention Cas Lek Cesk. 1999 Apr 26;138(9):272-5. (Czech). Tajtakova M, Capova J, Bires J, Sebokova E, Petrovicova J. Thyroid volume, urinary and milk iodine in mothers after delivery and their newborns in iodine-replete country. Endocr Regul. 1999 Mar;33(1):9-15. Delange F, Heidemann P, Bourdoux P, Larsson A, Vigneri R, Klett M, et al. Regional variations of iodine nutrition and thyroid function during the neonatal period in Europe. Biol Neonate. 1986;49(6):322-30. Gartner R. IDD status in Germany. J Endocrinol Invest. 2003;26 (Suppl. to n° 9):2223. Meng W, Schindler A. Iodine supply in Germany. In: Delange F, Robertson A, McLoughney E, Gerasimov G, editors. Elimination of Iodine Deficiency Disorders (IDD) in Central and Eastern Europe, the Commonwealth of the Independent States, and the Baltic States. Geneva: WHO publication; WHO/EURO/NUT/98.1. 1998: p. 21-30. Delange F, Van Onderbergen A, Shabana W, Vandemeulebroucke E, Vertongen F, Gnat D, et al. Silent iodine prophylaxis in Western Europe only partly corrects iodine deficiency; the case of Belgium. Eur J Endocrinol. 2000 Aug;143(2):189-96. Hollowell JG, Staehling NW, Hannon WH, Flanders DW, Gunter EW, Maberly GF, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994) J Clin Endocrinol Metab. 1998 Oct;83(10):3401-8. Elnagar B, Eltom A, Wide L, Gebre-Medhin M, Karlsson FA. Iodine status, thyroid function and pregnancy: study of Swedish and Sudanese women. Eur J Clin Nutr. 1998 May;52(5):351-5.

78. Soldin OP, Soldin SJ, Pezzullo JC. Urinary iodine percentile ranges in the United States. Clin Chim Acta. 2003 Feb;328(1-2):185-90. 79. Barnett CA, Visser TJ, Williams F, Toor HV, Duran S, Presas MJ, et al. Inadequate iodine intake of 40% of pregnant women from a region of Scotland. J Endocrinol Invest. 2002. Suppl. to N° 7, Abstract P110:90. 80. Kung AW, Lao TT, Low LC, Pang RW, Robinson JD. Iodine insufficiency and neonatal hyperthyrotropinaemia in Hong Kong. Clin Endocrinol (Oxf). 1997 Mar;46(3):315-9. 81. Vermiglio F, Lo Presti VP, Castagna MG, Violi MA, Moleti M, Finocchiaro MD, et al. Increased risk of maternal thyroid failure with pregnancy progression in an iodine deficient area with major iodine deficiency disorders. Thyroid. 1999 Jan;9(1):19-24. 82. Mocan MZ, Erem C, Telatar M, Mocan H. Urinary iodine levels in pregnant women with and without goiter in the Eastern Black Sea of Turkey. Trace Elements and Electrolytes. 1995;12:195-7. 83. Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen HE, Rasmussen OS, et al. Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. J Clin Endocrinol Metab. 1993 Oct;77(4):1078-83. 84. Nohr SB, Laurberg P, Borlum KG, Pedersen KM, Johannesen PL, Damm P, et al. Iodine deficiency in pregnancy in Denmark. Regional variations and frequency of individual iodine supplementation. Acta Obstet Gynecol Scand. 1993 Jul;72(5):350-3. 85. Antonangeli L, Maccherini D, Cavaliere R, Di Giulio C, Reinhardt B, Pinchera A, et al. Comparison of two different doses of iodide in the prevention of gestational goiter in marginal iodine deficiency: a longitudinal study. Eur J Endocrinol. 2002 Jul;147(1):29-34. 86. Romano R, Jannini EA, Pepe M, Grimaldi A, Olivieri M, Spennati P, et al. The effects of iodoprophylaxis on thyroid size during pregnancy. Am J Obstet Gynecol. 1991 Feb;164(2):482-5. 87. Liesenkotter KP, Gopel W, Bogner U, Stach B, Gruters A. Earliest prevention of endemic goiter by iodine supplementation during pregnancy. Eur J Endocrinol. 1996 Apr;134(4):443-8. 88. Mezosi E, Molnar I, Jakab A, Balogh E, Karanyi Z, Pakozdy Z, et al. Prevalence of iodine deficiency and goitre during pregnancy in east Hungary. Eur J Endocrinol. 2000 Oct;143(4):479-83. 89. Brown RS, Bloomfield S, Bednarek FJ, Mitchell ML, Braverman LE. Routine skin cleansing with povidone-iodine is not a common cause of transient neonatal hypothyroidism in North America: a prospective controlled study. Thyroid. 1997 Jun;7(3):395-400. 90. Delange F, Dalhem A, Bourdoux P, Lagasse R, Glinoer D, Fisher DA, et al. Increased risk of pri-

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mary hypothyroidism in preterm infants. J Pediatr. 1984 Sep;105(3):462-9. Bakker B, Vulsma T, de Randamie J, Achterhuis AM, Wiedijk B, Oosting H, et al. A negative iodine balance is found in healthy neonates compared with neonates with thyroid agenesis. J Endocrinol. 1999 Apr;161(1):115-20. Grebe SF, Rebeski F, Gent J, Müller KD. Iodine balance in neonates and their mothers. Klin Lab. 1993;39:143-6. Bohles H, Aschenbrenner M, Roth M, von Loewenich V, Ball F, Usadel KH. Development of thyroid gland volume during the first 3 months of life in breast-fed versus iodine-supplemented and iodine-free formula-fed infants. Clin Investig. 1993 Jan;71(1):13-20. Grüters A, Liesenkotter KP, Willgerodt H. Persistence of differences in iodine status in newborns after the reunification of Berlin. N Engl J Med. 1995 Nov 23;333(21):1429. Roth C, Meller J, Bobrzik S, Thal H, Becker W, Kulenkampff D, et al. The iodine supply of newborns. Comparison of iodine absorption and iodine excretion of mother and child. Dtsch Med Wochenschr. 2001 Mar 23;126(12):321-5. (German). Klett M, Ohlig M, Manz F, Troger J, Heinrich U. Effect of iodine supply on neonatal thyroid volume and TSH. Acta Paediatr Suppl. 1999 Dec;88(432):18-20.

97. Ciardelli R, Haumont D, Gnat D, Vertongen F, Delange F. The nutritional iodine supply of Belgian neonates is still insufficient. Eur J Pediatr. 2002 Oct;161(10):519-23. 98. Rapa A, Chiorboli E, Corbetta C, Sacco F, Bona G. Study, A.U. Urinary iodine excretion (UIE) screening in newborns exposed to iodinecontaining antiseptics. Horm Res. 1996;46:74. 99. Parravicini E, Fontana C, Paterlini GL, Tagliabue P, Rovelli F, Leung K, Stark RI. Iodine, thyroid function, and very low birth weight infants. Pediatrics. 1996 Oct;98(4 Pt 1):730-4. 100. Bona G, Chiorboli E, Rapa A, Weber G, Vigone MC, Chiumello G. Measurement of urinary iodine excretion to reveal iodine excess in neonatal transient hypothyroidism. J Pediatr Endocrinol Metab. 1998 Nov-Dec;11(6):739-43. 101. Barakat M, Carson D, Hetherton AM, Smyth P, Leslie H. Hypothyroidism secondary to topical iodine treatment in infants with spina bifida. Acta Paediatr. 1994 Jul;83(7):741-3. 102. Linder N, Davidovitch N, Reichman B, Kuint J, Lubin D, Meyerovitch J, et al. Topical iodinecontaining antiseptics and subclinical hypothyroidism in preterm infants. J Pediatr. 1997 Sep;131(3):434-9. 103. Peter F, Muzsnai A, Bourdoux P. Changes of urinary iodine excretion of newborns over a period of twenty years. J Endocrinol Invest. 2003;26(2 Suppl):S39-42.

International Journal of Endocrinology and Metabolism

EDITORIAL
El yodo durante la gestación, lactancia y primera infancia. Cantidades mínimas y máximas: de microgramos a gramos
G. Morreale de Escobar y F. Escobar del Rey
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC y UAM. Madrid. (An Esp Pediatr 2000; 53: 1-5)

Las hormonas tiroideas, tiroxina (T4) y 3,5,3’-triyodotironina (T3) son necesarias durante todas las fases de la vida para una función normal del sistema nervioso central (SNC). Son especialmente cruciales durante el desarrollo del SNC, pues una insuficiencia de estas hormonas se acompaña de lesiones y defectos neurológicos permanentes e irreversibles. Ambas hormonas contienen yodo, cuatro átomos por molécula en el caso de la T4, tres en el caso de la T3. Sin yodo no es posible su síntesis, a pesar de lo cual a lo largo de la evolución no han aparecido otras hormonas capaces de sustituirlas y que no tengan esta total dependencia de un elemento, que suele encontrarse en cantidades muy pequeñas fuera del ambiente acuático marino. En cambio, ha evolucionado una estructura, el folículo tiroideo, capaz de minimizar las consecuencias de un aporte asaz variable del yodo, obtenido en su mayor parte a través de los alimentos y el agua. Es la única estructura endocrina capaz de almacenar estas hormonas en forma de prohormona (la tiroglobulina), con tal eficacia que un adulto, que ha tenido una nutrición adecuada de yodo, puede hacer frente a las necesidades hormonales de su organismo durante varios meses después de iniciarse un período de carencia total del mismo en su alimentación. A su vez, la glándula tiroides del adulto es capaz de evitar las posibles consecuencias nocivas de la producción de un exceso de hormonas tiroideas, que podrían producirse al llegarle cantidades muy altas de yodo. Si embargo, surgen problemas importantes cuando la deficiencia de yodo en la alimentación se hace crónica, o cuando la exposición a un exceso de yodo es muy prolongada, sobre todo cuando esto ocurre durante un período del desarrollo en que la glándula aún no está plenamente preparada para ello. De no resolverse estos problemas, o de resolverse a destiempo, pueden producirse déficit más o menos graves e irreversibles del SNC.

En este breve comentario se intentará definir, con mayor precisión, cuáles son las cantidades mínimas para un desarrollo normal del SNC, y cuáles las que pueden dar lugar a problemas durante el embarazo y primera infancia, períodos en los que tienen lugar en el ser humano fases cruciales de maduración cerebral. Hay, sobre todo con respecto al exceso de yodo, bastantes problemas de índole práctico, tal y como describen con acierto y amplio apoyo bibliográfico Arena y Emparanza en este mismo número1.

CANTIDADES

MÍNIMAS DE YODO

Desde que, hace ya una década, fue ratificada por la práctica totalidad de los países del mundo la Declaración Mundial para la Supervivencia, Protección y Desarrollo de la Infancia, así como un Plan de Acción concreto, elaborado por la Convención sobre los Derechos de la Infancia, emanada a su vez de la Cumbre de la Infancia organizada por Naciones Unidas en 1989, se puede afirmar como derecho humano básico de la infancia2 que: 1. “Todo niño tiene el derecho a una cantidad adecuada de yodo en su dieta”. 2. “Toda madre debe tener una nutrición adecuada de yodo para evitar que el niño tenga un desarrollo mental afectado por una carencia de este micronutriente esencial”. El segundo punto se deriva de la creciente evidencia de que una deficiencia de yodo durante el embarazo puede llevar a concentraciones circulantes de T4 materna insuficientes para un desarrollo armónico del cerebro del feto y el neonato. Las bases científicas y epidemiológicas (que resumimos en un anterior número de esta Revista3) han llevado a la Organización Mundial de la Salud a declarar que la carencia de yodo es la causa mundial más frecuente de retraso mental y parálisis ce-

Correspondencia: Dra. G. Morreale de Escobar. Instituto de Investigaciones Biomédicas Alberto Sols, CSIC y UAM. Arturo Duperier, 4. 28029 Madrid. Correo electrónico: gmorreale@iib.uam.es

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G. Morreale de Escobar y F. Escobar del Rey

TABLA 1. Ingestas mínimas de yodo, recomendadas a partir de 19926
Grupo Edad µg de I /día

Prematuros Niños 0-5 meses 6-12 meses 1-3 años 4-6 años 7-10 años

> 30 µg/kg/día 90 90 90 90 120 150 230* 260*

Adultos Mujeres embarazadas Mujeres lactantes

*Estas son las recomendaciones mínimas en Alemania. Recientemente (después de 1992) el ICCIDD (International Council for the Control of Iodine Deficiency Disorders) ha elevado a 200-300 µg/día las ingestas recomendadas para las embarazadas.

rebral prevenibles, afectando en mayor o menor grado el desarrollo y bienestar de unos 1.600 millones de los actuales habitantes de nuestro planeta. Algunos de ellos viven en España, donde se ha constatado la persistencia de deficiencia de yodo en las 14 comunidades autónomas en las que se han realizado estudios recientes al respecto. En la tabla 1 aparecen las recomendaciones actuales sobre las cantidades mínimas de yodo que se consideran necesarias durante diferentes fases de la vida. Las cantidades han ido elevándose a medida que se han ido teniendo datos epidemiológicos más precisos, y un conocimiento más completo de las diferencias en la fisiología tiroidea a distintas edades. Nótese que las necesidades de yodo de niños prematuros, de neonatos y niños pequeños son notablemente más altas de lo que se deduciría, sobre la base de su peso corporal, de las definidas para escolares y adultos. En el caso de niños prematuros, los preparados humanizados comercializados para ellos no contenían yodo suficiente, pero en los últimos años su contenido se ha ido haciendo más acorde con los requerimientos4,5. También han ido aumentando las cantidades recomendadas durante el embarazo, a medida que se han completado los estudios realizados en Europa. En nuestro país, concretamente en la Comunidad Autónoma de Madrid, hemos observado que las embarazadas necesitan un suplemento de 250-300 µg/día para que puedan alcanzar concentraciones óptimas de T4 libre circulante, y para no desarrollar bocio durante el embarazo7,8. Dada la gran variabilidad del contenido en yodo de los alimentos de procedencia no marina, se recomienda asegurar estas cantidades mínimas mediante la suplementación de la dieta con sal yodada2. En España la legislación contempla la yodación de sal refinada de mesa en 60 µg I/g sal (60 mg/kg; 60 ppm). El uso habitual de esta sal yodada (que no incluye la sal marina, a no ser que el envase especifique que está yodada), parece suficiente para gran parte de la población. Pero quedan

precisamente excluidos los niños prematuros y lactantes y las mujeres embarazadas, que constituyen la parte de la población más vulnerable; los primeros tendrían que ingerir casi 2 g de sal yodada al día, y sus madres 5 g/día. Como esto no ocurre, por las recomendaciones actuales de evitar o restringir el uso de sal en dichos grupos de la población, se impone asegurar las cantidades mínimas de yodo mediante la suplementación diaria controlada. No habiendo en la farmacopea española actual preparados de yoduro o yodato potásico (en forma de tabletas, gotas o grageas) adecuados para ello, hay que recurrir a preparados polivitamínicos y minerales que sí lo contienen, como Calcinatal®, Multicentrum®, Superdyne® y Micebrina®. Cuando la madre ha tomado este suplemento durante todo el embarazo y sigue tomándolo durante la lactancia, su leche contiene las cantidades de yodo que necesita su hijo, sea o no prematuro. Pero en el caso de no ser posible la lactancia materna, habrá que recurrir a los preparados que estén adecuadamente enriquecidos con este micronutriente5. No hemos encontrado información sobre el contenido en yodo de los alimentos preparados para la alimentación de los niños cuando dejan la lactancia, por lo que la suplementación de su dieta con preparados polivitamínicos y minerales podría resultar aconsejable. Con frecuencia se expresa el temor de que, cuando la ingesta de yodo de la mujer ya era buena antes del embarazo, una suplementación de su dieta con 250-300 µg/día podría resultar excesiva y dañina. No hay base alguna para tal temor, ya que una ingesta de 1-2 mg diarios de yodo es frecuente en algunas poblaciones que consumen algas marinas, como algunas de Japón9, sin efectos nocivos. Medidas de yoduria en embarazadas de Chile, por ejemplo, sugieren ingestas de 500-700 µg10, también sin efectos negativos. Como éste es un punto de gran importancia, la Organización Mundial de la Salud encomendó su estudio a un comité internacional de expertos, de cuyas reuniones emanó el documento que demuestra que incluso el uso de aceites yodados (p. ej., Lipiodol®), utilizado como medida de urgencia para erradicar la deficiencia de yodo en países que no tienen establecida una adecuada red de distribución de sal yodada, está exento de problemas para la embarazada y el desarrollo de su feto11. Contrasta esto con los graves problemas relacionados con una ingesta materna deficiente en yodo durante el período de desarrollo fetal (tabla 2)12, problemas que se erradican con su utilización13,14. Debe tenerse en cuenta que 1 ml del aceite yodado empleado habitualmente (Lipiodol®) contiene 380 mg de I (¡380.000 µg!) y las dosis empleadas suelen ser de 2 ml, o más. Aunque se administre de una sola vez, por vía oral o intramuscular, y se retenga en el músculo y tejido graso, el yodo se va liberando paulatinamente. Pero, obviamente, lo hace en cantidad superior a lo que ingeriría una mujer que recibiese 300 µg/día durante todo el embarazo y la lactancia (110 mg).

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TABLA 2. Espectro de disfunciones por déficit de yodo (tanto más graves cuanto mayor es la deficiencia de yodo, y cuanto antes se padece)
Período en que se padece la Consecuencias principales deficiencia de yodo

Feto

Mayor número de abortos Nacidos muertos Anomalías congénitas Mayor mortalidad perinatal Mayor mortalidad infantil Cretinismo neurológico Deficiencia mental Sordomudez Diplejía, tetraplejía espástica Estrabismo Cretinismo mixedematoso Enanismo Deficiencia mental Retraso mental de los habitantes aparentemente normales Mayor susceptibilidad en caso de accidentes nucleares* Defectos psicomotores Bocio neonatal Hipotiroidismo neonatal Mayor susceptibilidad en caso de accidentes nucleares* Bocio Hipotiroidismo juvenil Deterioro de las facultades mentales Retraso en el desarrollo somático Mayor susceptibilidad en caso de accidentes nucleares* Bocio y sus complicaciones Hipotiroidismo Deterioro de las facultades mentales Hipotiroidismo por carencia de yodo Mayor susceptibilidad en caso de accidentes nucleares* Propensión a hipertiroidismo al instaurarse medidas profilácticas

Recién nacidos

Niños y adolescentes

Adultos

*Se debe a una mayor avidez de la glándula deficiente en yodo para concentrarlo, incluidos los isótopos radiactivos del mismo, que son liberados en grandes cantidades durante los accidentes nucleares. Toda la patología tiroidea, incluido el cáncer de tiroides, está aumentada en las zonas de deficiencia de yodo, y a todas las edades.

CANTIDADES

EXCESIVAS DE YODO

Se han descrito casos de grandes bocios en neonatos de madres que usaron sistemáticamente compuestos yodados durante el embarazo (jarabes yodados para la tos, desinfectantes yodados, etc., que contenían gramos de yodo)15, o que recibieron contrastes yodados para amniofetografía16. En algunos casos se produjo la muerte por asfixia. En la mayoría de los otros se produjo un bloqueo de la función tiroidea del feto y el neonato, cuyos efectos pueden prolongarse durante meses, precisamente durante períodos importantes de maduración cerebral. Debe tenerse en cuenta que para el desarrollo del

cerebro durante los primeros años de vida no hay diferencia entre un estado de hipotiroidismo permanente y uno transitorio, pues en ambos casos el niño requiere tratamiento con T4. En el caso de un bloqueo por yodo, el tratamiento debe prolongarse por lo menos hasta que se haya normalizado la yoduria. Por eso parece muy oportuno el artículo de Arena y Emparanza en este número de la Revista1, pues parece que en muchas consultas ginecológicas y en maternidades españolas no se ha eliminado totalmente el uso de antisépticos yodados, como el Betadine®, que contiene povidona yodada al 10%. Cuando hace dos décadas se extendieron por toda España los programas para la Detección Precoz del Hipotirodismo Congénito, se advirtió a todas las maternidades sobre los graves inconvenientes del uso de estos antisépticos, pero al parecer con el tiempo esto se ha ido olvidando, encontrándonos en varios congresos recientes que muchos de los asistentes no conocían su prohibición. También puede ocurrir que la prohibición sí se conozca, pero se haya interpretado erróneamente por una información inexacta. En algunos casos, se evita efectivamente el empleo de povidona yodada para desinfectar al recién nacido, sobre todo si es prematuro, pero sólo hasta después de tomar la muestra de sangre del talón que se envía al Centro de Detección Precoz de Hipotiroidismo Congénito, en la creencia errónea de que su uso “falsea las pruebas” por causas analíticas. A partir de ese momento, se utiliza libremente. En realidad, no es que el uso de la povidona yodada “falsee las pruebas”; lo que hace es provocar un estado de hipotiroidismo que no existía antes de su aplicación. “Falsea” en cuanto no se trata de un hipotiroidismo congénito permanente, sino de uno transitorio. Pero, como se ha indicado más arriba, estos niños requieren tratamiento posnatal con T4 mientras dure el hipotiroidismo, al igual que los niños con hipotiroidismo congénito permanente, si queremos evitar los déficit mentales permanentes que acompañan al hipotiroidismo perinatal tratado tardíamente. Este efecto nocivo de los desinfectantes yodados administrados a la madre y/o al recién nacido se debe a que en la glándula tiroides del feto y en la del neonato aún no han madurado plenamente los mecanismos de autorregulación tiroidea17, que en el adulto permiten obviar los riesgos de una producción excesiva de hormonas tiroideas al producir un aumento la cantidad de yodo disponible. En el individuo adulto sin patología tiroidea subyacente, el exceso de yodo no produce un bloqueo prolongado de la función tiroidea, ya que se han desarrollado “mecanismos de escape” que se vuelven operativos antes de que disminuyan las concentraciones de T4 y T3 por debajo de las normales. No se conoce bien cómo se ponen en marcha dichos “mecanismos

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TABLA 3. Concentración de yodo en diferentes medicamentos, desinfectantes y contrastes radiológicos de uso muy extendido, y de 1 g de sal yodada
Contenido en yodo Contenido en yodo frente a 150 µg /día*

Sal yodada Amiodarona Desinfectantes Solución de Lugol Betadine (povidona yodada) Yoduro sódico al 10% Vioformo/clioquinol Enterovioformo Contrastes radiológicos Hexabrix Oragrafin Lipiodol Renografin Telepaque

60 µg/1 g 7.500 µg/ comprimido 126.000 µg/ml 10.000 µg/ml 85.000 µg/ml 12.000 µg/ml 120.000 µg/ comprimido 320.000 µg/ml 308.000 µg/ cápsula 380.000 µg/ml 370.000 µg/ml 333.000 µg/ml

0,4 x 50 x

840 x 67 570 80 800 x x x x

2.100 x 2.050 x 2.500 x 2.500 x 2.200 x

*150 mg/día suele ser la ingesta diaria mínima considerada adecuada para jóvenes y adultos, excluyendo mujeres embarazadas y lactantes.

de escape”, pero sí se sabe que aún no son plenamente operativos en el recién nacido, y lo son tanto menos cuanto menor sea su edad gestacional. Éste es el motivo de la gran frecuencia con que se bloquea la glándula tiroidea del niño prematuro, al enfrentarse a cantidades de yodo que son toleradas perfectamente por un adulto. El riesgo de un bloqueo de la glándula del neonato no sólo aumenta en el caso de que haya nacido prematuramente, sino que depende también en gran medida de la ingesta de yodo materna. Cuando ésta ha sido insuficiente, el aclaramiento de yoduro por la glándula tiroides del niño, así como su tamaño, aumentan rápidamente y de forma considerable. Pero al volver a llegar yodo en cantidades adecuadas, o altas, no disminuye rápidamente la excesiva vascularización de la glándula, ni la captación aumentada de yodo. Hay un desfase temporal importante, por lo que al llegarle una cantidad excesiva de yodo, la glándula acumula una proporción mayor que en el caso de un recién nacido sin carencia anterior de yodo. Esto contribuye a que se observe un bloqueo de la glándula con dosis de yodo que no resultan excesivas cuando la población está bien nutrida. Los efectos bloqueadores del yodo se ven potenciados cuando se superponen una cierta deficiencia de yodo y la inmadurez de la glándula del prematuro. Por eso, en muchos países europeos (España incluida) el hipotiroidismo neonatal por exceso de yodo es mucho más frecuente que en Japón y en los Estados Unidos, donde la ingesta de yodo de la población es más alta.

Esta llamada de atención sobre los peligros de un exceso iatrogénico de yodo durante el embarazo y el período posnatal no debe, en manera alguna, utilizarse como justificación para dejar de instaurar medidas profilácticas que eviten la carencia de yodo durante el desarrollo fetal y posnatal. Siempre debe tenerse en cuenta la gran diferencia existente entre las cantidades mínimas necesarias y las cantidades de yodo potencialmente nocivas. Considérese que las cantidades mínimas necesarias se expresan en cientos de µg de yodo (200-300 µg en la embarazada). La cantidad de povidona yodada en 1 ml de Betadine® es de 100 mg (!!), lo que equivale a unos 100.000 µg. En cualquier aplicación de povidona yodada se emplea un volumen de desinfectante muy superior a 1 ml. Lo mismo ocurre cuando se usan contrastes yodados (tabla 3). Cualquier neonato, sobre todo si es prematuro, que inevitablemente tiene que someterse a pruebas diagnósticas o quirúrgicas que hagan imprescindible la administración de contrastes yodados, puede padecer un bloqueo de la función tiroidea como consecuencia de la intervención, y entrar en un estado de hipotiroidismo. Por eso, y por el frecuente retraso en el pleno funcionamiento de los mecanismos de retroalimentación negativa hipófisis-tiroides característicos de esa edad, se recomienda que no sólo se envíen al Centro de Detección Precoz de Hipotiroidismo Congénito las muestras de sangre tomadas a los pocos días del nacimiento, sino cada vez que se hayan administrado contrastes yodados. No debe darse el alta al paciente sin tener pruebas bioquímicas de que no padece hipotiroidismo, aunque sea adquirido y transitorio. Las cantidades de yodo de la mayoría de los contrastes yodados son incluso superiores a las mencionadas para la povidona yodada (tabla 3). A veces no se tiene conciencia de que el recién nacido está recibiendo esta sobredosis: la mera inserción de catéteres (no radioopacos) para alimentación parenteral conlleva la inyección de contraste en cantidades muy pequeñas, pero suficientes para bloquear la función tiroidea18, por lo que deben sustituirse por catéteres radioopacos. En resumen, en el caso de la mujer embarazada, el lactante y el neonato (sea éste prematuro o a término), hay que tener presente que: 1. Tienen derecho a que se le asegure el yodo necesario para el desarrollo óptimo de su cerebro. 2. Es sumamente improbable que reciba un exceso nocivo de yodo a través de la alimentación y el uso de suplementos polivitamínicos y minerales que lo contengan. 3. Puede ser el personal sanitario el primer responsable de que se vean expuestos a dosis excesivas, que provienen siempre del uso de diferentes medicamentos, desinfectantes yodados y contrastes radiológicos.

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BIBLIOGRAFÍA
1. Arena Ansotegui J, Emparanza Knörr JI. Los antisépticos yodados no son inocuos. An Esp Pediatr 2000; 53: 25-29. 2. Escobar del Rey F, Morreale de Escobar G. Yodación universal de la sal: un derecho humano de la infancia. Endocrinología 1998; 45: 4-16. 3. Morreale de Escobar G. Interrelaciones materno-fetales de las hormonas tiroideas. An Esp Pediatr 1999; 50 (Supl 125): 3643. 4. Ares S, Quero J, Duran S, Presas MJ, Herruzo R, Morreale de Escobar G. Iodine content of infant formulas and iodine intake of premature babies: high risk of iodine deficiency. Arch Dis Child (Fetal Neonatal) 1994; 71: F184-F191. 5. Ares S, Morrreale de Escobar G, Quero J. Lactancia artificial y deficiencia de yodo en el niño prematuro. An Esp Pediatr 1999; 50 (Supl 125): 47-51. 6. Delange F, Dunn JT, Glinoer D. Specific recommendation on iodine nutrition for mothers and infants in Europe. En: Delange F, Dunn JT , Glinoer D, editores. Iodine Deficiency in Europe. Nueva York: Plenum Press, 1993; 478-479. 7. De Santiago J, Pastor I, Escobar del Rey F, Morreale de Escobar G. Thyroid function in pregnant women from an area with mild (grade I) iodine deficiency [resumen 126]. J Endocrinol Inv 1999; 22 (Supl 6): 68. 8. De Santiago García J, Pastor I, Escobar del Rey F, Morreale de Escobar G. Deficiencia de yodo y función tiroidea de la embarazada. 41 Congreso Nacional de la Sociedad Española de Endocrinología y Nutrición. Málaga, 1999. 9. Katamine S, Mamiya K, Sekimoto N, Hoshino N, Totsuka K, Naruse A et al. Iodine contant of various meals currently consumed by urban Japanese. J Nutr Sci Vitaminol 1986; 32: 487492.

10. Liberman CS, Pino SC, Fang SL, Braverman LE, Emerson CH. Circulating iodide concentrations during and after pregnancy. J Clin Endocrinol Metab 1998; 83: 3545-3549. 11. WHO. Iodized oil during pregnancy. Safe use of iodized oil to prevent iodine deficiency in pregnant women: a WHO statement. Bull WHO 1996; 74: 1-3. 12. Hetzel BS. Historical development of concepts of brain-thyroid relationships. En: Stanbury JB, editor. The damaged brain of iodine deficiency. Elmsford, NY: Cognizant Communication Co., 1994; 1-8. 13. Pharoah POD, Buttfield IH, Hetzel BS. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1971; 13: 308-311. 14. Pretell EA, Cáceres A. Impairment of mental development by iodine deficiency and its correction. A retrospective view from studies in Peru. En: Stanbury JB, editor. The damaged brain of iodine deficiency. Elmsford, NY: Cognizant Communication Co., 1994; 187-192. 15. Carswell F, Kerr MM, Hutchison JH. Congenital goitre and hypothyroidism produced by maternal ingestion of iodides. Lancet 1970; 13: 1242-1247. 16. Rodesh F, Camus M, Ermans AM, Dodion J, Delange F. Adverse effects of amniofetography on fetal thyroid function. Amer J Obstet Gynecol 1976; 126: 723-726. 17. Delange F, Bourdoux P, Ermans AM. Transient disorders of thyroid function and regulation in preterm infants. En: Delange F, Fisher DA, Malvoux P, editores. Pediatric thyroidology. Basilea: S Karger AG, 1985; 14: 369-393. 18. Ares S, Pastor I, Quero J, Morreale de Escobar G. Thyroid complications, including overt hypothyroidism, related to the use of non-radiopaque silastic catheters for parenteral feeding in prematures requiring injection of small amounts of an iodinated contrast medium. Acta paediatr 1995; 84: 579-581.

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European Journal of Endocrinology (2004) 151 U25–U37

ISSN 0804-4643

Role of thyroid hormone during early brain development
´ Gabriella Morreale de Escobar, Marıa Jesus Obregon and Francisco Escobar del Rey ´ ´
´ ´ ´ Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Cientıficas (CSIC) y Universidad Autonoma de Madrid (UAM), Arturo Duperier, 4, 28029-Madrid, Spain (Correspondence should be addressed to G Morreale de Escobar; Email: gmorreale@iib.uam.es)

Abstract
The present comments are restricted to the role of maternal thyroid hormone on early brain development, and are based mostly on information presently available for the human fetal brain. It emphasizes that maternal hypothyroxinemia – defined as thyroxine (T4) concentrations that are low for the stage of pregnancy – is potentially damaging for neurodevelopment of the fetus throughout pregnancy, but especially so before midgestation, as the mother is then the only source of T4 for the developing brain. Despite a highly efficient uterine –placental ‘barrier’ to their transfer, very small amounts of T4 and triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks after conception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal fluids is not protein-bound: the ‘free’ T4 (FT4) available to fetal tissues is determined by the maternal serum T4, and reaches concentrations known to be of biological significance in adults. Despite very low T3 and ‘free’ T3 (FT3) in fetal fluids, the T3 generated locally from T4 in the cerebral cortex reaches adult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental results in the rat strongly support the conclusion that thyroid hormone is already required for normal corticogenesis very early in pregnancy. The first trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by the conceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substrate for the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unable to increase their production of T4 early in pregnancy would constitute a population at risk for neurological disabilities in their children. As mild– moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia in Western societies, the birth of many children with learning disabilities may already be preventable by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible. European Journal of Endocrinology 151 U25–U37

Introduction
The association between alterations of thyroid function early after birth and neurodevelopmental disorders has been recognized for more than a century. For many years of the 20th century there has been, however, less consensus regarding the stage during fetal life when thyroid hormone becomes necessary for normal brain development (more extensively reviewed by us in (1 –4)).This has mostly been due to opposing views regarding the importance of maternal thyroid hormones for the fetus. On the one hand, those who had personal field experience of iodine-deficiency disorders (IDDs) were convinced of its importance, because the severity of the central nervous system (CNS) damage of the progeny was related to the degree of maternal thyroxine (T4) deficiency and could only be prevented when the latter was corrected before midgestation. On the other hand, Western-trained physicians usually adhered to the idea that maternal thyroid hormones did not play a role in early neurodevelopment, an idea apparently supported by the good results obtained with prompt treatment of congenital

hypothyroidism (CH). This success was interpreted as proof that the developing fetal brain did not need thyroid hormone until after birth. The idea that the maternal thyroid hormones were of little relevance for the early fetal brain was reinforced by the increasing evidence of the existence of an efficient utero –placental ‘barrier’ that prevented the transfer of maternal thyroid hormones into the fetal compartment in amounts that could be physiologically relevant. The importance of an adequate provision of thyroid hormones for brain development during later phases of pregnancy was, however, increasingly accepted when the transfer of maternal T4 up to birth was shown in man (5) and its possible protective role in cases of CH was recognized (6). Despite the increasing awareness that thyroid hormone is already required for normal brain development during fetal life, the general consensus as late as 1999 was summarized by Utiger (7): ‘Thyroid deficiency during the latter two thirds of gestation and the first months after delivery can result in mental retardation and sometimes neurological deficits. Whether thyroid hormone is needed during the first trimester is less

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certain. If it is, it must be supplied by the mother, because none is secreted by the fetus until the middle trimester’. The same editorial drew attention to the many severe neurological defects found in children born to iodine-deficient mothers that require adequate intervention before midgestation for their prevention, and that do not occur in untreated CH infants. In the present contribution we will try to summarize what is known, and what is still unknown, regarding early fetal thyroid hormone physiology and its dependence on the production of T4 by the mother.

Findings from experimental rat models
Much of our present knowledge regarding transfer of thyroid hormones from the mother to the fetus and its possible role in fetal brain development has been prompted by previous findings in experimental animal models, especially in rats. There is an important similarity between man and rat with respect to placentation, which is hemochorial in both species. There are, however, major differences between human and rat brain development if we take birth as the point of reference, because the rat is born at a less mature stage, the newborn pup being comparable to a human fetus nearing the third trimester. Conversely, the human newborn might be compared with a 2- to 3-week-old rat pup, but with a very important difference that is often forgotten when postnatal findings in hypothyroid rat models are extrapolated to the third trimester human CH fetus. In man development of the fetal brain may still be protected by the transfer of maternal T4 during a period of development when the rat is deprived of this potential benefit, as rat milk does not contain thyroid hormone in relevant amounts. Valid comparisons may, however, be made by using the onset of active fetal thyroid function (FTF) as the milestone for comparisons. This coincides in both species with full maturation of the pituitary portal vessels, and occurs at E17.5-18 in the rat (with E0 being the day of conception and E21-22 the day of birth), and at 18 – 20 weeks of postmenstrual age (PMA) in man (at 16 –20 weeks postconception), with birth at 36 – 40 weeks PMA. Thus, most of the comparisons between both species will be restricted to development and maternal –fetal interrelations before FTF, unless stated otherwise. Findings relevant to the present topic are very briefly summarized here. For pertinent detailed references, see Table 3 in a previous review (1). References are mostly restricted to more recent studies. T4 and triiodothyronine (T3) of maternal origin are present, albeit at very low concentrations, in very early rat embryonic and fetal tissues, brain included, before onset of FTF, their concentrations being directly influenced by those in the maternal circulation, especially those of T4. Thyroid hormone receptor (TR) isoforms are already present in the brain at neural
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tube closure and are likely to mediate biological effects of the T3 that has been locally generated from T4 transferred from the mother. Therefore, if the mother is hypothyroxinemic, the brain of a hypothyroid rat fetus is T3-deficient, even if maternal and fetal T3 are normal, because during early development, serumderived T3 hardly contributes to cerebral T3 (6). Important phases of the development of the neocortex are altered by a period of maternal hypothyroxinemia preceding onset of FTF (8, 9), showing directly that thyroid hormone of maternal origin is important for neurodevelopment. If such experimental findings were relevant for man, they would explain why in most cases of CH there is no permanent severe CNS damage when T4 is supplied starting soon after birth. Most fetuses with CH have a normal mother, supplying enough T4 to the developing brain throughout gestation to preferentially avoid cerebral T3 deficiency. As a result, the fetal brain has not been severely damaged before birth, and its normal development can still be achieved by prompt postnatal treatment with T4. They would also explain the irreversible damage caused by an insufficient supply of T4 during early development, when the mother is the only source of hormone to the brain. The more severe damage would be expected to occur when both the mother and fetus are hypothyroxinemic throughout pregnancy, as occurs in iodine-deficient environments, and as increasingly confirmed by case reports (1 –4, 10).

Thyroid hormones and their nuclear receptors in the human fetal brain
As already indicated, during most of the second half of the 20th century the prevailing idea was that the early embryo actually developed in the absence of thyroid hormones. Supporting this conclusion was the evidence of a placental ‘barrier’ system that drastically limited their transfer from the mother. Recent information has confirmed the widespread distribution, mostly of deiodinases D2 and D3, in the utero –placental unit and the expression of D3 in fetal epithelia (11 –14). As in experimental animals, the existence of an active barrier, however, does not necessarily exclude that some iodothyronines of maternal origin actually do reach fetal tissues, and we shall briefly summarize the existing evidence, mostly as pertaining to the brain. Most of the experimental findings in the rat models, are being confirmed – and actually extended – in humans.

From conception to midgestation
Attempts to measure the very low concentrations of iodothyronines in fetal tissues had to await the development of adequate extraction methods that permitted their purification and determination by sensitive and specific RIAs. Most commercially available methods

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that have been developed for human sera are not adequate for the very low concentrations found up to midgestation in human fetal serum. Commercial kits for the estimation of ‘free’ T4 (FT4) are even less adequate, because of the great qualitative and quantitative differences in the composition of T4-binding proteins between fetal fluids and adult serum. During the 1980s, T4 and T3 were measured in tissue extracts from cerebral cortex, liver and lung of 8 –18 week PMA human fetuses, using improved specific and highly sensitive RIAs (15– 17). In liver, lung and heart, only T4 was found during the second trimester, although T3 could be demonstrated at somewhat earlier ages in lung nuclear extracts. T3 was quantified in purified extracts from human fetal brain, however, as early as 9 –10 weeks PMA, and increased steadily up to 18 weeks PMA, despite the fact that during this period plasma T3 was undetectable and , 10% of adult values. By midgestation the concentration of T3 in the fetal brain reached 34% of adult values, much higher than would have been inferred from their very low circulating T3. Another important methodological improvement was the development of transvaginal ultrasound-guided puncture of the embryonic cavities (Fig. 1) to obtain

samples from the fetal compartment without severing vascular connections with the mother. This procedure, combined with specific and sensitive RIAs, disclosed important new information regarding fetal thyroid hormones early in pregnancy (18). T4, T3 and reverse T3 (rT3) were found in the first trimester coelomic and amniotic fluids from 5.8 – 11 weeks PMA (3.8 – 9 weeks postconceptional age) (Fig. 2). The T4 concentrations in the coelomic fluid were positively correlated with the maternal circulating concentrations, but were , 1% of the maternal values. T3 was at least 10-fold lower than T4, with rT3 being clearly higher than T4, findings that confirmed the high D3 activities of the placental ‘barrier’ and fetal epithelia. Concentrations in the coelomic fluid were higher than in the amniotic compartment. Because of the minute amounts of the iodothyronines found in these fluids, their possible biological significance was often questioned. The results were essentially confirmed and extended in a second study (19) where transvaginal ultrasound-guided puncture of these cavities and of fetal blood was performed up to 17 weeks PMA. A specific methodology was developed for the determination of FT4. We confirmed the previous observation (18) that T4 in fetal fluids is more than 100-fold lower than in

Figure 1 Schematic representation of the maternal– fetal unit during the 1st (A) and 2nd (B) trimesters of pregnancy. (A) The human fetus is surrounded by two distinct fluid cavities separated from each other by a thin membrane: the inner, or amniotic cavity (AC) contains the fetus and the outer, or exocoelomic cavity (ECC), separates the amniotic cavity from the placenta and contains the secondary yolk sac (SYS). The latter is directly connected to the fetal digestive tract and circulation. The ECC is the site of important molecular exchanges between the mother and the fetus and contains the coelomic fluid (CF) that results from an ultrafiltrate of maternal serum with the addition of specific placental and SYS bioproducts. The ECC is a physiological liquid extension of the early placenta (P) and acts as a reservoir for nutrients needed by the developing fetus. There is no direct vascular connection between the mother and the umbilical cord of the fetus. (B) A second mode of transfer starts at the end of the 1st trimester. The SYS and two-thirds of the placental mass degenerate and the ECC is progressively obliterated by the growing AC containing the amniotic fluid (AF) surrounding the fetus. These major anatomical transformations modify considerably the spatial relationships between maternal tissue and developing fetus, and, consequently, the maternal– fetal exchange pathways. From 11–12 weeks onwards maternal nutrients, including thyroid hormone, are transferred from the placenta directly into the fetal circulation. The AF contains fetal urine and waste products. U, uterus; UC, umbilical cord; CL, chorion laeve (membranes in development).

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Figure 2 (A) Changes in concentrations of total T4 and FT4 in fetal fluids up to midgestation, as a function of maternal serum T4 values, which were within the normal range (18). (B) Concentrations of total and FT4, as a function of postmenstrual age, in fetal coelomic fluid (CF), amniotic fluid (AF), fetal blood (F-B) and maternal blood (M-B). The ordinates in both panels are on a logarithmic scale, in order to better visualize the similarity of the FT4 concentrations in fetal fluids to those in the corresponding mother, whereas there is a greater than 100-fold difference in the T4 concentrations (data from (19)). For both (A) and (B) the fetal fluids were obtained without severing maternal to fetal vascular connections.

maternal serum, with T3 being even lower. The new finding was that this great difference between the maternal and fetal concentrations of total T4 might be misleading with respect to their potential biological significance, because the proportion of T4 that is not bound to proteins is so much higher than in adult sera that the concentrations of T4 actually ‘available’ to developing tissues, namely those of FT4, reach values which are comparable to those known to be biologically active in their mothers (Fig. 2B). The FT4 levels in the fetal fluids are defined by the concentrations of T4-binding proteins and the concentrations of maternal T4 or FT4 that have escaped the placental ‘barrier’. The T4-binding capacity of the proteins in fetal fluids is determined ontogenically, is independent of the maternal thyroid status, and is far in excess of the amounts of total T4 that reach the fetal fluids. Thus, the availability of FT4 for embryonic and fetal tissues is ultimately determined by the maternal circulating T4 or FT4 and would decrease in hypothyroxinemic women, even if they are clinically euthyroid. The results explained why an efficient ‘barrier’ to maternal thyroid hormone transfer is actually necessary. If total T4 and T3 reached the same concentrations in fetal fluids as those in the maternal serum, the developing tissues would be exposed to inappropriately high, and possibly toxic, concentrations of FT4 and ‘free’ T3 (FT3). An inordinately high FT4 and/or FT3 could result in adverse effects on the timely sequence of thyroid hormone-sensitive developmental events in the human fetus, as recently confirmed (20). That thyroid hormone-sensitive developmental events may already occur before midgestation and onset of FTF is supported by the early presence of nuclear TRs in the human fetal brain. These were detected in the earliest samples of the cerebral cortex (9 weeks PMA) studied by Bernal & Pekonen (15) with their concentration increasing at least 10-fold by 18 weeks. Despite the very low fetal serum concentrations of T3, the occupation of the TRs by this iodothyronine was 25 – 30% throughout the study period (15 –17), strongly suggesting that biological effects of the hormone might already be occurring in the cerebral cortex during the first trimester of human pregnancy. A recent study (21) has confirmed the early expression of TR gene isoforms and related splice variants in the whole fetal brain studied between 8.1 and 13.9 weeks PMA. Expression of the TRb1, TRra1 and c-erbAa2 isoforms was detected in the 8.1 week brain sample, with TRa1 being the predominant form in early development, increasing steadily up to 13.9 weeks; so did the c-erbAa2 isoform. TRb1 expression appeared to present a more complex ontogenic pattern. The authors moreover point out that the repressor activity of un-liganded Tra1 on basal gene transcription may also become relevant when the maternal supply of hormone decreases: a decrease in the amount of T3 available for receptor binding

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would increase the proportion of the un-liganded isoform and its repressor activity, and further interfere with thyroid hormone-sensitive biological effects. The ontogenic patterns of the concentrations of T4, T3, rT3, and of D1, D2 and D3 activities have now been studied (22) in nine different cerebral areas from fetuses of 13 – 20 weeks PMA, when fetal serum T4 increased significantly from about 3 to 15 pmol/ml, whereas T3 did not correlate with PMA and remained at about 0.5 pmol/ml throughout the same developmental period (19). The ontogenic profiles of the concentrations of the iodothyronines in the different areas of the brain, and of their D2 and D3 activities, showed both spatial and temporal specificity, but with divergence in the cerebral cortex as compared with other brain areas (Fig. 3). In the cortex the concentration of T4 was increasing with PMA, as expected from the increase in fetal serum T4. But, in contrast with the very low and practically constant circulating levels, T3 increased significantly with PMA in the cortex between 13 and 20 weeks PMA to levels comparable to those reported in adults (2.5 pmol/g). These findings show that in the human cerebral cortex T3 is also generated locally from T4, and is hardly influenced by circulating T3. Considerable D2 activity was indeed found in the human cerebral cortex, whereas D3 activity was very low. In contrast, cerebellar D3 activities were very high until midgestation, and T3 was very low, only increasing after midgestation, when D3 activity was decreasing. Other regions with high D3 activities (midbrain, basal ganglia, brain stem, spinal cord,

hippocampus) also had low T3 concentrations up to midgestation. The study (22) supports the hypothesis that T3 is indeed required by the human cerebral cortex before midgestation, when the mother is the only source of the FT4 that is available to the fetal tissues. It confirms the important roles of D2 and D3 in the local bioavailability of cerebral T3 during fetal life; D2 generates T3 from T4 and D3 protects different brain regions from an untimely, or excessive, T3 until this hormone is required for differentiation. We do not, however, have precise information on the stage of human brain development when downregulation of D2 expression and/or activity might contribute to T3 bioavailability in conditions of maternal or fetal hypothyroxinemia; if down-regulation is delayed with respect to the onset of its expression, a decrease in maternal T4 would ultimately result in a lower intracellular concentration of T3 (4).

Between midgestation and birth
There is a dearth of information on the ontogenic patterns of thyroid hormone concentrations and iodothyronine deiodinase expression and/or activities in different fetal tissues during the second half of pregnancy. Studies performed so far have relied on autopsy material of babies who died of different causes and at variable intervals after a premature birth, and results are subject to many confounding factors other than their PMA. The most important ones are likely to be the premature interruption of the

Figure 3 Ontogenic changes in the concentrations of T4 (upper panels), and T3 (lower panels) in the human cerebral cortex (left-hand panels) and cerebellum (right-hand panels) up to midgestation when the mother is the only source of thyroid hormone for the developing fetus (data from (22)). During this period T4 in the fetal serum increases about 5-fold, from 3 to 15 pmol/ml, whereas circulating T3 remains very low, about 0.5 pmol/ml (equivalent to 0.5 pmol/g), and does not increase with PMA (19). D3 activities are very high in the cerebellum throughout this period.

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maternal supply of T4 and the sudden major decrease in circulating thyrotropin (TSH). For this reason such studies will not be included here. We will only summarize what is known regarding thyroid hormones and related indices of fetal thyroid physiology that have been obtained in utero and in vivo, restricting our knowledge to data obtained from serum samples. For many years most diagrams (23) describing ontogenic patterns of changes in fetal circulating levels of T4, T3, rT3, TSH, T4-binding globulin (TBG) etc. had been derived from premature babies, after interruption of maternal connections. Early in the 1990s, however, ultrasound-guided blood sampling from the umbilical cord and the heart was used to obtain fetal samples between 12 and 37 weeks PMA (24, 25) (Fig. 4). Some of the patterns previously described (23) for different parameters of FTF were confirmed: T3 and FT3 were very low throughout fetal life, as compared with those in both the maternal serum and in the adult population. In striking contrast, however, both T4 and FT4 increased steadily with fetal age, and reached maternal and adult concentrations by the beginning of the third trimester (25). Contrasting with previous reports of a negative feed-back between the fetal thyroid and the hypothalamic –pituitary system during the third trimester, Thorpe-Beeston et al. (25) found that FT4 and TSH were both increasing until birth. An even greater discrepancy concerned the intrauterine fetal levels of TSH that were much higher than maternal and adult values throughout the study period, a finding confirmed in our later study (19). This was in conceptual agreement with reports that in both normal and anencephalic fetuses, TSH bioactivity is greatly increased with respect to that circulating in the mothers, confirming that fetal serum TSH is neither of maternal origin, under hypothalamic neuroendocrine control, nor under negative feed-back control by thyroid hormones, whether of maternal or fetal origin (26). Fetal TSH levels are already high well before full maturation of hypothalamic – pituitary connections at midgestation. This poses unanswered questions regarding its origin; synthesis of TSH by the rat and monkey brain have been reported (27). More recently, a TSH receptor has been found in early human fetal brain and human astrocytes in primary culture (28). This receptor mediates extrathyroidal cAMP-independent biological effects of TSH, among which is, quite interestingly, the stimulation of D2 in astroglial cells. The possible cAMP-independent ‘extrathyroidal’ actions of TSH throughout human fetal development are most intriguing, especially if acting in brain development as a growth factor. Equally intriguing is why the high intrauterine TSH concentrations plummet with birth. Sudden severance from the placenta might be playing a role, as the placenta produces high amounts of thyrotropin-releasing hormone-like peptides that might be stimulating extrapituitary synthesis of TSH or TSH-like proteins.
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Figure 4 (A–C) The ontogenic changes in different parameters of thyroid hormone status from 12 weeks PMA until birth, obtained in vivo by cordocentesis, without interfering with the normal connections between mother and conceptus. The shaded areas enclose the values reported by Thorpe-Beeston et al. (25). (A and B) Show that fetal serum FT4 values reach maternal concentrations shortly after midgestation, whereas those of FT3 are low throughout pregnancy. (C) Draws attention to the very high levels of fetal TSH, most of which were higher than those of the mother. (A) Also shows the FT4 levels found in sera from premature babies (B, preterm) (30, 31) as compared with those in utero (25).

Fetal circulating T4 and FT4 are already increasing steadily in utero before the fetal thyroid is likely to be able to maintain such concentrations when deprived

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of the maternal contribution; the degree of iodination of thyroglobulin (Tg) and its T4 and T3 contents are very poor before 42 weeks PMA (29). This lack of full maturation of the fetal thyroid would contribute significantly to the neonatal hypothyroxinemia of premature infants, a possibility that is strongly supported when serum FT4 concentrations of such infants are plotted as a function of PMA and superimposed on the pattern found for age-paired living fetuses that are still in utero (Fig. 4) (30, 31). Such observations imply that the mother continues to contribute significantly to fetal circulating T4 and FT4 until birth, as described for experimental animals. That the transfer of maternal T4 to the fetus continues until the umbilical cord is severed was conclusively shown in 1989 by Vulsma et al. (5) who found concentrations of T4 in cord blood of seven neonates with complete organification defect, namely, a complete inability to iodinate proteins and, therefore, to synthesize the iodinated hormones. These concentrations varied between 35 and 70 nmol/l, values that are about 30 –60% of the mean concentrations reached by the normal fetus at term, 109 nmol/l (25). In hypothyroid rat fetuses, serum T4 concentrations ranging between 30 and 60% of normal, together with the compensatory increase of D2 activity in the brain, would be enough to preferentially avoid cerebral T3 deficiency (6). Extrapolation of the latter findings to the human CH fetus suggests that after midgestation the down-regulation of cerebral D2 is also operative in the human brain, and has contributed to protect it from major CNS damage until birth.

occur with maternal circulating levels that are still within the normal reference range for adults (Fig. 2). Although valuable new insights have been obtained regarding the ontogenic patterns of change of cerebral thyroid hormone concentrations, their nuclear receptors, and the roles of the deiodinating isoenzymes in tailoring the bioavailability of T3 to the developmental requirements of different cerebral structures, it is likely that we are still quite far from understanding all the mechanisms that may be involved, and their interrelationships. As summarized recently in somewhat more detail (4), little is known regarding the roles, in determining the availability of circulating T4 to the fetal brain, of the activities of the deiodinating enzyme isoforms in other fetal tissues, as well as those of the sulfotransferases, glucuronidases and sulfatases, and of recently identified specific iodothyronine plasma membrane transporters into, and out of, the fetal brain. We have already remarked (4) upon our ignorance with respect to a possible developmental role of the high levels of TSH throughout gestation, as well as the cause for their rapid decrease after premature birth. We still have insufficient information regarding the capacity of the fetal thyroid to meet the needs of the newborn preterm infant faced with the untimely interruption of the maternal supply of hormone. Mainly for this reason, effective procedures that might improve their neurodevelopment have not yet been fully established (32).

Direct evidence of a role of maternal T4 in neurogenesis
Present findings regarding regulatory mechanisms involved in the bioavailability of T3 in the human fetal cortex early in development, as well as the early expression of nuclear TRs, already occupied by T3, strongly support the hypothesis that an adequate supply of maternal T4 is already needed by the cerebral cortex early in pregnancy. In man, such an hypothesis cannot be directly verified, or negated, for obvious ethical constraints. In the rat, changes in maternal thyroid hormone availability during early stages of development – equivalent to the end of the first, and beginning of the second, trimester in man – affect neurogenesis irreversibly. Two models have been studied so far. One involved iodine-deficient rat dams (8). The other involved rat dams treated for only 3 days with a goitrogen (methyl-mercapto-imidazole (MMI)), a protocol that resulted in a transient and very mild degree of maternal thyroid hormone deficiency (3dMMI model) (9). In both models the dams were hypothyroxinemic between E14 and E16, a period of very active neurogenesis and of migrations of radial neurons into the developing cerebral cortex and hippocampus, the mother being the only source of thyroid hormone available to the developing fetus. The final location of
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Summarizing
Results so far confirm for the human developing brain the same principles that appear to modulate T3 bioavailability in different developing structures in many species, in a temporally and spatially specific sequence of events, namely by the ontogenetically programmed expression of the iodothyronine deiodinase isoenzymes, mainly D2 and D3. We have less information regarding mechanisms other than those involving the iodothyronine deiodinase isoforms that might also play important roles in tailoring T3 bioavailability to changing needs of developing human brain structures. Thus, both T4 and T3 are present in human embryonic and fetal fluids, with the FT4 reaching concentrations that are known to be biologically relevant in adults. The FT4 concentrations in these fluids are, moreover, directly dependent on the maternal T4 supply, and so is the FT4 available to fetal tissues, including the brain. It appears plausible to conclude that the lower the maternal T4 early in pregnancy, the lower the FT4 available to the fetal cortex and, presumably, the lower the amounts of T3 available for binding to cerebral TRs exerting biological effects. It is important to realize that this could already

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the cells generated during this period was aberrant, with neurons appearing in layers of the somatosensory cortex and hippocampus where they are never found in pups from normal dams. The cytoarchitectures of the barrel cortex and hippocampus were also affected. The short transient period of moderate maternal thyroid hormone deficiency between E12 and E15 (3dMMI model) (9) was sufficient to derange successive radial waves of neuronal migrations and to result in cytoarchitectural abnormalities that could only be prevented by the timely infusion of T4. This was of no benefit when delayed beyond the critical period of corticogenesis. An increased susceptibility to acoustic stimulation was also observed in a high proportion of the pups born to 3dMMI dams. Such findings clearly support the importance of an adequate early supply of maternal thyroid hormone for neurodevelopment. Extrapolation to man would define the period in human gestation when the fetal cerebral cortex is especially sensitive to changes in the availability of maternal thyroid hormone within the first half of pregnancy. In man, the two main waves of radial migrations of neurons into the cortex peak at 11 and 14 weeks PMA. The first one coincides approximately with the human chorionic gonadotropin (hCG)-driven maternal FT4 surge.

TSH is suppressed. Plotting mean maternal serum hCG levels as a function of gestational age shows peak concentrations at the end of the first trimester, with TSH levels falling in a mirror image (Fig. 5).

Thyroid function of the mother
It has been known for decades that important changes occur in thyroid hormone physiology during normal pregnancy. When it was initially observed that maternal circulating T4 was higher than in non-pregnant women, it was believed that this was a direct consequence of the estrogen-stimulated increase of circulating TBG and of TBG moieties that are more highly sialylated and have longer biological half-lives. The increase in circulating T4 was deemed necessary in order to keep circulating FT4 within the normal range, but the expected transient decrease in FT4, followed by a rise in TSH, necessary to attain the new equilibrium was not detected.

The transient initial surge of maternal circulating FT4
We now know that the increases in T4 and TBG do not occur simultaneously, and FT4 is actually significantly increased for several weeks before TBG concentrations plateau at midgestation (33). The increased concentrations of hCG in the maternal and fetal compartments are essential for the maintenance of the pregnancy and are imposed by the presence of the conceptus. During this period the woman’s thyroid is under the control of the high concentrations of hCG and hCG-related molecules that have TSH-like activity. During early pregnancy, when these are highest, secretion of both T4 and T3 is stimulated to the point that maternal circulating
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Figure 5 (A) shows that during the first trimester there is an increase in circulating hCG (A, upper panel) that results in a first trimester surge of maternal FT4 and FT3 (A, lower panel), and a suppression of circulating TSH (A, upper panel). These results support the present hypothesis that the surge in maternal FT4 before midgestation is controlled by the conceptus, and may have a biologically relevant role, and that an inadequate surge might not be detected using as the indicator an increase of serum TSH above the normal population range. Drawn using mean values reported by Glinoer (33). (B) An example of the effects of the iodine intake on the first trimester FT4 surge and on FT4 values throughout pregnancy, based on data from a study (46) of pregnant women with a median urinary iodine of 90–95 mg I/l throughout gestation, and of those in the same area advised to take potassium iodide (KI) supplements (approximately 250 mg I/day) from early pregnancy, and a mean urinary iodine excretion double that of the non-supplemented women. First trimester median FT4 values for non-supplemented and supplemented women were, respectively, 16.9 and 19.9 pmol/l.

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This phenomenon has even been observed in a case of thyroid hormone resistance (34); the already high serum T4 and T3 increased further at the onset of pregnancy and reached peak values when circulating hCG was highest, at 10 –12 weeks of gestation, with a mirror image in serum TSH that was temporarily suppressed. This initial adaptation of maternal thyroid physiology to the presence of the fetus may well be one more example of the control exerted by the conceptus on the maternal endocrine system. One possible interpretation is that it is essential for the conceptus to ensure, for its own benefit, high maternal FT4 concentrations that are relevant for early neurodevelopment. To achieve this, it would be necessary to transiently override the control of thyroid function through the negative hypothalamic –pituitary– thyroid feed-back mechanism. Increased production of T4 by the maternal thyroid Maternal thyroid hormone production during the first half of human pregnancy obviously has to increase very soon after its onset, in order to ensure the early surge in circulating FT4, considering, among other factors, that the plasma volume increases rapidly. There is also an increased degradation of the iodothyronines by the very high activity of D3 in the uterine –placental unit, possibly also a consequence of the increased estrogen levels (12). The increase in the size of the maternal T4 pool early in pregnancy has not yet been defined precisely, and may differ in different pregnancies of the same woman. Available information suggests that it imposes a considerable burden on the maternal thyroid. It has been known for years that hypothyroid women very often have to increase their T4 dose during pregnancy (35) to ‘normalize their TSH’, the standard goal of treatment for non-pregnant patients. A very recent study (36) has drawn attention to the need for increasing the levothyroxine dose already by the fifth week of gestation by about 50%, in order to keep TSH within the normal range. This early and significant increase of the T4 dose, however, failed to reproduce the first trimester FT4 peak and TSH nadir found in normal pregnant women. An even greater increase in the dose might have been required if the aim had been attainment of the physiological trimester-specific FT4 and TSH values (37). This possibility is in conceptual agreement with the marked increase in iodine requirements (38, 39), which almost double from the onset of pregnancy, and is not entirely explained by the increased renal iodide clearance.

functionally impaired, and (ii) that the supply of iodine for the synthesis of sufficient T4 is almost double. It is becoming increasingly evident that the frequency with which women from Western industrialized countries might not be able to respond adequately to the greatly increased demands of T4 placed by the presence of the conceptus, is a 100-fold greater, or more, than that of CH babies, whose detection and early treatment by mass screening programs have proved so successful. Impaired thyroid function In a recent summary by Glinoer & Smallridge (39) on ‘The impact of Maternal Thyroid Disease on the Developing Fetus: Implications for Diagnosis, Treatment and Screening’, four different conditions were discussed from a practical point of view: (i) clinical hypothyroidism, with low serum FT4 and high serum TSH; (ii) subclinical hypothyroidism, with normal FT4 and high TSH; (iii) thyroid autoimmunity features, with normal FT4, normal TSH with thyroid antibodies; and hypothyroxinemia with low FT4 and normal TSH, and (iv) hypothyroxinemia with low FT4 and normal TSH, and clinical euthyroidism. From North-American and Western European evaluations, up to 0.5% of pregnant women (1 in 200) may have overt hypothyroidism and up to 2.5% of them (1 in 40) subclinical hypothyroidism, undetected before pregnancy. With respect to the third condition, between 6 and 12% of women of child-bearing age (1 in 16 to 1 in 8) may have thyroid antibodies, with strictly normal FT4 and TSH. Most of these reports relied on an upper limit for ‘normal’ TSH of approximately 5 mU/l. The number of women diagnosed as clinically or subclinically hypothyroid would probably increase further if the newer upper limit of 2.5 mU TSH/l were used, and even more if first trimesterspecific ranges of serum FT4 and TSH values were available (37). Our present drawback is that we still lack reliable basic information regarding appropriate trimester-specific reference ranges for FT4, T4 and TSH obtained with samples from normal pregnancies in euthyroid women with a confirmed appropriate iodine intake (250 mg I/day) and without autoimmune disease (2, 35, 37). Maternal hypothyroxinemia Of the four conditions indicated above, maternal hypothyroxinemia is the most frequent, even in industrialized Western societies. In The Netherlands, a population considered as iodinesufficient, neurodevelopmental deficits have been reported (40) in one out of every two offspring from women with first trimester FT4 below the 10th percentile (1 in 20 births). The etiology of the maternal hypothyroxinemia reported in these studies has not been clarified. The maternal hypothyroxinemia that is caused by an iodine intake that fails to meet the increased needs imposed by the conceptus, is likely to be much more frequent than primary thyroid failure and thyroid autoimmunity. It has been amply documented that iodine
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Conditions required for the maternal thyroid to meet the demands imposed by the conceptus
There are two principal requisites for the maternal thyroid to be able to meet the burden imposed by the conceptus, namely (i) that thyroid tissue is not

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deficiency is, worldwide, the most frequent cause of reproductive failure, decreased mental and motor functions, and cerebral palsy (41 –43). Neurodevelopmental deficits not only occur in areas of severe iodine deficiency, more recent findings show that even mild degrees of iodine deficiency are potentially adverse for the outcome of pregnancy (38, 42, 44). A very recent 10-year follow up (45) of the progeny of women with mild iodine deficiency has shown an unusually high proportion (70%) of children with attention deficit hyperactivity disorders among those born to mothers who had been hypothyroxinemic during the first half of pregnancy. This, superimposed on the decrease, albeit moderate, of their intelligence quotients, constitutes an important handicap in our increasingly competitive societies. A recently published study (4) reveals that as many as 25% of pregnant women in the United States have iodine intakes that are less than half those recommended during pregnancy. Higher frequencies of this pregnancy-related iodine insufficiency are being reported from Western European populations where schoolchildren and non-pregnant women have an adequate iodine intake (3, 10, 39, 46, 47).

Remarks regarding maternal hypothyroxinemia caused by iodine deficiency
Why is this condition, potentially the most frequent preventable cause of learning disabilities in our industrialized societies, receiving so little attention in medical practice? We should like to point out a few of the possible reasons.

secretion of thyroid hormones is switched towards a preferential use of the decreasing iodine supply in favor of T3 over T4 (50, 52). As a consequence, circulating T4 decreases, but T3 does not, and may actually increase, preventing both an increase in serum TSH and clinical manifestations of hypothyroidism (53 – 55). Indeed, increased serum TSH is rarely found in goitrous individuals from areas with iodine deficiency alone, with increased Tg concentrations being a much more frequent finding in mild to moderate iodine deficiency. In the seminal studies by Glinoer and colleagues (10, 33, 56) on thyroid function in pregnant women from a population with moderate iodine deficiency, increased TSH levels were not found, even among the women with the lowest first trimester FT4 levels, whereas increased T3/T4 molar ratios and serum Tg, were already observed from the onset. Serum TSH tended to increase by the third trimester, but mostly remained within the normal range. The generalized, but inaccurate idea that iodine deficiency not only lowers T4 production, but results necessarily in increased circulating TSH is mostly derived from studies in iodine-deficient areas where additional factors (i.e. goitrogens, selenium deficiency, etc.) result in loss of functional thyroid tissue, and even in glandular atrophy (57, 58), curtailing adaptation through autoregulatory mechanisms.

Maintenance of euthyroidism
Iodine deficiency is also inaccurately associated with clinical manifestations of hypothyroidism; individuals are frequently referred to as hypothyroid, even in recent reviews (i.e. see (59) and keywords in (33)). This statement is correct in individuals from the same iodine-deficiency goiter endemias with myxoedema indicated above where TSH is increased. This widespread assumption has been inadvertently compounded by the inclusion of ‘hypothyroidism’ in the long list of IDDs that summarized findings from areas with endemic goiter (60). No distinction was made between IDDs reported from areas of iodine deficiency alone from those reported from areas where additional factors result in loss of functional thyroid tissue. Individuals from areas where the autoregulatory mechanism permit their adaptation to the inadequate iodine supply, are clinically euthyroid, even in situations of severe iodine deficiency (53) because of their normal, or increased, circulating T3. To further complicate the issue, tissues (such as the brain) that depend mostly on T4 for their availability of T3 may, however, be T3-deficient and selectively hypothyroid (60) without clinical manifestation of hypothyroidism of the individual as a whole. They are often described as ‘dull’, with whole populations appearing to ‘wake up’ when the iodine deficiency – and the hypothyroxinemia – are corrected (61).

Unchanged serum TSH
Regulation of thyroid function through the hypothalamic –pituitary– thyroid negative feed-back is so ingrained in our thinking, that a low T4 is automatically associated with a high TSH. Thus, the definition of hypothyroxinemia itself – a decreased T4 without an increase of TSH above normal – is instinctively rejected. Very efficient mechanisms controlling thyroid function – other than the negative feed-back – are overlooked by, or are even unknown to, most physicians. More than half a century ago it was shown that the immediate response of the gland to decreased circulating iodide triggers very efficient autoregulatory mechanisms that result, among others, in an increase in thyroid vascularity, iodine uptake, acinar cell height, hyperplasia and serum T3/T4 ratios. All these changes are independent from TSH, and occur even when hypophysectomized rats, or hypophysectomized animals on TSH substitution, are fed a diet low in iodine (48 –50). Their autonomy from TSH in man has recently been confirmed (51). Among the many changes that occur, one directly related to the present topic regarding maternal hypothyroxinemia is that the synthesis and
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Maternal vs fetal adaptation to iodine deficiency
The fetus constitutes an exception with respect to our previous comments regarding the unchanged serum TSH and the clinical euthyroidism of inhabitants of areas with iodine deficiency alone, because autoregulatory mechanisms are not yet fully operative until after birth (62); there would be no preferential secretion of T3 preventing an increase in serum TSH and hypothyroidism. This is in conceptual agreement with the observation that the proportion of newborns at screening with whole blood TSH above 5 mU/l is increased above 3% in populations with iodine deficiency (51). For the same reason, they would not be protected from hypothyroidism. Statements pertaining to the thyroid status of the mother should be dissociated from those regarding the fetus, as they are not necessarily the same.

Final comments
Presently available information that has been summarized here supports the hypothesis that an inappropriate first trimester surge in maternal FT4, whatever the circulating TSH, would interfere with the development of the cerebral cortex, even if maternal euthyroidism is maintained by normal circulating T3 (Fig. 6). There is at present increasing consensus that maternal hypothyroidism, both clinical and subclinical, requires early detection and prompt treatment, because of its important negative effects for the woman, the pregnancy and the child (i.e. see (1, 2, 4, 10, 35, 39, 59)). Their early detection, and that of women with thyroid autoimmunity, by mass screening programs poses considerable logistic problems in large countries such as the United States, but ought to be implemented in European countries already providing special health care for pregnant women, without further controlled prospective trials regarding the efficacy of treatment, which might no longer be ethically acceptable. With respect to mass screening for maternal hypothyroxinemia, the most frequent cause of preventable neurodevelopmental handicaps, there are still uncertainties regarding the cut-off points of laboratory data for its definition. This is the bad news. But the good news is that most cases of maternal hypothyroxinemia are related to a relative iodine deficiency during pregnancy that can be so easily prevented, with minimal expense, without risk (63) and with worldwide success (38, 41). It follows that we can already prevent a very frequent cause of learning disabilities of new generations by promoting: (i) the use of iodized salt throughout life, possibly by universal salt iodization (41); and (ii) the use of iodine supplements, both as vitamin – mineral mixtures that contain potassium iodide, or as potassium iodide tablets, where available, from the onset of pregnancy – or earlier if pregnancy is planned – just as folate supplements are

Figure 6 Possible timing in man of cerebral developmental events that are sensitive to maternal thyroid hormones in the rat (9) (lower panel), with respect to timing of first trimester events in maternal thyroid physiology controlled by the conceptus, such as the surge in maternal FT4 (middle panel), despite the suppression of circulating TSH (upper panel).

extensively promoted, whether or not folate deficiency is confirmed. In the early 1920s, David Marine, a precursor of present programs for the worldwide elimination of IDDs expressed his views that ‘simple goiter is the easiest to prevent of all known diseases. It can be excluded from the list of human diseases as soon as society decides to undertake the necessary effort’
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(quoted by Langer (64)). The same may still be said, more than 80 years later, about most cases of learning handicaps related to maternal hypothyroxinemia.

Acknowledgements
Written with the support of grant from Instituto de Salud Carlos III, RCMN (03/08) and from Instituto de Salud Carlos III PI031417 (03/1417), from Spain to G M E.

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Received 24 August 2004 Accepted 23 September 2004

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Santiago Fernández P, et al - DÉFICIT DE YODO Y COCIENTE INTELECTUAL

ORIGINAL

Déficit de yodo y cociente intelectual
Piedad Santiago Fernández P 1, Ureña Fernández T 2, Torres Barahona R 3, Muela Martínez JA 4, Lobón Hernández JA 5, Soriguer Escofet F 6.
Especialista en endocrinología y nutrición. FEA del complejo hospitalario de Jaén; 2 Especialista en medicina familiar y comunitaria. Distrito Sanitario Jaén; 3 Licenciada en psicología experimental de la Universidad de Jaén; 4 Profesor titular en el Departamento de Psicología Experimental en la Universidad de Jaén; 5 Profesor titular en el Departamento de Medicina de la Universidad de Granada; 6 Especialista en endocrinología y nutrición. Jefe del Servicio de endocrinología en el Hospital Carlos Haya de Málaga.
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DÉFICIT DE YODO Y COCIENTE INTELECTUAL

CORRELATION BETWEEN IODINE DEFICIT AND INTELLIGENCE QUOTIENT

Objetivo: comprobar la relación que pueda existir entre el grado de yoduria y el nivel de inteligencia general en población infantil. Diseño: Estudio descriptivo. Emplazamiento: se han elegido 14 pueblos (de la provincia de Jaén) mediante una tabla de números aleatorios, todos con menos de 5000 habitantes. Población y muestra: Se ha estudiado a 1209 escolares de 1.º y 5.º de primaria y de 2.º de ESO.
Intervenciones: Yoduria y el test de Cattell en sus diferentes niveles (nivel 1 para los niños de 1.º de primaria y nivel 2 para 5.º de primaria y 2.º de E.S.O.), obteniéndose para cada niño su cociente intelectual (CI).

Goal: To determine the possible correlation between iodine excretion levels and children’s overall intelligence quotients. Design: Descriptive study. Setting: 14 towns located in the province of Jaen, all with a population of under 5,000, were selected by using a randomly numbered chartA Population and sample: 1,209 school-aged children enrolled in first grade, fifth grade, and second year of high school were studied. Interventions: Concentration of iodine in urine was determined and different levels of the Cattell test were administered (level 1 for children in the first grade and level 2 for children in both fifth grade and their second year of high school) to obtain each child’s intellectual quotient (IQ). Results: Results showed statistically significant differences in the concentration of iodine in urine between the high IQ and the low IQ groups. The group with a low IQ also excreted a lower concentration of iodine than the group with a high IQ. No statistically significant differences were found in iodine concentration when comparing it with gender, or the grade the children were in, although there did appear to be statistically significant concentration of iodine in children’s urine in one of the province’s eastern counties, where the towns of Santo Tomé and Huesa are located. Children in that county were also found to have an above average IQ when compared to the rest of the children included in the study, although the differences were not statistically significant. Conclusions: This study again confirms the results of earlier studies showing that low levels of iodine excretion in an area where endemic goiter is low to moderate correlate to lower general intelligence levels in childhood (an hypothesis that would explain the data that points to a higher than average IQ in counties with higher levels of iodine excretion in urine. In addition, this study suggests the possibility that those who would most benefit from the protective effects of iodine on intelligence levels are pre-adolescent girls living in areas with a good concentration of this element. Key words: Iodine deficit; endemic goiter; psychological and motor development test; intelligence test.

Resultados: Los resultados muestran diferencias estadísticamente significativas en el grado de yoduria entre los grupos de alto y bajo CI. De tal forma que el grupo de bajo CI tiene un menor grado de yoduria que el grupo de alto CI. No se encuentran diferencias estadísticamente significativas en el CI en función del sexo, del curso o del municipio. Tampoco hay diferencias en yoduria por el sexo o el curso escolar de los niños, aunque sí aparece, de forma estadísticamente significativa, la comarca integrada por los pueblos de Sto. Tomé y Huesa (al este de la capital) como la zona de mayor concentración de yodo en la orina de los niños. Por otra parte, los niños de esta comarca muestran un CI superior a la media de todos los niños del estudio, aunque estas diferencias no son estadísticamente significativas. Conclusiones: Una vez más, y de acuerdo con estudios anteriores, se confirma que el bajo grado de yoduria en una zona de endemia bociosa leve/ moderada, se relaciona con una menor inteligencia general en la niñez (hipótesis que explicaría los datos que muestran un CI superior a la media en comarcas con mayor grado de yoduria). Además, este trabajo apunta la posibilidad de que los individuos que más se benefician, en el ámbito intelectual, de los efectos protectores del yodo son las niñas preadolescentes que viven en zonas con un buen nivel de este elemento. Palabras clave: Déficit de yodo; endemia bociosa; desarrollo psicomotor; test de inteligencia.

Correspondencia: Piedad Santiago Fernández. C/ Fuente de la Salud, 5, P-2, 5º E. 23006 Jaén. Telf: 953 25 23 50 / 629 94 76 78. E-mail: teuf@supercable.es; santiago@auna.com Recibido el 08-03-04; aceptado para publicación el 01-10-2004. Medicina de Familia (And) 2004; 5; 129-135

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Introducción

Material y métodos
El estudio se ha realizado en los colegios públicos de 14 municipios menores de 5000 habitantes de la provincia de Jaén, previa cita de los investigadores con los profesores y los padres de los escolares. El muestreo se ha realizado multietápico para garantizar la representatividad, teniendo como unidades de muestreo, en orden decreciente, la comarca (n = 5), el pueblo (n = 14), el colegio (n = 14) y los niños (n = 1209).

El déficit de yodo (DI) es un problema de salud pública que afecta a más de 1,800 millones de personas en todo el mundo y es el causante de problemas que pueden ser evitados si se realiza una yodoprofilaxis adecuada 1-3. De todos los trastornos asociados al DI, los más llamativos son los que provocan alteraciones neurointelectuales que van desde sus formas más graves, como son el cretinismo neurológico o mixedematoso, a formas más leves de deterioro intelectual 4, 5. El cretinismo, ya erradicado en los países desarrollados, gracias a la realización de cribado neonatal mediante la determinación de TSH en sangre de cordón o en sangre de talón, ha sido una realidad presente en nuestra sociedad hasta hace poco más de 20 años 6-9. No obstante, alteraciones más leves de retraso mental, persisten en sociedades sometidas a una deficiencia de yodo permanente, como son: bajo rendimiento en las habilidades visual-motoras, en destreza motora, habilidades perceptuales y neuromotoras y bajo cociente intelectual (CI). En España, son clásicos los estudios realizados en Las Hurdes (Cáceres) por la Dra. Morreale y su grupo 10. En esta comarca, ejemplo de endemia bociosa grave en nuestro país, se detectaban alteraciones en los test psicométricos utilizados con una puntuación media por debajo de una desviación estándar que la puntuación obtenida en escolares de una zona control. Sin embargo, son escasos los estudios realizados en zonas de endemia bociosa moderada o leve. Además, los trabajos realizados con relación al efecto beneficioso sobre la capacidad intelectual de la administración de yodo, no son concordantes: mientras que algunos encuentran un efecto beneficioso en la suplementación con yodo de niños entre 6-8 años 11, otros no consiguen encontrarla en niños entre 5-12 años 1, 12. Diferencias en el tipo de test psicométrico utilizado, en la severidad de la deficiencia en la zona estudiada, en el diseño del estudio, en la inclusión o no de un grupo control, así como de la dificultad de excluir otros factores nutricionales o educacionales asociados al riesgo de sufrir IDD, podrían explicar estas discordancias 1, 3, 10, 13. Por otro lado, las recomendaciones internacionales sobre ingesta de yodo estiman una ingesta mínima de 150 µg/d de yodo para cubrir las necesidades y esto se traduciría en una excreción urinaria de yodo de más de 100 µg/l 14. El objetivo de este estudio es investigar si la ingesta de yodo de la población rural escolar de Jaén se adecua a las recomendaciones internacionales y evaluar la asociación poblacional de la ingesta de yodo, medida por la yoduria, con la maduración intelectual (medida por determinados test psicológicos).

Variables: 1. Encuesta dietética : ha sido validada en otros estudios (15), y se trata de una encuesta de frecuencia en el consumo de diferentes tipos de alimentos. 2. Test psicométrico para la medida del CI. En esta investigación se ha utilizado el test del Factor G de Cattell 16, 17. Todas las evaluaciones psicométricas han sido realizadas por el mismo evaluador. El test de Catell es un test colectivo habiendo sido aplicada la Escala 1, indicada para niños de 4 a 8 años, en primero de primaria 16 y la Escala 2, indicada para niños de 9 a 14 años, en quinto de primaria y segundo de ESO 17. La validación de estos tests ha sido realizada para la población escolar española 18-20. 3. Yoduria: La medida del yodo urinario se ha realizado mediante la técnica de Benotti 21. Para ello se ha tomado una muestra de orina, la cual es congelada a –20º C hasta la posterior medición del yodo urinario. 4. Estudio estadístico: Los datos se presentan como porcentaje, media y desviación estándar. El contraste de hipótesis de las variables continuas se ha hecho mediante el test t de Student, en el caso de sólo dos comparaciones, o ANOVA de una o varias vías, en el caso de comparaciones múltiples. En este caso la significación entre las medias muestrales comparadas se ha hecho mediante el test de Duncan. En el caso de variables cualitativas, la asociación se ha estudiado mediante el test χ2. La fuerza de la asociación entre variables se ha medido mediante el cálculo de los odds ratio (OR) obtenidos a partir de modelos de regresión logística multivariantes. Los intervalos de confianza del 95 % se han calculado siguiendo a Miettinen 22. Para la inclusión de las variables en los modelos de regresión se han seguido las recomendaciones de Kleimbaun 23. En todos los casos el nivel de rechazo de la hipótesis nula se ha hecho para α = 0,05.

Resultados

1. Descripción general de la muestra Se han estudiado un total de 332 escolares de primero primaria, 408 de quinto de primaria y 444 de segundo de ESO. La edad media fue de 10’84 años oscilando entre un mínimo de 5’83 y un máximo de16’92 años. El 51.6% son varones y el 48.4% mujeres. 2. Yoduria La mediana de yoduria en el total de la muestra fue de 90 µg/l, pero una vez que se eliminan del estudio estadístico a los escolares que han sido tratados con desinfectantes yodados, es de 70 µg/l. Hay diferencias significativas en la distribución de la yoduria en función de las comarcas variando entre una media de 86’86 µg/l en Norte y condado y un máximo de 137 µg/l en Cazorla y Segura (p < 001). Así mismo la yoduria fue estadísticamente superior en los escolares que referían consumir sal yodada frente a los que consumían sal común ó marina (118’7 µg/l, 99’76 µg/l y

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Santiago Fernández P, et al - DÉFICIT DE YODO Y COCIENTE INTELECTUAL

94’18 µg/l respectivamente; p < 0,01); también es estadísticamente superior en los escolares que consumen leche con más frecuencia que en los que no (118’68 µg/l en los que la consumen más de 2 veces al día frente a 87 µg/l en los que la toman 1 ó menos veces al día; p < 0,001) 3. Tests de inteligencia El CI medio ha sido de 97’2 ± 17’1. Hay un 7.3% de escolares que tiene un CI < 70, límirte establecido por el DSM IV-TR como de retraso mental 24. La distribución por percentiles del CI puede verse en la Tabla 1. El CI no ha sido significativamente distinto en función del sexo, el nivel escolar o la presencia de bocio. Por el contrario el CI ha sido significativamente menor en los niños que tuvieron yodurias < 100 µg/L (p = 0,01) (Tabla 2). Estas diferencias de CI en función de los niveles de yoduria se mantienen en un modelo de ANOVA (p = 0,02) después de introducir en el modelo, junto a los niveles de yoduria, el sexo, el curso escolar y la presencia de bocio. El CI se ha correlacionado positivamente con la yoduria (r = 0,12; b = 0,026; p = 0,005). El riesgo de tener un CI por debajo del percentil 25 se asoció significativamente con una yoduria menor de 100 µg/L (OR = 1,40; IC 95%: 1,04-1,86; p = 0,02). La introducción en el modelo de otras variables, como el nivel de escolarización, presencia de bocio o sexo, no modificó la fuerza de la asociación entre los niveles de yoduria con el CI. (Tabla 3) Así mismo el CI se relacionó con la ingesta de sal yodada y con la frecuencia en el consumo de lácteos, pues los escolares que tomaban sal yodada y lácteos más frecuentemente, tenían un CI significativamente superior a los que consumían sal común ó marina ó tomaban lácteos con menos frecuencia (100’63 ± 15’44; p = 0,001 para los que consumen sal yodada; 98’01 ± 15’96; p = 0,0008 para los que toman leche con más frecuencia). El riesgo de tener un CI por debajo del P-25 de la distribución se asoció significativamente con la ingesta de sal común (OR = 1,70; IC 95%: 1,10-2,61; p = 0,01) (frente a la sal yodada) y con la ingesta de leche menos de 1 vez al día (frente a tres veces al día) (OR = 1,54; IC 95 %: 1,04-2,27; p = 0,03). La inclusión en el modelo del sexo y de la edad no ha modificado la fuerza de esta asociación (Tabla 4).
Discusión

de los niños 2, 25. En el presente trabajo se confirma esta asociación en una muestra representativa de una población escolar, étnica y socialmente homogénea, de un país desarrollado del sur de Europa, sin problemas nutricionales asociados. La asociación encontrada entre CI y yoduria, por un lado, y entre CI e ingesta de sal yodada y lácteos, por otro, apoya la naturaleza nutricional de esta asociación, así como la probable persistencia en el tiempo de la deficiente ingesta de yodo. En la presente investigación, el 7’3% de la muestra tiene un CI inferior a 70. El porcentaje medio esperado estaría en torno al 1% 24. El incremento en el número de niños con CI inferior a 70 en esta muestra no tiene por qué tener un valor diagnóstico en sí mismo. La prevalencia del 1% es el promedio de un abanico de porcentajes muy amplio encontrado en diferentes estudios cuyas tasas de prevalencia son muy diferentes y se deben a muchas causas. Por otra parte, un sesgo propio de las pruebas colectivas administradas en un aula escolar por una persona extraña a la situación docente habitual para el niño es la falta de implicación en la realización del test por parte de los alumnos. Un motivo que hace pensar en la correcta realización de los tests por parte de la gran mayoría de los sujetos es que coinciden los porcentajes de prevalencia de los distintos tipos de retraso mental con los establecidos en el DSM-IV (APA, 1995): el 83% de los niños con CI inferior a 70 podría clasificarse como Retraso Mental Leve (un CI entre 50 y 70), el 14% como Retraso Mental Moderado (un CI entre 35 y 50) y el resto, un 3%, como Retraso Mental Grave. También se han analizado las diferencias del nivel de yoduria tomando como punto de corte el percentil 25 del CI (seleccionado sólo con criterios estadísticos) y se siguen hallando los mismos resultados (aunque con mayor potencia) que cuando el punto de corte en el CI es menor o igual a 70. Los resultados muestran una asociación directa entre yoduria y CI, tomando como criterios de división entre alta y baja yoduria el valor de 100 mg/L 5 y el CI de 70 (APA, 1995) para dividir la muestra entre retraso mental (un CI inferior a ese valor) y normalidad (un CI igual o superior a 70). En este trabajo de investigación se ha encontrado que el riesgo de tener un CI < P-25, e incluso el riesgo de tener un CI ≤ 70 (CI clínicamente relevante) 24, ha sido mayor en aquellos niños con yodurias < 100 µg/L. También se ha encontrado la existencia un gradiente biológico entre el CI y los niveles de yoduria, gradiente que pone en duda que el punto de corte de 100 µg/L sea satisfactorio para evitar los TDY relacionados con la maduración psicomotora, como ya ha sido demostrado para el dintel auditivo 25.

Si bien no hay muchos estudios que contemplen los aspectos psíquicos en las áreas con déficit de yodo, se ha demostrado que en poblaciones con deficiencia de yodo existe una disminución de las capacidades psicomotoras

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El hecho de medir la inteligencia a través del factor G no es novedoso en este tipo de trabajos 26, 27; Ni tampoco el encontrar deterioro intelectual en áreas asociadas a déficit en yodo 26-30. La relación del déficit de yodo con la disminución en el nivel de inteligencia es hoy un hecho aceptado 28, 30 pese a existir estudios que no encuentren dicha relación 31. Quizás sea más llamativo el hecho de no haber partido, en este trabajo, de una zona yododeficiente para realizar el estudio. Normalmente, todos los estudios anteriores comparan el nivel intelectual de los habitantes de una zona yododeficiente con el mostrado por los que viven en otra zona no yododeficiente. En general, esas zonas suelen diferenciarse no sólo en el grado de déficit de yodo, sino que la zona más deficitaria en yodo suele ser también la más deprimida económica y socioculturalmente, mientras que la zona no deficiente en yodo suele ser más desarrollada y coincide mejor con las poblaciones muestrales que se utilizan en la baremación normativa de los tests de inteligencia. Así, no se trata aquí de comparar el desarrollo intelectual de los habitantes de dos zonas distintas en cuanto a ser o no deficitarias en yodo, sino de comprobar tales diferencias intelectuales en función de la yoduria presentada por los sujetos. Cuando se comparan zonas geográficas, se asume que la mayoría de los habitantes de la zona yododeficiente han padecido, en algún momento de su desarrollo, ese déficit (aunque en la actualidad pudiera haberse paliado). Lo que se mide son los efectos de la carencia de yodo a largo plazo. No obstante, con esta metodología, se corre el riesgo de incluir dentro de la zona carente de yodo a un número indeterminado de sujetos que, por cualquier causa (movilidad geográfica, hábitos de consumo saludables…), nunca hayan sufrido dicho déficit, o bien al contrario, considerar como no carentes de yodo a personas que sí lo sean pese a vivir en la actualidad en zonas no yododeficientes. De esta forma, al dividir la muestra en función, no de la zona de residencia, sino del nivel de yoduria que presentan los sujetos, se evitan los problemas anteriores, si bien, se corre el riesgo de tomar como algo estable (la ingesta de yodo), lo que puede ser el reflejo de algo coyuntural. Respecto a esto último, si se acepta que la principal fuente de yodo se suministra a través de la dieta, puede admitirse que ésta es eminentemente estable a través del tiempo (no sólo por la persistencia de los productos que se consumen, sino incluso por la fidelidad a las marcas de éstos). De esta forma, puede aceptarse que la yoduria sería, en la mayoría de los casos, el reflejo de un hábito de consumo estable 32. Finalmente, el grupo de alta yoduria en el presente estudio se compone de sujetos que conviven en las mismas

regiones geográficas que los niños con baja yoduria, lo que elimina otro error propio del uso indiscriminado de los tests de inteligencia como es el referido al grupo normativo en el que se basan los baremos. Finalmente, cuando se divide la muestra en dos grupos en función de que la yoduria sea superior o inferior a 100 µ g/L, se encuentran diferencias estadísticamente significativas entre estos grupos en la puntuación en la Escala de Apreciación del Comportamiento, en el sentido de que el grupo con menor yoduria muestra un peor comportamiento que el grupo de mayor yoduria. Este tipo de comportamiento hace referencia a la conducta disruptiva del niño en clase a juicio de su profesor. El hecho de que la menor yoduria se asocie con un peor comportamiento puede explicarse tomando la variable inteligencia como un factor mediador en esta relación. De este modo, los niños con menor yoduria muestran también un menor CI si se comparan con los de mayor yoduria. La relación entre menor inteligencia y peor comportamiento está bien establecida en la literatura 34. Posiblemente, los niños con un CI inferior tengan más dificultades para seguir el curso de las clases como lo hacen sus compañeros con un CI más elevado. Estas dificultades pueden llevar a que el niño no entienda la totalidad de lo que se explica en el aula con lo que, probablemente, dejará de prestar atención a las explicaciones del profesor. La consecuencia más plausible es que ante el aburrimiento opte por entretenerse hablando con sus compañeros o bromeando con ellos. No sería, así, el déficit de yodo el causante directo de la conducta disruptiva en el niño, sino la disminución de las habilidades intelectuales que dicho déficit conlleva. Podemos concluir, por tanto, que en la provincia de Jaén existe un grado de endemia bociosa leve que puede llegar a moderada en algunos municipios. La ingesta de sal yodada no se adecua a las recomendaciones internacionales puesto que sólo entre el 7 y el 30% de la población (dependiendo de los municipios) consumen este tipo de sal. Y que el déficit de yodo se relaciona con el CI y que esto podría derivar en una forma de vida que lleve a los pueblo a aun menor desarrollo socio-cultural que los mantenga en una deficiencia económica y social con respecto al resto del país.
Bibliografía
1. Bleichrodt N, García I, Rubio C, Morreale de Escobar G, Escobar del Rey F. Developmental disorders associated with severe iodine deficiency. En: Hetzel BS, Dunn JT, Stanbury JB, editors. The prevention and control of iodine deficiency disorders. Amsterdam/New York/Oxford: EIsevier; 1987: 65-84. 2. Fierro-Benítez R, Cazar R, Stanbury JB, Rodríguez P, Garces F, Fierro-Renoy F, et al. Long-term effect of correction of iodine deficiency on psychomotor and intellectual development. En: Dunn JT, Pretell EA,

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Daza CH, Viteri FE, editors. Towards the eradication of endemic goitre, cretinism, and iodine deficiency. Washington: PAHO; 1986. p. 182. Connolly KJ, Pharoah PO, Hetzel BS. Fetal iodine deficiency and motor performance during childhood. Lancet 1979; 2:1149-51. Delange F, Bastani S, Benmiloud M. Definitions of endemic goiter and cretinism, classification of goiter size and severity of endemias, and survey techniques. En: Dunn JT, Pretel EA, Daza CH, Viteri EF, editors. Towards the eradication of endemic goiter, cretinism and iodine deficiency. Washington DC: PAHO/WHO Sci 1986; 502:373-376. Querido A, Delange F, Dunn JT, Fierro-Benitez R, Ibbertson HK, Koutras DA, et al. Definitions of endemic goiter and cretinism, classification of endemic goiter size and severity of endemias, and survey techniques. En: Dunn JT, Medeiros-Nieto GA, editors. Endemic Goiter and Cretinism: Continuing Threats to World Health. Washington DC: PAHO; 1974. p. 267. Marrero-González N, Rodríguez-Fernández C. Hipotiroidismo congénito: historia e impacto del tamizaje. Rev Biomed 2000; 11:283-292. Prieto L, Gruñeiro de Papendieck L, Chiesa A, Bregada C. Screening for congenital hypothyroidism (CH): experience in cord blodd. En: Levy HL, Hermos RJ, Grady GF, editors. Proceedings of the Third Meeting of the International Society for neonatal Screening; 1996 Oct 20-23; Boston, EUA: IKON/MAP; 1996. p: 271-2. Fuse Y, Wakae E, Nemoto Y, Uga N, Tanaka M, Maeda M, et al. Influence of perinatal factors and sampling methods on TSH and thyroid hormones levels in cord blood. Endocrinol Japon 1991; 38: 297-302. Walfish P. Evaluation of three thyroid-function screening tests for detecting neonatal hypothyroidism. The Lancet 1976; p. 1208-1212. García I, Rubio C, Alonso E, Turmo G, Morreale de Escobar G, Escobar del Rey F. Alteraciones por deficiencia de yodo en las Hurdes. I. Deficiencia de yodo y efectos del Lipiodo. Endocrinología 1987; 34: 61-73. Van den Briel T, West CE, Bleichrodt N, Van de Vijver FJ, Ategbo EA, Hautvast JG. Improved iodine status is associated with improved mental performance of schoolchildren in Benin. American Journal of Clinical Nutrition 2000; 5:179-85. Bautista A, Barker PA, Dunn JT, Sanchez M, Kaiser DL. The effects of oral iodized oil on intelligence, thyroid status, and somatic growth in school-age children from an area of endemic goiter. American Journal of Clinical Nutrition 1982; 35: 127-34. Wu T, Liu GJ, Li P, Clar C. Iodised salt for preventing iodine deficiency disorders. Cochrane Database of Systematic Reviews 2002; 3: CD003204. Delange F, Benker G, Caron Ph, Eber O, Ott W, Peter F, et al. Tyroide volume and urinary iodine in European schoolchildren:standarization of values for assessment of iodine deficiency. Eur J Endocrinol 1997; 136: 180-187. Millon Ramírez MC. Prevalencia de bocio endémico y otros trastornos relacionados con la deficiencia de yodo en la dieta en la comarca de la Axarquía (Málaga) [tesis Doctoral]. Facultad de Medicina de la Universidad de Málaga; 2000. Cattell RB, Cattell AKS. Test de Factor G-Escala 1. Madrid: TEA; 1989.

17. Cattell RB, Cattell AKS. Test de Factor G-Escalas 2 y 3. Madrid: TEA; 1994. 18. Alonso Tapia J. Evaluación de la inteligencia y las aptitudes desde el enfoque factorial. En: Fernández Ballesteros R editor. Introducción a la Evaluación Psicológica. Vol. 1. Madrid: Pirámide ;1992. p. 384-414. 19. Alonso Tapia J. Evaluación de la inteligencia desde el enfoque BinetTerman-Wechsler. En: Fernández Ballesteros R, editor. Introducción a la Evaluación Psicológica. Vol. 1. Madrid: Pirámide;1992. p. 349-383. 20. Almeida LS, Buela-Casal G. Evaluación de la inteligencia general. En: Buela-Caal G, Sierra JC, editors. Manual de evaluación psicológica: Fundamentos, técnicas y aplicaciones. Madrid: Siglo XXI de España Editores; 1997. 21. Benotii J, Benotti N. Protein bound iodine, total iodine and protein and butanol extractable iodine by partial automation. Clin Chem 1963; 9: 408-416. 22. Miettinen O. Estimability and estimation in case-referent studies. American Journal of Epidemiology 1976; 103: 226-35. 23. Kleinbaum D, Kupper LL, Muller KE. Applied Regression Analysis and Other Multivariable Methods. 2nd ed. Boston: PWS-Kent Pub; 1988. 24. APA. Manual diagnóstico y estadístico de los trastornos mentales (DSMIV). Barcelona: Masson; 1995. 25. Soriguer F, Millón MC, Muñoz R, Mancha I, López Siguero JP, Martínez Aedo MJ, et al. The auditory threshold in a school-age population is related to iodine intake and thyroid function. Thyroid 2000; 10:991-9. 26. Azizi F, Sarshar A, Nafarabadi M, Ghazi A, Kimiagar M, Noohi S, et al. Impairment of neuromotor and cognitive development in iodine-deficient schoolchildren with normal physical growth. Acta Endocrinologica 1993; 129: 501-4. 27. Azizi F, Kalani H, Kimiagar M, Ghazi A, Sarshar A, Nafarabadi M, et al. Physical, neuromotor and intellectual impairment in non-cretinous schoolchildren with iodine deficiency. International Journal for Vitamin & Nutrition Research 1995; 65: 199-205. 28. Fu LX, Cheng ZH, Deng LQ. Effects of iodine nutritional status of fetuses, infants and young children on their intelligence development in the areas whit iodine-deficiency disorders. Zhonghua Yu Fang Yi Xue Za Zhi 1994; 28: 330-332. 29. Escobar del Rey F, Martín T, Turmo C, Mallol J, Obregón MJ, Morreale de Escobar G. Alteraciones por deficiencia de yodo en Las Hurdes. I. Deficiencia de yodo y efectos del Lipiodol ®. Endocrinología 1987; 40 (Suppl 2): 61-73. 30. Delange F. The disorders induced by iodine deficiency. Thiroid 1994; 4: 107-127. 31. Aghini Lombardi F, Pinchera A, Antonangeli L. Mild iodine deficiency during fetal/neonatal life and neuropsychological impairment in Tuscanny. J Endocrinol. Invest 1995; 18: 57-62. 32. Greenblatt DJ, Ransil BJ, Harmatz JS, Smith TW, Duhme DW, Kochwesher J. Variability of 24-hour urinary creatinine excretion by normal subjects. J Clin Pharmacol 1975; 16: 321-328. 33. Webb E. Delinquency: the role of the paediatrician. Current Paediatrics 2003; 13: 279-283.

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TABLA 1. COCIENTE INTELECTUAL (CI) DE TODA LA POBLACIÓN ESCOLAR ESTUDIADA Y SU DISTRIBUCIÓN POR PERCENTILES. CI Total (media ± SD) Percentiles de CI: P-5 P-10 P-25 P-50 P-75 P-90 P-95 97,2 ± 17,1 65,1 74 87,3 99 109 117 121

TABLA 2. COCIENTE INTELECTUAL (CI) EN FUNCIÓN DE SEXO, CURSO ESCOLAR, BOCIO Y NIVELES DE YODURIA.

Variable de clasificación Sexo: Niños Niñas Curso: 1.º Primaria 5.º Primaria 2.º E.S.O. Bocio: No IA IB Yoduria: = 100 µg/L > 100 µg/L

CI 96,34 ± 17,44 98,17 ± 16,73 97,73 ± 14,58 96,27 ± 19,34 97,78 ± 16,69 97,36 ± 17,11 96,10 ± 17,10 100,48 ± 17,22 96,40 ± 17,46 99,03 ± 15,81

P NS

NS

NS

0,01

NS: no significativo. E.S.O.: Enseñanza Secundaria Obligatoria. TABLA 3. PREVALENCIA (%) Y RIESGO (OR) DE TENER UN COCIENTE INTELECTUAL (CI) POR DEBAJO DEL PERCENTIL 25 EN FUNCIÓN DE NIVELES DECRECIENTES DE YODURIA (µ G/L). Yoduria *** > 150 > 100 y ≤ 150 > 50 y ≤ 100 > 25 y ≤ 50 ≤ 52
* ** ***

% niños con CI ≤ p-25 16,5 22,5 26,4 26,7 30,1

β

EEβ β

OR ** 1

IC 95 %

P*

0,39 0,6 0,63 0,83

0,28 0,25 0,31 0,31

1,48 1,83 1,89 2,31

0,85-2,56 1,12-2,97 1,02-3,45 1,25-4,21

0,16 0,01 0,04 0,007

Ajustado por la edad y el sexo. Riesgo (OR) de tener un CI por debajo del P-25 en función de los diferentes niveles de yoduria (variable exposición). Yoduria (variable dummy). Categoría de referencia yoduria >150 µg/L.

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TABLA 4. MODELOS DE REGRESIÓN LOGÍSTICA: Variable Dependiente: CI= 0 (CI > P-25); CI = 1 (CI <= P-25). Variables Independientes: – Consumo de sal (sal) (variable dummy): 1= sal común; 2= sal marina; 3= sal yodada (categoría de referencia= 3). – Consumo de lácteos (variable dummy): 0= 3 veces/día; 1= 2 veces/día; 2= menos de 1 vez/día (categoría de referencia= 1). – Sexo: 0= niños; 1= niñas (categoría de referencia= niñas). – Edad (años)= variable continua. β EEβ β

Modelos

Variable dependiente Sal: 2 vs 3 1 vs 3 Lácteos: 1 vs 0 2 vs 0 Sal: 2 vs 3 1 vs 3 Lácteos: 1 vs 0 2 vs 0 Sal: 2 vs 3 1 vs 3 Lácteos: 1 vs 0 2 vs 0 Sexo Edad

OR

IC 95 %

P

Modelo 1

0,33 0,53 -0,12 0,45 0,32 0,53 -0,1 0,43 0,31 0,45 -0,09 0,45 0,3 0,0013

0,18 0,22 0,18 0,2 0,18 0,22 0,18 0,2 0,18 0,21 0,18 0,21 0,16 0,027

1,39 1,7 0,88 1,57 1,38 1,74 0,89 1,54 1,36 1,75 0,91 1,58 1.35 1

0,98-1,98 1,10-2,61 0,62-1,26 1,06-2,32 0,97-1,96 1,10-2,61 0,63-1,29 1,04-2,27 0,96-1,94 1,04-2,37 0,64-1,30 1,04-2,37 0,99-1,85 0,95-1,06

0,07 0,01 0,5 0,02 0,08 0,01 0,55 0,03 0,09 0,01 0,61 0,03 0,06 0,96

Modelo 2

Modelo 3

Modelo 4

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Los antisépticos yodados no son inocuos
J. Arena Ansoteguia y J.I. Emparanza Knörrb
aUnidad

de Metabolopatías. Servicio de Pediatría.bUnidad de Epidemiología Clínica. Hospital Aránzazu. San Sebastián.

(An Esp Pediatr 2000; 53: 25-29)

El uso de antisépticos yodados es una práctica aún extendida en nuestras maternidades. La aplicación de antisépticos yodados tanto a la madre en los momentos previos al parto como al recién nacido provoca una sobrecarga yodada incontrolada. La absorción del yodo a través de la piel de la madre es tan rápida que la yodemia en sangre de cordón aumenta en un 50% tras la aplicación en los momentos previos al expulsivo de antisépticos yodados a la madre. La sobrecarga yodada en la madre se manifiesta con aumento de la yoduria y del contenido de yodo en la leche hasta 10 veces en los días inmediatamente posteriores al parto, si las curas de la episiotomía se realizan con povidona yodada. La elevada concentración de yodo en la leche agrava la sobrecarga al recién nacido. Especialmente en zonas con déficit nutricional de yodo, esta sobrecarga yodada puede provocar un bloqueo transitorio del tiroides neonatal que tiene repercusiones negativas sobre el programa de detección del hipotiroidismo congénito, aumentando el número de falsos positivos, y sus inmediatas consecuencias: ansiedad de los padres y un importante aumento de los costes del programa. Más graves son las consecuencias que este bloqueo puede producir en el desarrollo del recién nacido. Parece ineludible realizar una llamada de atención sobre las alteraciones que provocan los antisépticos yodados y desaconsejar su uso en el período perinatal.

Iodine overload also occurs in the mother. Urinary and breast-milk iodine are increased more than 10-fold in the days after delivery if providone-iodine is used in episiotomy. The overload in the neonate is even higher if breastfed. Particularly in iodine-deficient areas, this overload can produce thyroid blockade with undesirable effects in congenital hypothyroidism screening, raising the number of false positives and its consequences: parental anxiety and screening costs. The potential effects that this thyroid blockade can produce in the neonate are even more serious. Attention should be drawn to the undesirable effects of iodine antiseptics and their use in the perinatal period should be avoided.

Key words:
Providone-iodine. Iodine. Thyroid hormones. Hypothyroidism. Newborn.

INTRODUCCIÓN
La aplicación de antisépticos yodados a la madre gestante y al recién nacido es un ejemplo de actividades médicas o sanitarias que, pese a ser aparentemente inocuas, pueden provocar alteraciones fisiológicas importantes. Actualmente, la utilización de antisépticos yodados en el período perinatal es casi la norma, no sólo en nuestro país sino en gran parte de las maternidades de las que se conocen sus protocolos. Hoy en día, sabemos que su aplicación cutánea o mucosa se sigue de una absorción rápida de yodo por la piel o mucosas que produce una sobrecarga yodada. Esta sobrecarga puede provocar al recién nacido un bloqueo tiroideo de duración variable que repercute de forma inmediata sobre el cribado neonatal del hipotiroidismo congénito: aumenta el número de falsos positivos, aumenta el gasto por la necesidad de repetir la

Palabras clave:
Povidona-yodada. Yodo. Hormonas tiroideas. Hipotiroidismo. Recién nacido.

IODINE ANTISEPTICS ARE NOT HARMLESS
The use of iodine-containing antiseptics is still common in obstetrics and neonatology. Topical iodine given both to the mother before delivery and to the neonate causes iodine overload. The absorption of maternal iodine through the skin is so fast that iodine in the blood of the umbilical cord increases by 50% a few minutes before delivery.

Correspondencia: Dr. J. Arena Ansotegui. Servicio de Pediatría. Hospital Aránzazu. P. Dr. Beguiristáin, s/n. 20014 San Sebastián. Correo electrónico: jarena@chdo.osakidetza.net Recibido en mayo de 2000. Aceptado para su publicación en junio de 2000.

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3,5 3,0 2,5 p < 0,001 2,0 1,5 1,0 0,5 0,0 Recién nacidos no tratados Recién nacidos tratados

Hipertirotropinemia transitoria Hipotiroidismo transitorio

Figura 1. Frecuencia, en porcentaje, de hipotiroidismo transitorio e hipertirotropinemia.

La alarma la dio un incremento brusco de las alteraciones transitorias de la función tiroidea reconocidas en el cribado neonatal del hipotiroidismo congénito, y la asociación estadísticamente significativa de estos trastornos con la aplicación de PVP-I al muñón umbilical nos permitió aceptarlo como un bloqueo transitorio de la función tiroidea por sobrecarga yodada. A partir de entonces se eliminaron los antisépticos yodados de nuestra unidad neonatal. En aquel momento no supimos interpretar la elevada tasa de hipertirotropinemia e hipotiroidismo transitorio que presentaban los recién nacidos del grupo control (0,42 y 0,25%, respectivamente). Posteriormente, observamos que las alteraciones transitorias de la función tiroidea afectaban casi exclusivamente a los recién nacidos alimentados al pecho, con una tasa del 0,82% comparada con el 0,10% de los que se alimentaban con fórmula, lo que nos hizo pensar en una iatrogenia ligada a la lactancia materna.

APLICACIÓN
prueba, provoca ansiedad en los padres por lo que comporta una prueba positiva, y lo más preocupante es que pueda afectar en alguna medida a su desarrollo cerebral. El bloqueo, a menudo transitorio, del tiroides neonatal, como consecuencia de una sobrecarga yodada de la que no puede desembarazarse, produce el llamado efecto de Wolf-Chaikoff, y ha sido demostrado en numerosas publicaciones1-41. La afectación del tiroides feto-neonatal dependerá fundamentalmente de la intensidad y duración de la sobrecarga, de la madurez del tiroides, y sobre todo de la presencia o no de un déficit nutricional de yodo en la madre. La utilización de antisépticos yodados siempre provoca una sobrecarga yodada, pero no siempre afecta a la función tiroidea, ya que la hipersensibilidad del tiroides feto-neonatal a sustancias bociogénicas como el yodo depende en gran medida de que exista o no un déficit del mismo en la madre, de aquí que pequeñas sobrecargas de yodo puedan provocar bloqueos importantes y a la inversa grandes sobrecargas puedan tener escasa repercusión sobre la función tiroidea5,39,42. Nuestra experiencia al respecto fue de interés y no ha perdido actualidad a pesar de los años transcurridos1,2.

DE YODO A LA MADRE

Al descubrir que la PVP-I se utilizaba sistemáticamente en nuestra maternidad, tanto para la preparación perineal de la madre y las curas diarias de la episiotomía en el parto vaginal, como para preparar el campo quirúrgico y las curas de la herida en el caso de una cesárea, realizamos un estudio a doble ciego para investigar si la PVP-I aplicada la madre en el parto vaginal podría provocar en su hijo una sobrecarga yodada tan importante como para bloquear el tiroides, y valorar el papel que ejercía la lactancia materna en todo el proceso. El estudio se llevó a cabo en 36 parejas madre-hijo distribuidas al azar en dos grupos, a uno de los cuales se le aplicó como antiséptico PVP-I al 10% con dos subgrupos según la alimentación fuera natural o con fórmula, y al otro grupo se la administró clorhexidina al 0,5%. Los controles analíticos practicados se reflejan en la tabla 1. Los resultados (tabla 2) demostraron una yoduria materna inicial similar en ambos grupos, pero inferior a 100 µg/l, con un incremento progresivo y muy importante en los días siguientes al parto, que reflejaba la sobrecarga yodada producida por la absorción del yodo aplicado en la madre y que se manifestaba también en la elevada excreción de yodo en la leche.

APLICACIÓN

DE YODO AL RECIÉN NACIDO TABLA 1. Controles practicados
Madre Yoduria anteparto Yoduria diaria posparto (4 días) TSH y T4 anteparto y al 4.o día posparto + I2 , en leche al 4.o día Recién nacido + I2 , TSH y T4 en sangre de cordón TSH y T4 al 5.o y 7.o días Yoduria diaria (24-48-96 h)

En el año 19842 pudimos comprobar, en un estudio retrospectivo, que la aplicación diaria de Betadine® (povidona yodada al 10%) en el muñón umbilical de 356 recién nacidos, durante los días que permanecieron en la maternidad, se acompañó de un aumento significativo de la hipertirotropinemia transitoria y del hipotiroidismo transitorio frente a otros 5.507 recién nacidos que no recibieron povidona yodada (PVP-I), tal y como se refleja en la figura 1.

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La yodemia elevada de forma significativa en la sangre de cordón de los recién nacidos del grupo PVP (tabla 3) sólo puede explicarse por una rapidísima absorción y distribución del yodo aplicado a la piel de la madre pocos minutos antes de obtener la muestra del cordón, pero son exclusivamente los recién nacidos que lactan, y a cuyas madres se les sigue curando la episiotomía con PVP-I, los que sufren una sobrecarga yodada suficientemente importante y mantenida como para presentar un bloqueo tiroideo. Estos resultados sugieren que: a) la piel del adulto es muy permeable al yodo de la PVP-yodada, y que la utilización de antisépticos yodados para la preparación perineal de la madre y las curas diarias de la episiotomía produce una importante sobrecarga yodada a la madre, y b) la excreción elevada de yodo por la leche materna, como expresión de su yodemia también elevada, es responsable de la sobrecarga yodada de los recién nacidos que lactan y explica el incremento de los trastornos transitorios de su función tiroidea.

TABLA 2. Yoduria materna y concentración de yodo en la leche materna (µg/l)
CLHX PVP-I

Orina Anteparto 24 h 48 h 96 h Leche (96 h)

96 176 135 76 105

61 1.427* 1.881* 2.171* 1.216*

*p < 0,001. CLHX: clorhexidina; PVP-I: povidona yodada.

TABLA 3. Iodemia y ioduria en el recién nacido (µg/l)
CLHX PVP-LM PVP-LA

Sangre de cordón Orina 24 h 48 h 96 h

68* 65* 69* 579 270 283 8.326**

100 620 395 374

CLHX: clorhexidina; PVP-LM: povidona yodada-lactancia materna; PVP-LA: povidona yodad-lactancia artificial; *p < 0,01 CLHX frente a PVP. **p < 0,001 PVP-LM frente a CLHX y PVP-LA.

COMENTARIO
A partir de estos estudios1,2 dejamos de utilizar los antisépticos yodados, no sólo en el recién nacido sino también durante el embarazo, el parto y la lactancia, con lo que se redujo a la mitad la cifra de hipertirotropinemia en el conjunto de la Comunidad Autónoma Vasca (CAV). Desde entonces usamos la clorhexidina, cuya eficacia ha sido suficientemente probada43-46, como antiséptico habitual en el período perinatal. En la CAV existe un déficit nutricional de yodo, considerado leve según los indicadores internacionales 47,48, que se expresa con una yoduria media en los escolares entre 50 y 99 µg/l según las zonas, de los que un 21,2% presentan bocio49, y un 3-5% de recién nacidos con TSH entre 5 y 10 mU/l en el cribado neonatal realizado a las 48 h de vida (datos no publicados del Programa de Cribado Endocrino-Metabólico de la CAV). Este déficit puede explicar la existencia de un 0,28% de recién nacidos con hipertirotropinemia transitoria, como ocurre en otros lugares donde existe un déficit nutricional de yodo50-52 , y justifica la profilaxis con sal yodada en la población general que se lleva a cabo en la CAV. Sin embargo, las ventas de sal yodada en nuestra comunidad apenas alcanzan el 55% del total de ventas de sal (Servicio de Información al Consumidor de Eroski; abril 2000). Una vez eliminados los antisépticos yodados en el período perinatal, nuestro objetivo será erradicar los trastornos causados por el déficit de yodo con una política más agresiva como sería la yodación universal de la sal de consumo humano y animal, incluso la empleada en la industria alimentaria, siguiendo las recomendaciones de la OMS-UNICEF-ICCIDD53-54, y suplementar a la mujer embarazada con 250-300 µg de yodo al día durante toda la gestación. La deficiencia nutricional de yodo es un problema generalizado en Europa, y España no es una excepción. De ahí que las políticas de yodación de la sal y la eliminación de los antisépticos yodados en el período perinatal sean dos acciones sanitarias de absoluta necesidad55.

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