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Int J Endocrinol Metab 2004; 2:1-12

RE

VI E

W ARTI CLEOptimal Iodine Nutrition during Pregnancy,

Lactation and the Neonatal Period

Delange F.

International Council for Control of Iodine Deficiency Disorders (ICCIDD); Department ofPediatrics, 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 in-creased during pregnancy and lactation. Thispaper reevaluates the iodine requirements dur-ing pregnancy, lactation and the neonatal periodand formulates original proposals for the me-dian concentrations of urinary iodine indicating optimal iodine nutrition during these three criti-cal periods of life. Based on an extensive andcritical review of the literature on thyroidphysiopathology during the perinatal period, thefollowing proposals are made: the iodine re-quirements are 250-300 g/day during pregnancy,

225-350 g/day during lactation and 90 g/dayduring the neonatal period. The median urinaryiodine indicating optimal iodine nutrition dur-ing these three periods should be in the range150-230 g/L. These figures are higher than thoserecommended so far by international agencies.

Key Words : Iodine, Nutrition, Pregnancy, Lacta-tion, Neonatal Period, Median urinary iodine

IntroductionThe thyroid economy undergoes a series of

metabolic changes during pregnancy and lac-tation. 1-4 One of the factors involved in these

changes is the increased requirement of io-

dine in the mother due to the transfer of thy-roxine (T 4) and of iodide from mother to fe-tus during pregnancy and to the loss of iodidein breast milk during lactation. These two

processes are required in order to ensurenormal 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 re-

garding the median concentrations of urinaryiodine indicating optimal iodine nutritionduring these critical periods of life.

Requirement of Iodine DuringPregnancy and Lactation

The requirement of iodine is increased dur-ing pregnancy because of at least three fac-tors: 1) There is an increased requirement of T4 in order to maintain a normal global me-tabolism in the mother. 2) There is a transfer of T 4 and iodide from the mother to the fetus

and 3) There is supposed to be an increasedloss of iodide through the kidney due to anincrease in the renal clearance of iodide.

I

Correspondence: Professor Franois Delange, MD,PhD, 153, avenue de la Fauconnerie B-1170, Brus-sels, Belgium

E-mail : [email protected]


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International Journal of Endocrinology and Metabolism

Because of these three factors, the recom-mended dietary intake of iodine during preg-nancy is higher than the value of 150 g/dayrecommended for non-pregnant adults andadolescents. 11,12 Below this critical thresholdof 150 g/day, the iodine balance is negativeduring pregnancy. 13 WHO/UNICEF/ICCIDD

recommend an iodine intake of 200 g/dayfor pregnant women, 11 i.e. a percentage in-crease of 33% over non-pregnant women.The Institute of Medicine (IOM) of the USAcademy of Sciences recommends a higher intake of 220 g/day, 12 i.e. an increase of some 47%, and other organizations recom-mend 175 to 230 g/day. 14,15

Increase in the T 4 requirementsThe daily requirement of T 4 in order to

maintain euthyroidism in hypothyroid women

increases by 10 to 150% during pregnancywith a median increment of 40-50%. 16-18 Thisrepresents an additional dose of 75 to 150 gT4/day, i.e. 50 to 100 g iodine .

Transfer of T 4 and iodide from mother to fe-tus

The transfer of T 4 from mother to fetus, in-cluding before the onset of fetal thyroid func-tion, is not quantified but it is has been esti-mated that up to 40% of the T 4 measured oncord at birth is still of maternal origin. 8

The transfer of iodide is also difficult toquantify but considering that the iodine con-tent of the fetal thyroid increases progres-sively from less than 2 g at 17 weeks of ges-tation 19 up to 300 g at term, 20-23 that the T 4 iodine at term probably averages 500 g 24 and that the substitutive dose of T 4 in hypo-thyroid neonates is 50-75 g/day, 25,26 it can

be estimated that the transfer of iodide frommother to fetus represents some 50 g/day. Ithas been estimated at 75 g/day by theIOM. 12

Increased renal clearance of iodide It is often stated that the increase in iodine

requirement during pregnancy is largely dueto an increased loss of iodide through the

kidney because of an increased renal clear-ance of iodide. This should decrease the se-rum concentration of plasma inorganic io-dide, PII. 27-30 However, Liberman et al. 31 showed on the contrary that there is no sig-nificant decline in the PII during pregnancy.In addition, as shown by the data collected in

Table 1 and already by Dworkin et al.,13

al-most all studies on urinary iodine during

pregnancy showed that, in a given environ-ment, the urinary excretion of iodide is al-most similar in pregnant and non-pregnantwomen and in the general population, irre-spective of the status of iodine nutrition inthe population. Only the studies conducted bythe group of Smyth et al. 32,33 in Ireland, theUnited Kingdom and Sri Lanka, by Kung etal. in Hong Kong 34 and perhaps by Hess et al.in Switzerland 35 have shown a clear-cut in-

crease in the urinary iodine excretion during pregnancy. The results reported for Switzer-land by Brander et al. 36 are difficult to inter-

pret because of the surprisingly low value of the urinary iodine in the general populationreported in this study as Switzerland isknown to be iodine sufficient. 37 On the con-trary, some studies showed that urinary io-dine decreases during gestation. 38-40 It thusappears that the concept of systematically in-creased urinary loss of iodine during preg-nancy is not firmly established.

Finally, it has to be underlined that no dataare available on the possible storage and lossof iodide in the placenta itself.

Taking all these variables into considera-tion, it can be speculated that the additionalrequirement of iodine during pregnancy is atleast 100-150 g/day, i.e. an increment of almost 100% as compared to non-pregnantadults instead of the 33% proposed byWHO/UNICEF/ICCIDD. 11 Consequently, therequirement of iodine during pregnancy is atleast 250 g/day, probably in the range of

250 to 300 g/day. This figure is still higher than the figure of 220 g/day proposed by theIOM, 12 which did not take into account theincreased requirement of T 4 during preg-nancy.


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Perinatal iodine nutrition


3

Table 1. Comparison of the median or mean (in bold) urinary iodine (g/L) in pregnant women and inthe general population or in non-pregnant controls (publications 1990-2003)

Pregnant womenCountry Generalpopulationor controls

n S/C

Trimester Urinaryiodine

Countries with no iodine deficiency

Chile31

- 19 S 1 594*

2 4693 786

3 months PP 459Iran 43 193-312 403 C 1-3 186-338 Sweden 77 - 51 S 1 180 *

51 S 2 17051 S 3 145

Srilanka 33 147 - C 1 181 - C 2 136- C 3 154

USA 78 130 290 C 1-3 148

Switzerland 35 (2000)

115 511 C 2,3 138

Scotland 79 138 433 C 1 137 Switzerland 36 (1992)

91 153 C 1-3 205 *

31 C 1 26756 C 2 20666 C 3 17215 S 1 32515 S 2 16615 S 3 183

Iodine deficient countriesSingapore 34,80 98 253 C 3 124

230 S 1 107 - 2 116- 3 124- 6 weeks PP 105- 3 months PP 104

Sicily (Italy) 54,81 46* 10 S 1,2,3 33 * Turkey 82 85* 80 S 1-3 91 * Ireland 32,33 70 38 S 1 135

38 S 2 12538 S 3 122

108 C 6 weeks PP 70

Pregnant womenCountry Generalpopulationor controls

n S/C

Trimester Urinaryiodine

UK 33 73 - C 1 125

- C 2 170- C 3 147

France 40 50-80 * 306 S 1 50 224 S 3 54

Belgium 38 50-75 * 334 C 1-2 50 334 C 2-3 45136 C 1 56 133 C 2 5049 C 3 50

Denmark 83 50* 26 S 2 51 26 S 3 4026 S 1 week PP 3026 S 26 weeks

PP50

26 S 52 weeksPP

58

Denmark 84 - C 5 days PP 40 Sudan 55 76 47 S 3 38

47 S 3 months PP 5147 S 6 months

PP30

47 S 9 monthsPP

63

New Zealand49

24-47*

35 S Monthlyduring

pregnancyand 3, 6and 12

months PP

24-52*

Italy 85

(2002)Marginal

ID67 C 1,2 74

Italy 86

(1991)Marginal

ID18 C 3 50 *

Germany 87 Mild ID 70 S 1 55 70 S 11 days PP 50

Hungary88

Mild ID 119 C 1,2,3 57

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 g/L = 0.78 mol/L* g/day; g/L; g/g creatinine


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Table 2. Selective examples of the iodine con-tent of breastmilk *

Countries Medians or means (g/L) No iodine deficiency

Korea 892Japan 661

33-385USA 146

168124145145

Sweden 939070

Switzerland 78Mild to moderate iodine deficiency

Germany 9315-150

Belgium 95

France 82777470

Spain 10877

United KingdomHungary 64Guatemala 60Philippines 57Thailand 50

Italy (Sicily) 43Severe iodine deficiencyMarocco 27Ethiopia 5-16

64Congo 15

13* Compiled from Semba-Delange 2001 41 andDorea 2002, 42 where detailed data and referencesare to be found.

During lactation, considering that the io-dine content of breastmilk in conditions of

iodine sufficiency is in the range of 150-180g/L 41,42 (Table 2) and that the milk produc-tion is from 0.5 to 1.1 liter per day up to theage of 6 months, the daily loss of iodine inhuman milk is estimated at some 75 to 200

g/day. Consequently, the iodine requirementduring lactation is estimated at 225 to 350g/day. The slight difference, if any, as com-

pared to the figure of 290 g/day recom-mended by IOM 12 results from more recentdata on the iodine content of breast milk. 41,42

Level of Urinary Iodine IndicatingOptimal Iodine Nutrition DuringPregnancy and Lactation

Considering that most (above 90%) of theiodine absorbed in the body eventually ap-

pears in the urine, urinary iodine excretion isa good marker of a very recent dietary iodineintake. 11 Therefore, a median urinary iodinein the general population varying from 100 to199 g/L is considered as an indicator of an

adequate iodine intake and an optimal statusof iodine nutrition. 11 As the iodine require-ment is increased during pregnancy, the me-dian urinary iodine during pregnancy indicat-ing optimal iodine nutrition needs to behigher than 100 g/L. Table 1 compares thedata available in the literature on urinary io-dine in pregnant women and in the general

population. In this Table, the countries arearbitrarily listed on the basis of roughly de-creasing iodine intake of the general popula-tion, starting with Chile 31 which is exposed toiodine excess based on theWHO/UNICEF/ICCIDD criteria, 11 down tocountries where different degrees of mild tomoderate iodine deficiency have been docu-mented. As indicated earlier, there is a strik-ing similarity between the urinary iodine in

pregnant women and in the global populationexcept in the reports published by Smyth etal.32,33 in which the values during pregnancyare systematically markedly higher than innon-pregnant controls. Therefore, it appearsdifficult to derive a reference value for uri-nary iodine during pregnancy and lactationfrom the data collected in countries with noiodine deficiency as this value varies from800 g/L in Chile 31 to 138 g/L in Switzer-land, where the median urinary iodine in the


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Table 3. Median or mean (in bold) urinary iodine (UI) concentrations (g/L) in neonates in iodine suf-ficiency and iodine deficiency

Countries and loca-tion

n Gestationalage

Urinary io-dine (g/L) *

Range Reference

Japan 118 FT Breastfed 736 Harada et al. 1994 63 Hokkaido 182 FT Bottlefed 521

United StatesBoston ? PT 36 weeks 148 16-510 Brown et al. 1997 89Torrance 50 FT 921 Delange et al. 1984 90

CanadaToronto 81 FT 148 Delange et al. 1986 72

The NetherlandsRotterdam 64 FT 162 Delange et al. 1986 72 Amesterdam 36 FT 150 Bakker et al. 1999 91

SwedenStockholm 39 FT 112 Delange et al. 1986 72 Stockholm 61 FT 96 Heidemann et al. 1984 65

Mild to moderate iodine deficiencyGermany

Nine towns 1983 461 FT 12-29 Heidemann et al. 198465Berlin West 1985 87 FT 28 Delange et al. 1986 72 Kiel 1992 50 FT 33 Grebe et al 1993 92

Frankfurt 1992 21 FT 37 Bohles et al. 199393

Berlin West 1994 177 FT 31 Grters et al. 1995 94

Berlin East 1994 213 FT 44 Grters et al. 1995 94 Gottingen 2000 22 FT 50 Roth et al. 2001 95 Heidelberg 1999 32 FT 95 Klett et al. 1999 96

BelgiumBrussels 1983 103 PT+FT 35 10-150 Delange et al. 1984 90

Brussels 1985 196 FT 48 Delange et al. 1986 72Brussels 2000 90 FT 86 Ciardelli et al. 2001 97

ItalyRome 1985 114 FT 47 Delange et al. 1986 72

Catania 1985 14 FT 71 Delange et al. 1986 72 ?towns 1995 195 FT 56 10-950 Rapa er al. 1996 98

Milano 1995 18 PT 30 weeks 123 Parravicini et al. 1996 99

Torino 9 FT 67 10-162 Bono et al 1998 100

FranceLille 1985 82 FT 58 Delange et al. 1986 72 Toulouse 1985 37 FT 29 Delange et al. 1986 72

IrelandBelfast 1993 ? FT 100 Barakat et al. 1994 101

IsraelTel Aviv 1996 55 PT 30-31 wks 55-100 Linder et al. 1997 102

Czech RepublicPrague 1998 50 FT 79 Hnikova et al. 1999 70

Prisbram 1998 50 PT 78Hungary

Budapest 2002 55 FT 35 Peter et al. 2003 103

Gyor 2002 65 FT 57Miskole 2002 54 FT 59

Nyiregyhaza 35 FT 75Severe iodine deficiencyGottingen 1985 81 FT 15 Delange et al. 1986 72Heidelberg 1985 39 FT 13 Delange et al. 1986 72 Freiburg 1985 39 FT 11 Delange et al. 1986 72 n: number; FT: Full-term, PT: Pre-term* Values are medians or means (bold).


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resulted in a situation of positive iodine bal-ance, which is required in order to insure a

progressively increased intrathyroidal iodine pool in the growing young infant. Such io-dine balance studies were conducted inhealthy preterm and in fullterm infants aged

approximately one month in Belgium, acountry with mild iodine deficiency. 61 Thesestudies, reported extensively elsewhere, 60 in-dicate that the iodine intake required in order to achieve a positive iodine balance is at least15 g/kg/day in fullterms and 30 g/kg/dayin preterms. This corresponds approximatelyto 90 g/day and is consequently twicehigher than the 1989 US recommendations of 40-50 g/day 62 but is still a bit lower than the

present recommendation of 110 g/day bythe IOM. 12

Level of Urinary Iodine IndicatingOptimal Iodine Nutrition in Neonates

Table 3 summarizes the data from the lit-erature on the median urinary iodine in neo-nates in countries or areas with iodine suffi-ciency and with different degrees of iodinedeficiency. There is a large variability in theresults even in iodine sufficient countries,where they vary from 736 g/L in Hokkaido,Japan, 63 which is submitted to an extremelyhigh iodine intake 64 to 96 g/L in Stock-

holm.65

Therefore, again, the data from the litera-

ture do not help substantially in identifyingthe optimal urinary iodine level and this levelhas also to be defined on the basis of theo-retical considerations. Based on an iodine re-quirement of 90 g/day and a volume of urines in neonates of some 0.4 to 0.5liter/day, 66 the median urinary iodine indicat-ing optimal iodine nutrition in neonates can

be evaluated at some 180 to 225 g/L whenignoring 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 onerecommended for schoolchildren and adults,is indeed observed when healthy young in-fants are supplemented with a daily

are supplemented with a daily physiologicaldose of 90 g/day. 67 It is also the value re-

ported in some parts of the United Statessupposed to be iodine sufficient. 68,69 On theother hand, studies reported in the literaturein which urinary iodine has been determined

simultaneously in mothers at delivery and inneonates during the first days of life 39,70,71 in-dicate that these levels are almost similar inmothers and neonates. Therefore, based onthe considerations on optimal urinary iodinein pregnant mothers, it can be extrapolatedthat the level in neonates should be around150 to 230 g/L, which is almost similar tothe figure derived from the iodine require-ments of the neonates.

The data reported from neonates in condi-tions of mild, moderate and severe iodine de-

ficiency are indeed much lower than normal,down to less than 20 g/L in Germany 72 be-fore the partly successful implementation of a

program of voluntary salt iodization. 73 It is particularly interesting to observe that thislevel progressively increased with time inGermany and in Belgium for examplefollowing the implementation of programs of iodine supplementation 73,74 and silent iodine

prophylaxis, respectively. 75 In summary, the recommended dietary in-

take of iodine in neonates is 90 g/day and

the median urinary iodine to be expected whenthis requirement is met is 180 to 225 g/L, avalue almost similar to the one recommendedfor pregnant women.

ConclusionPregnant and lactating women and neonates

are the main targets to the effects of iodinedeficiency because of the impact of maternal,fetal and neonatal hypothyroxinemia on braindevelopment of the progeny. 5-10 Therefore,any program of salt iodization in a population

should pay special attention to these particu-lar groups. And yet, no firm recommendationsare presently available on the level of urinaryiodine indicating optimal iodine nutrition inthese groups. This paper constitutes an attempt


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8 F. Delange


to propose such normative values. It appearsthat an extensive review of the literature

based in particular on the evaluation of uri-nary iodine in these groups in iodine replete

populations does not offer clear answers tothe questions because of the variability of in-dividual results even in iodine sufficient

countries. One first conclusion of this paper is thus that more accurate data should be col-lected in iodine sufficient countries, compar-ing systematically and at the same time theurinary iodine in the general population, innon-pregnant adults, schoolchildren, pregnantand lactating women and in neonates.

However, based on the data from the litera-ture and on metabolic considerations, it is

proposed that the recommended dietary in-take of iodine is 250-300 g/day for pregnantwomen, 225-350 g/day for lactating women

and 90 g/day for neonates and young in-fants. It is proposed that the median level of urinary iodine indicating optimal iodinenutrition during pregnancy and lactation is inthe range 150-230 g/L. Recommendationsfor neonates are still more difficult not only

because of the lack of accurate data but also because the neonate is not in a steady stateregarding iodine metabolism and that urinaryiodine probably represents a relatively impre-cise estimation of the iodine intake. How-

ever, based on the data from the literature andon theoretical considerations, it can be con-cluded that the median urinary iodine indicat-ing optimal iodine nutrition in the neonateshould be in the same range of 180-225 g/L,almost similar to the value recommended for their mothers.

It has to be emphasized again that theselevels are higher than the ones recommendedfor the general population and are supposedto be potentially responsible for side effectsin adolescents and non-pregnant adults. 11 Therefore, special attention should be fo-cused on iodine supplementation and moni-toring urinary iodine during pregnancy and

possibly during the neonatal period in addi-tion to programs of Universal Salt Iodizationin countries with iodine deficiency. 58 Thisrecommendation is particularly relevant con-

sidering that pregnant and lactating womenand neonates have usually a limited access tosalt in general and, consequently, to iodizedsalt, and that even in the United States, wherethe status of iodine nutrition is adequate inthe general population (median urinary iodineof 145 g/L), 6.7% of the pregnant womenare still affected by moderate to severe iodinedeficiency (urinary iodine below 50 g/L). 76

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Endocrinol Metab. 1998 Oct;83(10):3401-8.77. Elnagar B, Eltom A, Wide L, Gebre-Medhin M,

Karlsson FA. Iodine status, thyroid function and pregnancy: study of Swedish and Sudanesewomen. 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 ChimActa. 2003 Feb;328(1-2):185-90.

79. Barnett CA, Visser TJ, Williams F, Toor HV,Duran S, Presas MJ, et al. Inadequate iodine intakeof 40% of pregnant women from a region of Scot-land. J Endocrinol Invest. 2002. Suppl. to N 7,Abstract P110:90.

80. Kung AW, Lao TT, Low LC, Pang RW, RobinsonJD. Iodine insufficiency and neonatal hyperthyro-tropinaemia in Hong Kong. Clin Endocrinol (Oxf).1997 Mar;46(3):315-9.

81. Vermiglio F, Lo Presti VP, Castagna MG, VioliMA, Moleti M, Finocchiaro MD, et al. Increasedrisk of maternal thyroid failure with pregnancy

progression in an iodine deficient area with major iodine deficiency disorders. Thyroid. 1999Jan;9(1):19-24.

82. Mocan MZ, Erem C, Telatar M, Mocan H. Urinaryiodine levels in pregnant women with and withoutgoiter in the Eastern Black Sea of Turkey. TraceElements and Electrolytes. 1995;12:195-7.

83. Pedersen KM, Laurberg P, Iversen E, KnudsenPR, Gregersen HE, Rasmussen OS, et al. Amelio-ration of some pregnancy-associated variations inthyroid function by iodine supplementation. J ClinEndocrinol Metab. 1993 Oct;77(4):1078-83.

84. Nohr SB, Laurberg P, Borlum KG, Pedersen KM,Johannesen PL, Damm P, et al. Iodine deficiencyin pregnancy in Denmark. Regional variations andfrequency of individual iodine supplementation.Acta Obstet Gynecol Scand. 1993 Jul;72(5):350-3.

85. Antonangeli L, Maccherini D, Cavaliere R, DiGiulio C, Reinhardt B, Pinchera A, et al. Compari-son of two different doses of iodide in the preven-tion of gestational goiter in marginal iodine defi-ciency: 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 iodo- prophylaxis on thyroid size during pregnancy. AmJ 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, KaranyiZ, Pakozdy Z, et al. Prevalence of iodine defi-ciency and goitre during pregnancy in east Hun-gary. Eur J Endocrinol. 2000 Oct;143(4):479-83.

89. Brown RS, Bloomfield S, Bednarek FJ, MitchellML, Braverman LE. Routine skin cleansing with

povidone-iodine is not a common cause of tran-

sient neonatal hypothyroidism in North America: a prospective controlled study. Thyroid. 1997Jun;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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ANALESESPAOLES DEPEDIATRA. VOL. 53, N.o 1, 2000 1

EDITORIAL

El yodo durante la gestacin, lactancia y primerainfancia. Cantidades mnimas y mximas:de microgramos a gramos

Las hormonas tiroideas, tiroxina (T4) y 3,5,3-triyodo-tironina (T3) son necesarias durante todas las fases de la

vida para una funcin normal del sistema nervioso cen-tral (SNC). Son especialmente cruciales durante el desa-rrollo del SNC, pues una insuficiencia de estas hormo-

nas se acompaa de lesiones y defectos neurolgicospermanentes e irreversibles.

Ambas hormonas contienen yodo, cuatro tomos pormolcula en el caso de la T4, tres en el caso de la T3.Sin yodo no es posible su sntesis, a pesar de lo cual alo largo de la evolucin no han aparecido otras hormo-nas capaces de sustituirlas y que no tengan esta total de-pendencia de un elemento, que suele encontrarse encantidades muy pequeas fuera del ambiente acuticomarino.

En cambio, ha evolucionado una estructura, el folcu-lo tiroideo, capaz de minimizar las consecuencias de un

aporte asaz variable del yodo, obtenido en su mayorparte a travs de los alimentos y el agua. Es la nica es-tructura endocrina capaz de almacenar estas hormonasen forma de prohormona (la tiroglobulina), con tal efi-cacia que un adulto, que ha tenido una nutricin ade-cuada de yodo, puede hacer frente a las necesidadeshormonales de su organismo durante varios meses des-pus de iniciarse un perodo de carencia total del mis-mo en su alimentacin. A su vez, la glndula tiroides deladulto es capaz de evitar las posibles consecuencias no-civas de la produccin de un exceso de hormonas tiroi-deas, que podran producirse al llegarle cantidades muy altas de yodo. Si embargo, surgen problemas importan-tes cuando la deficiencia de yodo en la alimentacin sehace crnica, o cuando la exposicin a un exceso de yo-do es muy prolongada, sobre todo cuando esto ocurredurante un perodo del desarrollo en que la glndulaan no est plenamente preparada para ello. De no re-solverse estos problemas, o de resolverse a destiempo,pueden producirse dficit ms o menos graves e irre-

versibles del SNC.

En este breve comentario se intentar definir, con mayor precisin, cules son las cantidades mnimas para undesarrollo normal del SNC, y cules las que pueden darlugar a problemas durante el embarazo y primera infan-cia, perodos en los que tienen lugar en el ser humano

fases cruciales de maduracin cerebral. Hay, sobre todocon respecto al exceso de yodo, bastantes problemas dendole prctico, tal y como describen con acierto y am-plio apoyo bibliogrfico Arena y Emparanza en este mis-mo nmero1.

CANTIDADES MNIMAS DE YODODesde que, hace ya una dcada, fue ratificada por la

prctica totalidad de los pases del mundo la Declara-cin Mundial para la Supervivencia, Proteccin y De-sarrollo de la Infancia, as como un Plan de Accinconcreto, elaborado por la Convencin sobre los Dere-

chos de la Infancia, emanada a su vez de la Cumbre dela Infancia organizada por Naciones Unidas en 1989, sepuede afirmar como derecho humano bsico de la in-fancia2 que:

1. Todo nio tiene el derecho a una cantidad ade-cuada de yodo en su dieta.

2. Toda madre debe tener una nutricin adecuada de yodo para evitar que el nio tenga un desarrollo men-tal afectado por una carencia de este micronutrienteesencial.

El segundo punto se deriva de la creciente evidenciade que una deficiencia de yodo durante el embarazopuede llevar a concentraciones circulantes de T4 mater-na insuficientes para un desarrollo armnico del cerebrodel feto y el neonato. Las bases cientficas y epidemio-lgicas (que resumimos en un anterior nmero de estaRevista3) han llevado a la Organizacin Mundial de laSalud a declarar que la carencia de yodo es la causamundial ms frecuente de retraso mental y parlisis ce-

G. Morreale de Escobar y F. Escobar del Rey

Instituto de Investigaciones Biomdicas Alberto Sols, CSIC y UAM. Madrid.

(An Esp Pediatr 2000; 53: 1-5)

Correspondencia : Dra. G. Morreale de Escobar. Instituto de Investigaciones Biomdicas Alberto Sols, CSIC y UAM. Arturo Duperier, 4. 28029 Madrid.Correo electrnico: [email protected]


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2 ANALESESPAOLES DEPEDIATRA. VOL. 53, N.o 1, 2000

rebral prevenibles, afectando en mayor o menor gradoel desarrollo y bienestar de unos 1.600 millones de los

actuales habitantes de nuestro planeta. Algunos de ellos viven en Espaa, donde se ha constatado la persistenciade deficiencia de yodo en las 14 comunidades autno-mas en las que se han realizado estudios recientes al res-pecto.

En la tabla 1 aparecen las recomendaciones actualessobre las cantidades mnimas de yodo que se conside-ran necesarias durante diferentes fases de la vida. Lascantidades han ido elevndose a medida que se han idoteniendo datos epidemiolgicos ms precisos, y un co-nocimiento ms completo de las diferencias en la fisio-loga tiroidea a distintas edades. Ntese que las necesi-

dades de yodo de nios prematuros, de neonatos y ni-os pequeos son notablemente ms altas de lo que sededucira, sobre la base de su peso corporal, de las de-finidas para escolares y adultos. En el caso de nios pre-maturos, los preparados humanizados comercializadospara ellos no contenan yodo suficiente, pero en los l-timos aos su contenido se ha ido haciendo ms acordecon los requerimientos4,5.

Tambin han ido aumentando las cantidades reco-mendadas durante el embarazo, a medida que se hancompletado los estudios realizados en Europa. En nues-tro pas, concretamente en la Comunidad Autnoma deMadrid, hemos observado que las embarazadas necesi-tan un suplemento de 250-300 g/da para que puedanalcanzar concentraciones ptimas 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 recomiendaasegurar estas cantidades mnimas mediante la suple-mentacin de la dieta con sal yodada2. En Espaa la le-gislacin contempla la yodacin de sal refinada de me-sa en 60 g I/g sal (60 mg/kg; 60 ppm). El uso habitualde esta sal yodada (que no incluye la sal marina, a noser que el envase especifique que est yodada), parecesuficiente para gran parte de la poblacin. Pero quedan

precisamente excluidos los nios prematuros y lactantes y las mujeres embarazadas, que constituyen la parte dela poblacin ms vulnerable; los primeros tendran queingerir casi 2 g de sal yodada al da, y sus madres 5 g/da.Como esto no ocurre, por las recomendaciones actualesde evitar o restringir el uso de sal en dichos grupos dela poblacin, se impone asegurar las cantidades mnimasde yodo mediante la suplementacin diaria controlada.No habiendo en la farmacopea espaola actual prepara-dos de yoduro o yodato potsico (en forma de tabletas,gotas o grageas) adecuados para ello, hay que recurrir apreparados polivitamnicos y minerales que s lo contie-nen, como Calcinatal, Multicentrum, Superdyne y Micebrina. Cuando la madre ha tomado este suple-mento durante todo el embarazo y sigue tomndolo du-rante la lactancia, su leche contiene las cantidades de

yodo que necesita su hijo, sea o no prematuro. Pero enel caso de no ser posible la lactancia materna, habr que

recurrir a los preparados que estn adecuadamente en-riquecidos con este micronutriente5. No hemos encon-trado informacin sobre el contenido en yodo de los ali-mentos preparados para la alimentacin de los nioscuando dejan la lactancia, por lo que la suplementacinde su dieta con preparados polivitamnicos y mineralespodra resultar aconsejable.

Con frecuencia se expresa el temor de que, cuando laingesta de yodo de la mujer ya era buena antes del em-barazo, una suplementacin de su dieta con 250-300 g/da podra resultar excesiva y daina. No hay base al-guna para tal temor, ya que una ingesta de 1-2 mg diarios

de yodo es frecuente en algunas poblaciones que consu-men algas marinas, como algunas de Japn9, sin efectosnocivos. Medidas de yoduria en embarazadas de Chile,por ejemplo, sugieren ingestas de 500-700 g10, tambinsin efectos negativos. Como ste es un punto de gran im-portancia, la Organizacin Mundial de la Salud encomen-d su estudio a un comit internacional de expertos, decuyas reuniones eman el documento que demuestra queincluso el uso de aceites yodados (p. ej., Lipiodol), utili-zado como medida de urgencia para erradicar la deficien-cia de yodo en pases que no tienen establecida una ade-cuada red de distribucin de sal yodada, est exento deproblemas para la embarazada y el desarrollo de su feto11.Contrasta esto con los graves problemas relacionados conuna ingesta materna deficiente en yodo durante el pero-do de desarrollo fetal (tabla 2)12, problemas que se erra-dican con su utilizacin13,14. Debe tenerse en cuenta que1 ml del aceite yodado empleado habitualmente (Lipio-dol) contiene 380 mg de I (380.000 g!) y las dosis em-pleadas suelen ser de 2 ml, o ms. Aunque se administrede una sola vez, por va oral o intramuscular, y se reten-ga en el msculo y tejido graso, el yodo se va liberandopaulatinamente. Pero, obviamente, lo hace en cantidad su-perior a lo que ingerira una mujer que recibiese 300 g/da durante todo el embarazo y la lactancia (110 mg).

EDITORIAL. G. Morreale de Escobar y F. Escobar del Rey

TABLA 1.Ingestas mnimas de yodo, recomendadasa partir de 19926

Grupo Edad g de I /da

Prematuros > 30 g/kg/da

Nios 0-5 meses 90

6-12 meses 901-3 aos 904-6 aos 907-10 aos 120

Adultos 150Mujeres embarazadas 230*Mujeres lactantes 260*

*Estas son las recomendaciones mnimas en Alemania. Recientemente(despus de 1992) el ICCIDD (International Council for the Control of IodineDeficiency Disorders) ha elevado a 200-300 g/da las ingestas recomendadaspara las embarazadas.


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El yodo durante la gestacin, lactancia y primera infancia

CANTIDADES EXCESIVAS DE YODOSe han descrito casos de grandes bocios en neonatosde madres que usaron sistemticamente compuestos yo-dados durante el embarazo (jarabes yodados para la tos,desinfectantes yodados, etc., que contenan gramos de

yodo)15, o que recibieron contrastes yodados para am-niofetografa16. En algunos casos se produjo la muertepor asfixia. En la mayora de los otros se produjo un blo-queo de la funcin tiroidea del feto y el neonato, cuyosefectos pueden prolongarse durante meses, precisamen-te durante perodos importantes de maduracin cere-bral. Debe tenerse en cuenta que para el desarrollo del

cerebro durante los primeros aos de vida no hay dife-rencia entre un estado de hipotiroidismo permanente y uno transitorio, pues en ambos casos el nio requieretratamiento con T4. En el caso de un bloqueo por yodo,el tratamiento debe prolongarse por lo menos hasta quese haya normalizado la yoduria. Por eso parece muy oportuno el artculo de Arena y Emparanza en este n-mero de la Revista1, pues parece que en muchas con-sultas ginecolgicas y en maternidades espaolas no seha eliminado totalmente el uso de antispticos yodados,como el Betadine, que contiene povidona yodada al10%. Cuando hace dos dcadas se extendieron por todaEspaa los programas para la Deteccin Precoz del Hi-potirodismo Congnito, se advirti a todas las materni-dades sobre los graves inconvenientes del uso de estosantispticos, pero al parecer con el tiempo esto se haido olvidando, encontrndonos en varios congresos re-cientes que muchos de los asistentes no conocan su

prohibicin.Tambin puede ocurrir que la prohibicin s se co-

nozca, pero se haya interpretado errneamente por unainformacin inexacta. En algunos casos, se evita efecti-

vamente el empleo de povidona yodada para desinfec-tar al recin nacido, sobre todo si es prematuro, peroslo hasta despus de tomar la muestra de sangre deltaln que se enva al Centro de Deteccin Precoz de Hi-potiroidismo Congnito, en la creencia errnea de quesu uso falsea las pruebas por causas analticas. A par-tir de ese momento, se utiliza libremente. En realidad,no es que el uso de la povidona yodada falsee las prue-

bas; lo que hace es provocar un estado de hipotiroidis-mo que no exista antes de su aplicacin. Falsea encuanto no se trata de un hipotiroidismo congnito per-manente, sino de uno transitorio. Pero, como se ha in-dicado ms arriba, estos nios requieren tratamientoposnatal con T4 mientras dure el hipotiroidismo, al igualque los nios con hipotiroidismo congnito permanen-te, si queremos evitar los dficit mentales permanentesque acompaan al hipotiroidismo perinatal tratado tar-damente.

Este efecto nocivo de los desinfectantes yodados ad-ministrados a la madre y/o al recin nacido se debe aque en la glndula tiroides del feto y en la del neonatoan no han madurado plenamente los mecanismos deautorregulacin tiroidea17, que en el adulto permitenobviar los riesgos de una produccin excesiva de hor-monas tiroideas al producir un aumento la cantidad de

yodo disponible.En el individuo adulto sin patologa tiroidea subya-

cente, el exceso de yodo no produce un bloqueo pro-longado de la funcin tiroidea, ya que se han desarro-llado mecanismos de escape que se vuelven operati-

vos antes de que disminuyan las concentraciones deT4 y T3 por debajo de las normales. No se conocebien cmo se ponen en marcha dichos mecanismos

TABLA 2.Espectro de disfunciones por dficit de yodo(tanto ms graves cuanto mayor es ladeficiencia de yodo, y cuanto antes se padece)

Perodo en quese padece la Consecuencias principalesdeficiencia de yodo

Feto Mayor nmero de abortosNacidos muertos

Anomalas congnitasMayor mortalidad perinatalMayor mortalidad infantilCretinismo neurolgico

Deficiencia mentalSordomudezDipleja, tetrapleja espsticaEstrabismo

Cretinismo mixedematosoEnanismoDeficiencia mental

Retraso mental de los habitantesaparentemente normales

Mayor susceptibilidad en casode accidentes nucleares*

Recin nacidos Defectos psicomotoresBocio neonatalHipotiroidismo neonatalMayor susceptibilidad en caso

de accidentes nucleares*

Nios y Bocioadolescentes Hipotiroidismo juvenil

Deterioro de las facultades mentalesRetraso en el desarrollo somticoMayor susceptibilidad en caso

de accidentes nucleares*

Adultos Bocio y sus complicacionesHipotiroidismoDeterioro de las facultades mentalesHipotiroidismo por carencia de yodoMayor susceptibilidad en caso

de accidentes nucleares*Propensin a hipertiroidismo al

instaurarse medidas profilcticas

*Se debe a una mayor avidez de la glndula deficiente en yodo paraconcentrarlo, incluidos los istopos radiactivos del mismo, que son liberadosen grandes cantidades durante los accidentes nucleares.Toda la patologa tiroidea, incluido el cncer de tiroides, est aumentada enlas zonas de deficiencia de yodo, y a todas las edades.


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4 ANALESESPAOLES DEPEDIATRA. VOL. 53, N.o 1, 2000

EDITORIAL. G. Morreale de Escobar y F. Escobar del Rey

de escape, pero s se sabe que an no son plena-mente operativos en el recin nacido, y lo son tantomenos cuanto menor sea su edad gestacional. ste esel motivo de la gran frecuencia con que se bloquea laglndula tiroidea del nio prematuro, al enfrentarse a

cantidades de yodo que son toleradas perfectamentepor un adulto.El riesgo de un bloqueo de la glndula del neonato no

slo aumenta en el caso de que haya nacido prematu-ramente, sino que depende tambin en gran medida dela ingesta de yodo materna. Cuando sta ha sido insufi-ciente, el aclaramiento de yoduro por la glndula tiroi-des del nio, as como su tamao, aumentan rpida-mente y de forma considerable. Pero al volver a llegar

yodo en cantidades adecuadas, o altas, no disminuyerpidamente la excesiva vascularizacin de la glndula,ni la captacin aumentada de yodo. Hay un desfase tem-poral importante, por lo que al llegarle una cantidad ex-cesiva de yodo, la glndula acumula una proporcinmayor que en el caso de un recin nacido sin carenciaanterior de yodo. Esto contribuye a que se observe unbloqueo de la glndula con dosis de yodo que no re-sultan excesivas cuando la poblacin est bien nutrida.Los efectos bloqueadores del yodo se ven potenciadoscuando se superponen una cierta deficiencia de yodo y la inmadurez de la glndula del prematuro. Por eso, enmuchos pases europeos (Espaa incluida) el hipotiroi-dismo neonatal por exceso de yodo es mucho ms fre-cuente que en Japn y en los Estados Unidos, donde laingesta de yodo de la poblacin es ms alta.

Esta llamada de atencin sobre los peligros de un ex-ceso iatrognico de yodo durante el embarazo y el pe-rodo posnatal no debe, en manera alguna, utilizarse co-mo justificacin para dejar de instaurar medidas profi-lcticas que eviten la carencia de yodo durante eldesarrollo fetal y posnatal.

Siempre debe tenerse en cuenta la gran diferenciaexistente entre las cantidades mnimas necesarias y lascantidades de yodo potencialmente nocivas. Considre-se que las cantidades mnimas necesarias se expresan encientos de g de yodo (200-300 g en la embarazada).La cantidad de povidona yodada en 1 ml de Betadinees de 100 mg (!!), lo que equivale a unos 100.000 g. Encualquier aplicacin de povidona yodada se emplea un

volumen de desinfectante muy superior a 1 ml. Lo mis-mo ocurre cuando se usan contrastes yodados (tabla 3).

Cualquier neonato, sobre todo si es prematuro, queinevitablemente tiene que someterse a pruebas diagns-

ticas o quirrgicas que hagan imprescindible la adminis-tracin de contrastes yodados, puede padecer un blo-queo de la funcin tiroidea como consecuencia de la in-tervencin, y entrar en un estado de hipotiroidismo. Poreso, y por el frecuente retraso en el pleno funciona-miento de los mecanismos de retroalimentacin negati-

va hipfisis-tiroides caractersticos de esa edad, se reco-mienda que no slo se enven al Centro de DeteccinPrecoz de Hipotiroidismo Congnito las muestras desangre tomadas a los pocos das del nacimiento, sino ca-da vez que se hayan administrado contrastes yodados.No debe darse el alta al paciente sin tener pruebas bio-

qumicas de que no padece hipotiroidismo, aunque seaadquirido y transitorio.Las cantidades de yodo de la mayora de los contras-

tes yodados son incluso superiores a las mencionadaspara la povidona yodada (tabla 3). A veces no se tieneconciencia de que el recin nacido est recibiendo estasobredosis: la mera insercin de catteres (no radioopa-cos) para alimentacin parenteral conlleva la inyeccinde contraste en cantidades muy pequeas, pero sufi-cientes para bloquear la funcin tiroidea18, por lo quedeben sustituirse por catteres radioopacos.

En resumen, en el caso de la mujer embarazada, ellactante y el neonato (sea ste prematuro o a trmino),hay que tener presente que:

1. Tienen derecho a que se le asegure el yodo nece-sario para el desarrollo ptimo de su cerebro.

2. Es sumamente improbable que reciba un excesonocivo de yodo a travs de la alimentacin y el uso desuplementos polivitamnicos y minerales que lo con-tengan.

3. Puede ser el personal sanitario el primer responsa-ble de que se vean expuestos a dosis excesivas, queprovienen siempre del uso de diferentes medicamentos,desinfectantes yodados y contrastes radiolgicos.

TABLA 3.Concentracin de yodo en diferentesmedicamentos, desinfectantes y contrastesradiolgicos de uso muy extendido,y de 1 g de sal yodada

ContenidoContenido en yodo

en yodo frente a 150 g /da*

Sal yodada 60 g/1 g 0,4 x Amiodarona 7.500 g/ 50 x

comprimidoDesinfectantes

Solucin de Lugol 126.000 g/ml 840 xBetadine (povidona

yodada) 10.000 g/ml 67 x Yoduro sdico al 10% 85.000 g/ml 570 x Vioformo/clioquinol 12.000 g/ml 80 xEnterovioformo 120.000 g/ 800 x

comprimidoContrastes radiolgicos

Hexabrix 320.000 g/ml 2.100 x

Oragrafin 308.000 g/ 2.050 xcpsula

Lipiodol 380.000 g/ml 2.500 xRenografin 370.000 g/ml 2.500 xTelepaque 333.000 g/ml 2.200 x

*150 mg/da suele ser la ingesta diaria mnima considerada adecuada parajvenes y adultos, excluyendo mujeres embarazadas y lactantes.


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11. WHO. Iodized oil during pregnancy. Safe use of iodized oilto prevent iodine deficiency in pregnant women: a WHO sta-tement. Bull WHO 1996; 74: 1-3.

12. Hetzel BS. Historical development of concepts of brain-thy-roid relationships. En: Stanbury JB, editor. The damagedbrain of iodine deficiency. Elmsford, NY: Cognizant Commu-nication Co., 1994; 1-8.

13. Pharoah POD, Buttfield IH, Hetzel BS. Neurological damageto the fetus resulting from severe iodine deficiency duringpregnancy. Lancet 1971; 13: 308-311.

14. Pretell EA, Cceres A. Impairment of mental development by iodine deficiency and its correction. A retrospective viewfrom studies in Peru. En: Stanbury JB, editor. The damagedbrain of iodine deficiency. Elmsford, NY: Cognizant Commu-nication Co., 1994; 187-192.

15. Carswell F, Kerr MM, Hutchison JH. Congenital goitre and hy-pothyroidism produced by maternal ingestion of iodides.Lancet 1970; 13: 1242-1247.

16. Rodesh F, Camus M, Ermans AM, Dodion J, Delange F. Ad- verse 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: De-lange F, Fisher DA, Malvoux P, editores. Pediatric thyroido-logy. Basilea: S Karger AG, 1985; 14: 369-393.

18. Ares S, Pastor I, Quero J, Morreale de Escobar G. Thyroidcomplications, including overt hypothyroidism, related to theuse of non-radiopaque silastic catheters for parenteral fee-ding in prematures requiring injection of small amounts of aniodinated contrast medium. Acta paediatr 1995; 84: 579-581.


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Role of thyroid hormone during early brain developmentGabriella Morreale de Escobar, Mar a Jesus Obrego n and Francisco Escobar del ReyInstituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Cientcas (CSIC) y Universidad Autonoma de Madrid (UAM),Arturo Duperier, 4, 28029-Madrid, Spain

(Correspondence should be addressed to G Morreale de Escobar; Email: [email protected])

AbstractThe present comments are restricted to the role of maternal thyroid hormone on early brain develop-ment, and are based mostly on information presently available for the human fetal brain. It emphasizesthat maternal hypothyroxinemia dened as thyroxine (T4) concentrations that are low for the stageof pregnancy is potentially damaging for neurodevelopment of the fetus throughout pregnancy, butespecially so before midgestation, as the mother is then the only source of T4 for the developing brain.Despite a highly efcient uterineplacental barrier to their transfer, very small amounts of T4 and

triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks afterconception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal uids is notprotein-bound: the free T4 (FT4) available to fetal tissues is determined by the maternal serum T4,and reaches concentrations known to be of biological signicance in adults. Despite very low T3and free T3 (FT3) in fetal uids, the T3 generated locally from T4 in the cerebral cortex reachesadult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental resultsin the rat strongly support the conclusion that thyroid hormone is already required for normal corti-cogenesis very early in pregnancy.The rst trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by theconceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substratefor the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unableto increase their production of T4 early in pregnancy would constitute a population at risk for neuro-logical disabilities in their children. As mildmoderate iodine deciency is still the most widespreadcause of maternal hypothyroxinemia in Western societies, the birth of many children with learningdisabilities 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 U25U37

Introduction

The association between alterations of thyroid functionearly after birth and neurodevelopmental disorders hasbeen recognized for more than a century. For manyyears of the 20th century there has been, however,less consensus regarding the stage during fetal lifewhen thyroid hormone becomes necessary for normal

brain development (more extensively reviewed by us in(1 4)).This has mostly been due to opposing viewsregarding the importance of maternal thyroidhormones for the fetus. On the one hand, those whohad personal eld experience of iodine-deciencydisorders (IDDs) were convinced of its importance,because the severity of the central nervous system(CNS) damage of the progeny was related to thedegree of maternal thyroxine (T4) deciency and couldonly be prevented when the latter was corrected beforemidgestation. On the other hand, Western-trained phys-icians usually adhered to the idea that maternal thyroidhormones did not play a role in early neurodevelop-ment, an idea apparently supported by the goodresults obtained with prompt treatment of congenital

hypothyroidism (CH). This success was interpreted asproof that the developing fetal brain did not need thyroidhormone until after birth. The idea that the maternalthyroid hormones were of little relevance for the earlyfetal brain was reinforced by the increasing evidenceof the existence of an efcient uteroplacental barrierthat prevented the transfer of maternal thyroidhormones into the fetal compartment in amounts

that could be physiologically relevant. The importanceof an adequate provision of thyroid hormones forbrain development during later phases of pregnancywas, however, increasingly accepted when thetransfer of maternal T4 up to birth was shown in man(5) and its possible protective role in cases of CH wasrecognized (6).

Despite the increasing awareness that thyroid hor-mone is already required for normal brain developmentduring fetal life, the general consensus as late as 1999was summarized by Utiger (7): Thyroid deciencyduring the latter two thirds of gestation and the rstmonths after delivery can result in mental retardationand sometimes neurological decits. Whether thyroidhormone is needed during the rst 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 themany severe neurological defects found in childrenborn to iodine-decient mothers that require adequateintervention before midgestation for their prevention,and that do not occur in untreated CH infants. In thepresent contribution we will try to summarize what isknown, and what is still unknown, regarding earlyfetal thyroid hormone physiology and its dependenceon 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 beenprompted by previous ndings in experimental animalmodels, especially in rats. There is an important simi-larity between man and rat with respect to placent-ation, which is hemochorial in both species. Thereare, however, major differences between human andrat brain development if we take birth as the point of reference, because the rat is born at a less maturestage, the newborn pup being comparable to ahuman fetus nearing the third trimester. Conversely,the human newborn might be compared with a 2- to3-week-old rat pup, but with a very important differ-ence that is often forgotten when postnatal ndings inhypothyroid rat models are extrapolated to the third tri-mester human CH fetus. In man development of thefetal brain may still be protected by the transfer of maternal T4 during a period of development whenthe rat is deprived of this potential benet, as rat milkdoes not contain thyroid hormone in relevant amounts.

Valid comparisons may, however, be made by usingthe onset of active fetal thyroid function (FTF) as themilestone for comparisons. This coincides in bothspecies with full maturation of the pituitary portalvessels, and occurs at E17.5-18 in the rat (with E0being 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 3640 weeks PMA. Thus, most of thecomparisons between both species will be restrictedto development and maternal fetal interrelationsbefore FTF, unless stated otherwise. Findings relevantto the present topic are very briey summarized here.For pertinent detailed references, see Table 3 in aprevious review (1). References are mostly restrictedto more recent studies.

T4 and triiodothyronine (T3) of maternal origin arepresent, albeit at very low concentrations, in veryearly rat embryonic and fetal tissues, brain included,before onset of FTF, their concentrations being directlyinuenced by those in the maternal circulation,especially those of T4. Thyroid hormone receptor (TR)isoforms are already present in the brain at neural

tube closure and are likely to mediate biological effectsof the T3 that has been locally generated from T4 trans-

ferred from the mother. Therefore, if the mother ishypothyroxinemic, the brain of a hypothyroid ratfetus is T3-decient, even if maternal and fetal T3 arenormal, because during early development, serum-derived T3 hardly contributes to cerebral T3 (6).Important phases of the development of the neocortexare altered by a period of maternal hypothyroxinemiapreceding onset of FTF (8, 9), showing directly thatthyroid hormone of maternal origin is important forneurodevelopment.

If such experimental ndings were relevant for man,they would explain why in most cases of CH there isno permanent severe CNS damage when T4 is suppliedstarting soon after birth. Most fetuses with CH have a

normal mother, supplying enough T4 to the developingbrain throughout gestation to preferentially avoid cer-ebral T3 deciency. As a result, the fetal brain has notbeen severely damaged before birth, and its normaldevelopment can still be achieved by prompt postnataltreatment with T4. They would also explain the irre-versible damage caused by an insufcient supply of T4during early development, when the mother is theonly source of hormone to the brain. The more severedamage would be expected to occur when both themother and fetus are hypothyroxinemic throughoutpregnancy, as occurs in iodine-decient environments,and as increasingly conrmed by case reports (14, 10).

Thyroid hormones and their nuclearreceptors in the human fetal brain

As already indicated, during most of the second half of the 20th century the prevailing idea was that the earlyembryo actually developed in the absence of thyroidhormones. Supporting this conclusion was the evidenceof a placental barrier system that drastically limitedtheir transfer from the mother. Recent informationhas conrmed the widespread distribution, mostly of deiodinases D2 and D3, in the utero placental unitand the expression of D3 in fetal epithelia (11 14).

As in experimental animals, the existence of an activebarrier, however, does not necessarily exclude that someiodothyronines of maternal origin actually do reachfetal tissues, and we shall briey summarize the existingevidence, mostly as pertaining to the brain. Most of theexperimental ndings in the rat models, are being con-rmed 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 develop-ment of adequate extraction methods that permittedtheir purication and determination by sensitive andspecic RIAs. Most commercially available methods

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that have been developed for human sera are notadequate for the very low concentrations found up to

midgestation in human fetal serum. Commercial kitsfor the estimation of free T4 (FT4) are even less ade-quate, because of the great qualitative and quantitativedifferences in the composition of T4-binding proteinsbetween fetal uids and adult serum.

During the 1980s, T4 and T3 were measured intissue extracts from cerebral cortex, liver and lung of 8 18 week PMA human fetuses, using improvedspecic and highly sensitive RIAs (15 17). In liver,lung and heart, only T4 was found during the secondtrimester, although T3 could be demonstrated at some-what earlier ages in lung nuclear extracts. T3 wasquantied in puried extracts from human fetal brain,however, as early as 910 weeks PMA, and increased

steadily up to 18 weeks PMA, despite the fact thatduring this period plasma T3 was undetectable and, 10% of adult values. By midgestation the concen-tration of T3 in the fetal brain reached 34% of adultvalues, much higher than would have been inferredfrom their very low circulating T3.

Another important methodological improvement wasthe development of transvaginal ultrasound-guidedpuncture of the embryonic cavities (Fig. 1) to obtain

samples from the fetal compartment without severingvascular connections with the mother. This procedure,

combined with specic and sensitive RIAs, disclosedimportant new information regarding fetal thyroidhormones early in pregnancy (18). T4, T3 and reverseT3 (rT3) were found in the rst trimester coelomicand amniotic uids from 5.811 weeks PMA (3.89weeks postconceptional age) (Fig. 2). The T4 concen-trations in the coelomic uid were positively correlatedwith the maternal circulating concentrations, butwere , 1% of the maternal values. T3 was at least10-fold lower than T4, with rT3 being clearly higherthan T4, ndings that conrmed the high D3 activitiesof the placental barrier and fetal epithelia. Concen-trations in the coelomic uid were higher than in theamniotic compartment. Because of the minute amounts

of the iodothyronines found in these uids, their possiblebiological signicance was often questioned.

The results were essentially conrmed and extendedin a second study (19) where transvaginal ultra-sound-guided puncture of these cavities and of fetalblood was performed up to 17 weeks PMA. A specicmethodology was developed for the determination of FT4. We conrmed the previous observation (18) thatT4 in fetal uids is more than 100-fold lower than in

Figure 1 Schematic representation of the maternalfetal unit during the 1st (A) and 2nd (B) trimesters of pregnancy. (A) The humanfetus is surrounded by two distinct uid cavities separated from each other by a thin membrane: the inner, or amniotic cavity (AC) con-tains the fetus and the outer, or exocoelomic cavity (ECC), separates the amniotic cavity from the placenta and contains the secondaryyolk sac (SYS). The latter is directly connected to the fetal digestive tract and circulation. The ECC is the site of important molecularexchanges between the mother and the fetus and contains the coelomic uid (CF) that results from an ultraltrate of maternal serumwith the addition of specic placental and SYS bioproducts. The ECC is a physiological liquid extension of the early placenta (P) andacts as a reservoir for nutrients needed by the developing fetus. There is no direct vascular connection between the mother and theumbilical 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 placentalmass degenerate and the ECC is progressively obliterated by the growing AC containing the amniotic uid (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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maternal serum, with T3 being even lower. The newnding was that this great difference between the

maternal and fetal concentrations of total T4 mightbe misleading with respect to their potential biologicalsignicance, because the proportion of T4 that is notbound to proteins is so much higher than in adultsera that the concentrations of T4 actually availableto developing tissues, namely those of FT4, reachvalues which are comparable to those known to bebiologically active in their mothers (Fig. 2B).

The FT4 levels in the fetal uids are dened by theconcentrations of T4-binding proteins and the concen-trations of maternal T4 or FT4 that have escaped theplacental barrier. The T4-binding capacity of the pro-teins in fetal uids is determined ontogenically, is inde-pendent of the maternal thyroid status, and is far in

excess of the amounts of total T4 that reach the fetaluids. Thus, the availability of FT4 for embryonic andfetal tissues is ultimately determined by the maternalcirculating T4 or FT4 and would decrease in hypothyr-oxinemic women, even if they are clinically euthyroid.The results explained why an efcient barrier tomaternal thyroid hormone transfer is actually necess-ary. If total T4 and T3 reached the same concentrationsin fetal uids as those in the maternal serum, the devel-oping tissues would be exposed to inappropriately high,and possibly toxic, concentrations of FT4 and free T3(FT3). An inordinately high FT4 and/or FT3 couldresult in adverse effects on the timely sequence of thyroid hormone-sensitive developmental events inthe human fetus, as recently conrmed (20).

That thyroid hormone-sensitive developmentalevents may already occur before midgestation andonset of FTF is supported by the early presence of nuclear TRs in the human fetal brain. These weredetected in the earliest samples of the cerebral cortex(9 weeks PMA) studied by Bernal & Pekonen (15)with their concentration increasing at least 10-fold by18 weeks. Despite the very low fetal serum concen-trations of T3, the occupation of the TRs by thisiodothyronine was 25 30% throughout the studyperiod (1517), strongly suggesting that biologicaleffects of the hormone might already be occurring in

the cerebral cortex during the rst trimester of human pregnancy. A recent study (21) has conrmedthe early expression of TR gene isoforms and relatedsplice variants in the whole fetal brain studied between8.1 and 13.9 weeks PMA. Expression of the TR b 1,TRr a 1 and c-erbA a 2 isoforms was detected in the 8.1week brain sample, with TR a 1 being the predominantform in early development, increasing steadily up to13.9 weeks; so did the c-erbA a 2 isoform. TR b 1expression appeared to present a more complex onto-genic pattern. The authors moreover point out thatthe repressor activity of un-liganded Tr a 1 on basalgene transcription may also become relevant whenthe maternal supply of hormone decreases: a decreasein the amount of T3 available for receptor binding

Figure 2 (A) Changes in concentrations of total T4 and FT4 infetal uids up to midgestation, as a function of maternal serum T4values, which were within the normal range (18). (B) Concen-trations of total and FT4, as a function of postmenstrual age, infetal coelomic uid (CF), amniotic uid (AF), fetal blood (F-B) andmaternal blood (M-B). The ordinates in both panels are on alogarithmic scale, in order to better visualize the similarity of theFT4 concentrations in fetal uids to those in the correspondingmother, whereas there is a greater than 100-fold difference in theT4 concentrations (data from (19)). For both (A) and (B) the fetaluids were obtained without severing maternal to fetal vascularconnections.


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would increase the proportion of the un-liganded iso-form 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 nowbeen studied (22) in nine different cerebral areas fromfetuses of 13 20 weeks PMA, when fetal serum T4increased signicantly from about 3 to 15 pmol/ml,whereas T3 did not correlate with PMA and remainedat about 0.5pmol/ml throughout the same develop-mental period (19). The ontogenic proles of theconcentrations of the iodothyronines in the differentareas of the brain, and of their D2 and D3 activities,showed both spatial and temporal specicity, but withdivergence in the cerebral cortex as compared withother brain areas (Fig.3). In thecortexthe concentration

of T4 was increasing with PMA, as expected fromthe increase in fetal serum T4. But, in contrast withthe very low and practically constant circulating levels,T3 increased signicantly with PMA in the cortexbetween 13 and 20 weeks PMA to levels comparable tothose reported in adults (2.5 pmol/g). These ndingsshow that in the human cerebral cortex T3 is also gener-ated locally from T4, and is hardly inuenced bycirculating T3. Considerable D2 activity was indeedfound in the human cerebral cortex, whereas D3 activitywas very low. In contrast, cerebellar D3 activities werevery high until midgestation, and T3 was very low,only increasing after midgestation, when D3 activitywas decreasing. Other regions with high D3 activities(midbrain, basal ganglia, brain stem, spinal cord,

hippocampus)also hadlow T3 concentrations up to mid-gestation. The study (22) supports the hypothesis that

T3 is indeed required by the human cerebral cortexbefore midgestation, when the mother is the onlysource of the FT4 that is available to the fetal tissues. Itconrms the important roles of D2 and D3 in the localbioavailability of cerebral T3 during fetal life; D2 gener-ates T3 from T4 and D3 protects different brain regionsfrom an untimely, or excessive, T3 until this hormoneis required for differentiation.

We do not, however, have precise information onthe stage of human brain development when down-regulation of D2 expression and/or activity mightcontribute to T3 bioavailability in conditions of maternal or fetal hypothyroxinemia; if down-regulationis delayed with respect to the onset of its expression, a

decrease in maternal T4 would ultimately result in alower intracellular concentration of T3 (4).

Between midgestation and birth

There is a dearth of information on the ontogenicpatterns of thyroid hormone concentrations andiodothyronine deiodinase expression and/or activitiesin different fetal tissues during the second half of pregnancy. Studies performed so far have relied onautopsy material of babies who died of differentcauses and at variable intervals after a prematurebirth, and results are subject to many confounding fac-tors other than their PMA. The most important onesare 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-handpanels) and cerebellum (right-hand panels) up to midgestation when the mother is the only source of thyroid hormone for the developingfetus (data from (22)). During this period T4 in the fetal serum increases about 5-fold, from 3 to 15 pmol/ml, whereas circulating T3remains very low, about 0.5pmol/ml (equivalent to 0.5 pmol/g), and does not increase with PMA (19). D3 activities are very high in thecerebellum throughout this period.

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maternal supply of T4 and the sudden major decreasein circulating thyrotropin (TSH). For this reason such

studies will not be included here. We will only summar-ize what is known regarding thyroid hormones andrelated indices of fetal thyroid physiology that havebeen obtained in utero and in vivo, restricting ourknowledge to data obtained from serum samples.

For many years most diagrams (23) describing onto-genic patterns of changes in fetal circulating levels of T4, T3, rT3, TSH, T4-binding globulin (TBG) etc. hadbeen derived from premature babies, after interruptionof maternal connections. Early in the 1990s, however,ultrasound-guided blood sampling from the umbilicalcord and the heart was used to obtain fetal samplesbetween 12 and 37 weeks PMA (24, 25) (Fig. 4). Someof thepatterns previously described(23) fordifferent par-

ameters of FTF were conrmed: T3 and FT3 were verylow throughout fetal life, as compared with those inboth the maternal serum and in the adult population.In striking contrast, however, both T4 and FT4 increasedsteadily with fetal age, and reached maternal and adultconcentrations by the beginning of the third trimester(25). Contrasting with previous reports of a negativefeed-back between the fetal thyroid and the hypothala-mic pituitary system during the third trimester,Thorpe-Beeston et al. (25) found that FT4 and TSHwere both increasing until birth.

An even greater discrepancy concerned the intrau-terine fetal levels of TSH that were much higher thanmaternal and adult values throughout the studyperiod, a nding conrmed in our later study (19).This was in conceptual agreement with reports that inboth normal and anencephalic fetuses, TSH bioactivityis greatly increased with respect to that circulating inthe mothers, conrming that fetal serum TSH is neitherof maternal origin, under hypothalamic neuroendo-crine control, nor under negative feed-back control bythyroid hormones, whether of maternal or fetal origin(26). Fetal TSH levels are already high well before fullmaturation of hypothalamic pituitary connections atmidgestation. This poses unanswered questions regard-ing its origin; synthesis of TSH by the rat and monkeybrain have been reported (27). More recently, a TSH

receptor has been found in early human fetal brainand human astrocytes in primary culture (28). Thisreceptor mediates extrathyroidal cAMP-independentbiological effects of TSH, among which is, quite inter-estingly, the stimulation of D2 in astroglial cells. Thepossible cAMP-independent extrathyroidal actions of TSH throughout human fetal development are mostintriguing, especially if acting in brain development asa growth factor. Equally intriguing is why the highintrauterine TSH concentrations plummet with birth.Sudden severance from the placenta might be playinga role, as the placenta produces high amounts of thyrotropin-releasing hormone-like peptides thatmight be stimulating extrapituitary synthesis of TSHor TSH-like proteins.

Fetal circulating T4 and FT4 are already increasingsteadily in utero before the fetal thyroid is likely to beable to maintain such concentrations when deprived

Figure 4 (AC) The ontogenic changes in different parametersof thyroid hormone status from 12 weeks PMA until birth,obtained in vivo by cordocentesis, without interfering with thenormal connections between mother and conceptus. Theshaded areas enclose the values reported by Thorpe-Beestonet al. (25). (A and B) Show that fetal serum FT4 values reachmaternal concentrations shortly after midgestation, whereasthose of FT3 are low throughout pregnancy. (C) Draws attentionto the very high levels of fetal TSH, most of which were higherthan those of the mother. (A) Also shows the FT4 levels foundin sera from premature babies ( B , preterm) (30, 31) as com-pared with those in utero (25).


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of the maternal contribution; the degree of iodinationof thyroglobulin (Tg) and its T4 and T3 contents are

very poor before 42 weeks PMA (29). This lack of fullmaturation of the fetal thyroid would contribute signi-cantly to the neonatal hypothyroxinemia of prematureinfants, a possibility that is strongly supported whenserum FT4 concentrations of such infants are plottedas a function of PMA and superimposed on the patternfound for age-paired living fetuses that are still in utero(Fig. 4) (30, 31). Such observations imply that themother continues to contribute signicantly to fetalcirculating T4 and FT4 until birth, as described forexperimental animals.

That the transfer of maternal T4 to the fetus con-tinues until the umbilical cord is severed was conclus-ively shown in 1989 by Vulsma et al. (5) who foundconcentrations of T4 in cord blood of seven neonateswith complete organication defect, namely, a completeinability to iodinate proteins and, therefore, to syn-thesize the iodinated hormones. These concentrationsvaried between 35 and 70 nmol/l, values that areabout 30 60% of the mean concentrations reachedby the normal fetus at term, 109 nmol/l (25). Inhypothyroid rat fetuses, serum T4 concentrationsranging between 30 and 60% of normal, togetherwith the compensatory increase of D2 activity in thebrain, would be enough to preferentially avoid cerebralT3 deciency (6). Extrapolation of the latter ndings tothe human CH fetus suggests that after midgestationthe down-regulation of cerebral D2 is also operativein the human brain, and has contributed to protect itfrom major CNS damage until birth.

Summarizing

Results so far conrm for the human developing brainthe same principles that appear to modulate T3bioavailability in different developing structures inmany species, in a temporally and spatially specicsequence of events, namely by the ontogenetically pro-grammed expression of the iodothyronine deiodinaseiso-enzymes, mainly D2 and D3. We have less informationregarding mechanisms other than those involving the

iodothyronine deiodinase isoforms that might also playimportant roles in tailoring T3 bioavailability to chan-ging needs of developing human brain structures.

Thus, both T4 and T3 are present in humanembryonic and fetal uids, with the FT4 reachingconcentrations that are known to be biologically rel-evant in adults. The FT4 concentrations in theseuids are, moreover, directly dependent on thematernal T4 supply, and so is the FT4 available tofetal tissues, including the brain. It appears plausibleto conclude that the lower the maternal T4 early inpregnancy, the lower the FT4 available to the fetalcortex and, presumably, the lower the amounts of T3available for binding to cerebral TRs exerting biologicaleffects. It is important to realize that this could already

occur with maternal circulating levels that are stillwithin the normal reference range for adults (Fig. 2).

Although valuable new insights have been obtainedregarding the ontogenic patterns of change of cerebralthyroid hormone concentrations, their nuclear recep-tors, and the roles of the deiodinating isoenzymes intailoring the bioavailability of T3 to the developmentalrequirements of different cerebral structures, it is likelythat we are still quite far from understanding all themechanisms that may be involved, and their inter-relationships. As summarized recently in somewhatmore detail (4), little is known regarding the roles, indetermining the availability of circulating T4 to thefetal brain, of the activities of the deiodinating enzymeisoforms in other fetal tissues, as well as those of the sul-fotransferases, glucuronidases and sulfatases, and of

recently identied specic iodothyronine plasma mem-brane transporters into, and out of, the fetal brain.We have already remarked (4) upon our ignorancewith respect to a possible developmental role of thehigh levels of TSH throughout gestation, as well asthe cause for their rapid decrease after prematurebirth. We still have insufcient information regardingthe capacity of the fetal thyroid to meet the needs of thenewborn preterm infant faced with the untimely inter-ruption of the maternal supply of hormone. Mainlyfor this reason, effecti

clubdelateta ref 330 yodo y lactancia 1 0

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