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

I 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. This
paper reevaluates the iodine requirements dur-
ing pregnancy, lactation and the neonatal period
and 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 and
critical review of the literature on thyroid
physiopathology during the perinatal period, the
following proposals are made: the iodine re-
quirements 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 dur-
ing these three periods should be in the range
150-230 µg/L. These figures are higher than those
recommended so far by international agencies.
Key Words: Iodine, Nutrition, Pregnancy, Lacta-
tion, Neonatal Period, Median urinary iodine
Introduction
The thyroid economy undergoes a series of
metabolic changes during pregnancy and lac-
tation.1-4 One of the factors involved in these
Correspondence: Professor François Delange, MD,
PhD, 153, avenue de la Fauconnerie B-1170, Brus-
sels, Belgium
E-mail: fdelange@ulb.ac.be
changes is the increased requirement of io-
dine in the mother due to the transfer of thy-
roxine (T4) and of iodide from mother to fe-
tus 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 re-
garding the median concentrations of urinary
iodine indicating optimal iodine nutrition
during these critical periods of life.
Requirement of Iodine During
Pregnancy 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 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.
2 F. Delange
Because of these three factors, the recom-
mended dietary intake of iodine during preg-
nancy 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 in-
crease 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 recom-
mend 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 fe-
tus
The transfer of T4 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 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 con-
tent of the fetal thyroid increases progres-
sively from less than 2 µg at 17 weeks of ges-
tation19 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 hypo-
thyroid 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
International Journal of Endocrinology and Metabolism
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-pregnant
women and in the general population, irre-
spective 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 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 population
reported in this study as Switzerland is
known to be iodine sufficient.37 On the con-
trary, some studies showed that urinary io-
dine decreases during gestation.38-40 It thus
appears 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 data
are available on the possible storage and loss
of iodide in the placenta itself.
Taking all these variables into considera-
tion, 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 preg-
nancy.
 Perinatal iodine nutrition 3

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 n S/C Pregnant women Country General n S/C Pregnant women
population Trimester Urinary population Trimester Urinary
or controls iodine or controls iodine
Countries with no iodine deficiency UK33 73† - C 1 125†
Chile31 - 19 S 1 594* - C 2 170
2 469 - C 3 147
3 786 France40 50-80* 306 S 1 50†
3 months PP 459 224 S 3 54
Iran43 193-312† 403 C 1-3 186-338† Belgium38 50-75* 334 C 1-2 50†
Sweden77 - 51 S 1 180* 334 C 2-3 45
51 S 2 170 136 C 1 56†
51 S 3 145 133 C 2 50
Srilanka33 147† - C 1 181† 49 C 3 50
- C 2 136 Denmark83 50* 26 S 2 51†
- C 3 154 26 S 3 40
USA78 130 290 C 1-3 148 26 S 1 week PP 30
Switzerland35 115† 511 C 2,3 138† 26 S 26 weeks 50
(2000) PP
Scotland79 138† 433 C 1 137† 26 S 52 weeks 58
Switzerland36 91‡ 153 C 1-3 205* PP
(1992) Denmark84 - C 5 days PP 40‡
31 C 1 267 Sudan55 76† 47 S 3 38†
56 C 2 206 47 S 3 months PP 51
66 C 3 172 47 S 6 months 30
15 S 1 325 PP
15 S 2 166 47 S 9 months 63
15 S 3 183 PP
Iodine deficient countries New Zealand
49
24-47* 35 S Monthly 24-52*
Singapore34,80 98† 253 C 3 124† during
230 S 1 107† pregnancy
- 2 116 and 3, 6
- 3 124 and 12
- 6 weeks PP 105 months PP
- 3 months PP 104 Italy85 Marginal 67 C 1,2 74‡
54,81
Sicily (Italy) 46* 10 S 1,2,3 33* (2002) ID
Turkey82 85* 80 S 1-3 91* Italy86 Marginal 18 C 3 50*
32,33
Ireland 70† 38 S 1 135† (1991) ID
38 S 2 125 Germany87 Mild ID 70 S 1 55‡
38 S 3 122 70 S 11 days PP 50
108 C 6 weeks PP 70 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 µg/L = 0.78 µmol/L
* µg/day; † µg/L; ‡ µg/g creatinine

International Journal of Endocrinology and Metabolism

4 F. Delange

Table 2. Selective examples of the iodine con- µg/day. Consequently, the iodine requirement
tent of breastmilk * during lactation is estimated at 225 to 350
µg/day. The slight difference, if any, as com-
Countries Medians or means (µg/L) pared to the figure of 290 µg/day recom-
No iodine deficiency mended by IOM12 results from more recent
Korea 892 data on the iodine content of breast milk.41,42
Japan 661
33-385
USA 146 Level of Urinary Iodine Indicating
168
124 Optimal Iodine Nutrition During
145 Pregnancy and Lactation
145 Considering that most (above 90%) of the
Sweden 93 iodine absorbed in the body eventually ap-
90 pears in the urine, urinary iodine excretion is
70 a good marker of a very recent dietary iodine
Switzerland 78 intake.11 Therefore, a median urinary iodine
Mild to moderate iodine deficiency in the general population varying from 100 to
Germany 93
199 µg/L is considered as an indicator of an
15-150
Belgium 95 adequate iodine intake and an optimal status
of iodine nutrition.11 As the iodine require-
France 82 ment is increased during pregnancy, the me-
77 dian urinary iodine during pregnancy indicat-
74 ing optimal iodine nutrition needs to be
70 higher than 100 µg/L. Table 1 compares the
Spain 108 data available in the literature on urinary io-
77 dine in pregnant women and in the general
United Kingdom population. In this Table, the countries are
Hungary 64
arbitrarily listed on the basis of roughly de-
Guatemala 60
Philippines 57 creasing iodine intake of the general popula-
Thailand 50 tion, starting with Chile31 which is exposed to
Italy (Sicily) 43 iodine excess based on the
11
Severe iodine deficiency WHO/UNICEF/ICCIDD criteria, down to
Marocco 27 countries where different degrees of mild to
Ethiopia 5-16 moderate iodine deficiency have been docu-
64 mented. As indicated earlier, there is a strik-
Congo 15 ing similarity between the urinary iodine in
13 pregnant women and in the global population
* Compiled from Semba-Delange 200141 and except in the reports published by Smyth et
Dorea 2002,42 where detailed data and references al.32,33 in which the values during pregnancy
are to be found. are systematically markedly higher than in
During lactation, considering that the io- non-pregnant controls. Therefore, it appears
dine content of breastmilk in conditions of difficult to derive a reference value for uri-
iodine sufficiency is in the range of 150-180 nary iodine during pregnancy and lactation
µg/L41,42 (Table 2) and that the milk produc- from the data collected in countries with no
tion is from 0.5 to 1.1 liter per day up to the iodine deficiency as this value varies from
age of 6 months, the daily loss of iodine in 800 µg/L in Chile31 to 138 µg/L in Switzer-
human milk is estimated at some 75 to 200 land, where the median urinary iodine in the

International Journal of Endocrinology and Metabolism


general population is barely above the lower
limit of normal.35 In Iran, where iodine defi-
ciency 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 val-
ues 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 in-
dicating 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 uri-
nary 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) cor-
responds 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 rec-
ommended 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 recom-
mended for non-pregnant adults.
It has to be recognized that thyroid function
and volume remained perfectly normal dur-
ing pregnancy in Iran44 as well as in Chile31
for values still twice higher, which strongly
suggests that these values are not excessive
International Journal of Endocrinology and Metabolism
Perinatal iodine nutrition 5
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 in-
clude progressive decrease in free T4 and in-
crease 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 supplemen-
tation 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 pro-
posed earlier, especially by
WHO/UNICEF/ICCIDD,11 and that a median
urinary iodine indicating optimal iodine nu-
trition during pregnancy and lactation could
be in the range 150-230 µg/L.
Requirement of Iodine in Neonates
As underlined by the IOM,12 no functional
criteria of iodine status have been demon-
strated that reflect response to dietary intake
in infants. Consequently, the recommended
intake of iodine in neonates reflects the ob-
served mean iodine intake of young infants
exclusively fed human milk in iodine replete
areas. Up to the late sixties, the iodine con-
tent of breast milk in such areas was usually
around 50 µg/L.41,42,59 Considering a daily in-
take 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 preg-
nant 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 meta-
bolic studies by determining the value which
6 F. Delange

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

Countries and loca- n Gestational Urinary io- Range Reference

tion age dine (µg/L) *
Japan 118 FT Breastfed 736 Harada et al. 199463
Hokkaido 182 FT Bottlefed 521
United States
Boston ? PT≤ 36 weeks 148 16-510 Brown et al. 199789
Torrance 50 FT 921 Delange et al. 198490
Canada
Toronto 81 FT 148 Delange et al. 198672
The Netherlands
Rotterdam 64 FT 162 Delange et al. 198672
Amesterdam 36 FT 150 Bakker et al. 199991
Sweden
Stockholm 39 FT 112 Delange et al. 198672
Stockholm 61 FT 96 Heidemann et al. 198465
Mild to moderate iodine deficiency
Germany
Nine towns 1983 461 FT 12-29 Heidemann et al. 198465
Berlin West 1985 87 FT 28 Delange et al. 198672
Kiel 1992 50 FT 33 Grebe et al 199392
Frankfurt 1992 21 FT 37 Bohles et al. 199393
Berlin West 1994 177 FT 31 Grüters et al. 199594
Berlin East 1994 213 FT 44 Grüters et al. 199594
Gottingen 2000 22 FT 50 Roth et al. 200195
Heidelberg 1999 32 FT 95 Klett et al. 199996
Belgium
Brussels 1983 103 PT+FT 35 10-150 Delange et al. 198490
Brussels 1985 196 FT 48 Delange et al. 198672
Brussels 2000 90 FT 86 Ciardelli et al. 200197
Italy
Rome 1985 114 FT 47 Delange et al. 198672
Catania 1985 14 FT 71 Delange et al. 198672
?towns 1995 195 FT 56 10-950 Rapa er al. 199698
Milano 1995 18 PT 30 weeks 123 Parravicini et al. 199699
Torino 9 FT 67 10-162 Bono et al 1998100
France
Lille 1985 82 FT 58 Delange et al. 198672
Toulouse 1985 37 FT 29 Delange et al. 198672
Ireland
Belfast 1993 ? FT 100 Barakat et al. 1994101
Israel
Tel Aviv 1996 55 PT 30-31 wks 55-100 Linder et al. 1997102
Czech Republic
Prague 1998 50 FT 79 Hnikova et al. 199970
Prisbram 1998 50 PT 78
Hungary
Budapest 2002 55 FT 35 Peter et al. 2003103
Gyor 2002 65 FT 57
Miskole 2002 54 FT 59
Nyiregyhaza 35 FT 75
Severe iodine deficiency
Gottingen 1985 81 FT 15 Delange et al. 198672
Heidelberg 1985 39 FT 13 Delange et al. 198672
Freiburg 1985 39 FT 11 Delange et al. 198672
n: number; FT: Full-term, PT: Pre-term
* Values are medians or means (bold).

International Journal of Endocrinology and Metabolism


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 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 in-
dicate 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 lit-
erature on the median urinary iodine in neo-
nates in countries or areas with iodine suffi-
ciency 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 Stock-
holm.65
Therefore, again, the data from the litera-
ture do not help substantially in identifying
the optimal urinary iodine level and this level
has also to be defined on the basis of theo-
retical considerations. Based on an iodine re-
quirement 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 indicat-
ing 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 in-
fants are supplemented with a daily
International Journal of Endocrinology and Metabolism
Perinatal iodine nutrition 7
are supplemented with a daily physiological
dose of 90 µg/day.67 It is also the value re-
ported 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 in-
dicate 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 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 µg/L in Germany72 be-
fore 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 in-
take 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 particu-
lar 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
8 F. Delange
to propose such normative values. It appears
that 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 to
the 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 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 litera-
ture and on metabolic considerations, it is
proposed that the recommended dietary in-
take 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 in-
fants. 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 impre-
cise estimation of the iodine intake. How-
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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’-triyodo-
tironina (T3) son necesarias durante todas las fases de la
vida para una función normal del sistema nervioso cen-
tral (SNC). Son especialmente cruciales durante el desa-
rrollo del SNC, pues una insuficiencia de estas hormo-
nas 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 hormo-
nas capaces de sustituirlas y que no tengan esta total de-
pendencia de un elemento, que suele encontrarse en
cantidades muy pequeñas fuera del ambiente acuático
marino.
En cambio, ha evolucionado una estructura, el folícu-
lo 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 es-
tructura endocrina capaz de almacenar estas hormonas
en forma de prohormona (la tiroglobulina), con tal efi-
cacia que un adulto, que ha tenido una nutrición ade-
cuada de yodo, puede hacer frente a las necesidades
hormonales de su organismo durante varios meses des-
pués de iniciarse un período de carencia total del mis-
mo en su alimentación. A su vez, la glándula tiroides del
adulto es capaz de evitar las posibles consecuencias no-
civas de la producción de un exceso de hormonas tiroi-
deas, que podrían producirse al llegarle cantidades muy
altas de yodo. Si embargo, surgen problemas importan-
tes cuando la deficiencia de yodo en la alimentación se
hace crónica, o cuando la exposición a un exceso de yo-
do 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 re-
solverse estos problemas, o de resolverse a destiempo,
pueden producirse déficit más o menos graves e irre-
versibles del SNC.
En este breve comentario se intentará definir, con ma-
yor 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 infan-
cia, 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 am-
plio apoyo bibliográfico Arena y Emparanza en este mis-
mo número1.
CANTIDADES MÍNIMAS DE YODO
Desde que, hace ya una década, fue ratificada por la
práctica totalidad de los países del mundo la Declara-
ción Mundial para la Supervivencia, Protección y De-
sarrollo de la Infancia, así como un Plan de Acción
concreto, elaborado por la Convención sobre los Dere-
chos 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 in-
fancia2 que:
1. “Todo niño tiene el derecho a una cantidad ade-
cuada de yodo en su dieta”.
2. “Toda madre debe tener una nutrición adecuada de
yodo para evitar que el niño tenga un desarrollo men-
tal 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 mater-
na insuficientes para un desarrollo armónico del cerebro
del feto y el neonato. Las bases científicas y epidemio-
lógicas (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

ANALES ESPAÑOLES DE PEDIATRÍA. VOL. 53, N.o 1, 2000 1

EDITORIAL. 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 > 30 µg/kg/día
Niños 0-5 meses
6-12 meses
1-3 años
4-6 años
7-10 años
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 autóno-
mas en las que se han realizado estudios recientes al res-
pecto.
En la tabla 1 aparecen las recomendaciones actuales
sobre las cantidades mínimas de yodo que se conside-
ran 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 co-
nocimiento más completo de las diferencias en la fisio-
logía tiroidea a distintas edades. Nótese que las necesi-
dades de yodo de niños prematuros, de neonatos y ni-
ños pequeños son notablemente más altas de lo que se
deduciría, sobre la base de su peso corporal, de las de-
finidas para escolares y adultos. En el caso de niños pre-
maturos, los preparados humanizados comercializados
para ellos no contenían yodo suficiente, pero en los úl-
timos años su contenido se ha ido haciendo más acorde
con los requerimientos4,5.
También han ido aumentando las cantidades reco-
mendadas durante el embarazo, a medida que se han
completado los estudios realizados en Europa. En nues-
tro país, concretamente en la Comunidad Autónoma de
Madrid, hemos observado que las embarazadas necesi-
tan 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 suple-
mentación de la dieta con sal yodada2. En España la le-
gislación contempla la yodación de sal refinada de me-
sa 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
2 ANALES ESPAÑOLES DE PEDIATRÍA. VOL. 53, N.o 1, 2000
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
90
de evitar o restringir el uso de sal en dichos grupos de
90
90 la población, se impone asegurar las cantidades mínimas
90 de yodo mediante la suplementación diaria controlada.
120 No habiendo en la farmacopea española actual prepara-
150 dos de yoduro o yodato potásico (en forma de tabletas,
230* gotas o grageas) adecuados para ello, hay que recurrir a
260* preparados polivitamínicos y minerales que sí lo contie-
nen, como Calcinatal®, Multicentrum®, Superdyne® y
Micebrina®. Cuando la madre ha tomado este suple-
mento durante todo el embarazo y sigue tomándolo du-
rante 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 en-
riquecidos con este micronutriente5. No hemos encon-
trado información sobre el contenido en yodo de los ali-
mentos 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 em-
barazo, una suplementación de su dieta con 250-300
µg/día podría resultar excesiva y dañina. 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 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 im-
portancia, la Organización Mundial de la Salud encomen-
dó 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®), utili-
zado como medida de urgencia para erradicar la deficien-
cia de yodo en países que no tienen establecida una ade-
cuada 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 perío-
do de desarrollo fetal (tabla 2)12, problemas que se erra-
dican con su utilización13,14. Debe tenerse en cuenta que
1 ml del aceite yodado empleado habitualmente (Lipio-
dol®) contiene 380 mg de I (¡380.000 µg!) y las dosis em-
pleadas suelen ser de 2 ml, o más. Aunque se administre
de una sola vez, por vía oral o intramuscular, y se reten-
ga en el músculo y tejido graso, el yodo se va liberando
paulatinamente. Pero, obviamente, lo hace en cantidad su-
perior a lo que ingeriría una mujer que recibiese 300
µg/día durante todo el embarazo y la lactancia (110 mg).
 El yodo durante la gestación, lactancia y primera infancia

TABLA 2. Espectro de disfunciones por déficit de yodo cerebro durante los primeros años de vida no hay dife-
(tanto más graves cuanto mayor es la rencia entre un estado de hipotiroidismo permanente y
deficiencia de yodo, y cuanto antes se padece) uno transitorio, pues en ambos casos el niño requiere
tratamiento con T4. En el caso de un bloqueo por yodo,
Período en que
se padece la Consecuencias principales el tratamiento debe prolongarse por lo menos hasta que
deficiencia de yodo se haya normalizado la yoduria. Por eso parece muy
Feto Mayor número de abortos oportuno el artículo de Arena y Emparanza en este nú-
Nacidos muertos mero de la Revista1, pues parece que en muchas con-
Anomalías congénitas
sultas ginecológicas y en maternidades españolas no se
Mayor mortalidad perinatal
Mayor mortalidad infantil ha eliminado totalmente el uso de antisépticos yodados,
Cretinismo neurológico como el Betadine®, que contiene povidona yodada al
Deficiencia mental 10%. Cuando hace dos décadas se extendieron por toda
Sordomudez
España los programas para la Detección Precoz del Hi-
Diplejía, tetraplejía espástica
Estrabismo potirodismo Congénito, se advirtió a todas las materni-
Cretinismo mixedematoso dades sobre los graves inconvenientes del uso de estos
Enanismo antisépticos, pero al parecer con el tiempo esto se ha
Deficiencia mental
Retraso mental de los habitantes
ido olvidando, encontrándonos en varios congresos re-
aparentemente normales cientes que muchos de los asistentes no conocían su
Mayor susceptibilidad en caso prohibición.
de accidentes nucleares* También puede ocurrir que la prohibición sí se co-
Recién nacidos Defectos psicomotores nozca, pero se haya interpretado erróneamente por una
Bocio neonatal
Hipotiroidismo neonatal
información inexacta. En algunos casos, se evita efecti-
Mayor susceptibilidad en caso vamente el empleo de povidona yodada para desinfec-
de accidentes nucleares* tar al recién nacido, sobre todo si es prematuro, pero
sólo hasta después de tomar la muestra de sangre del
Niños y Bocio talón que se envía al Centro de Detección Precoz de Hi-
adolescentes Hipotiroidismo juvenil
Deterioro de las facultades mentales
potiroidismo Congénito, en la creencia errónea de que
Retraso en el desarrollo somático su uso “falsea las pruebas” por causas analíticas. A par-
Mayor susceptibilidad en caso tir de ese momento, se utiliza libremente. En realidad,
de accidentes nucleares* no es que el uso de la povidona yodada “falsee las prue-
bas”; lo que hace es provocar un estado de hipotiroidis-
Adultos Bocio y sus complicaciones
Hipotiroidismo
mo que no existía antes de su aplicación. “Falsea” en
Deterioro de las facultades mentales cuanto no se trata de un hipotiroidismo congénito per-
Hipotiroidismo por carencia de yodo manente, sino de uno transitorio. Pero, como se ha in-
Mayor susceptibilidad en caso dicado más arriba, estos niños requieren tratamiento
de accidentes nucleares*
Propensión a hipertiroidismo al posnatal con T4 mientras dure el hipotiroidismo, al igual
instaurarse medidas profilácticas que los niños con hipotiroidismo congénito permanen-
*Se debe a una mayor avidez de la glándula deficiente en yodo para te, si queremos evitar los déficit mentales permanentes
concentrarlo, incluidos los isótopos radiactivos del mismo, que son liberados que acompañan al hipotiroidismo perinatal tratado tar-
en grandes cantidades durante los accidentes nucleares.
Toda la patología tiroidea, incluido el cáncer de tiroides, está aumentada en díamente.
las zonas de deficiencia de yodo, y a todas las edades. Este efecto nocivo de los desinfectantes yodados ad-
ministrados a la madre y/o al recién nacido se debe a
que en la glándula tiroides del feto y en la del neonato
CANTIDADES EXCESIVAS DE YODO aún no han madurado plenamente los mecanismos de
Se han descrito casos de grandes bocios en neonatos autorregulación tiroidea17, que en el adulto permiten
de madres que usaron sistemáticamente compuestos yo- obviar los riesgos de una producción excesiva de hor-
dados durante el embarazo (jarabes yodados para la tos, monas tiroideas al producir un aumento la cantidad de
desinfectantes yodados, etc., que contenían gramos de yodo disponible.
yodo)15, o que recibieron contrastes yodados para am- En el individuo adulto sin patología tiroidea subya-
niofetografía16. En algunos casos se produjo la muerte cente, el exceso de yodo no produce un bloqueo pro-
por asfixia. En la mayoría de los otros se produjo un blo- longado de la función tiroidea, ya que se han desarro-
queo de la función tiroidea del feto y el neonato, cuyos llado “mecanismos de escape” que se vuelven operati-
efectos pueden prolongarse durante meses, precisamen- vos antes de que disminuyan las concentraciones de
te durante períodos importantes de maduración cere- T4 y T3 por debajo de las normales. No se conoce
bral. Debe tenerse en cuenta que para el desarrollo del bien cómo se ponen en marcha dichos “mecanismos

ANALES ESPAÑOLES DE PEDIATRÍA. VOL. 53, N.o 1, 2000 3

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

TABLA 3. Concentración de yodo en diferentes Esta llamada de atención sobre los peligros de un ex-
medicamentos, desinfectantes y contrastes ceso iatrogénico de yodo durante el embarazo y el pe-
radiológicos de uso muy extendido, ríodo posnatal no debe, en manera alguna, utilizarse co-
y de 1 g de sal yodada mo justificación para dejar de instaurar medidas profi-
Contenido lácticas que eviten la carencia de yodo durante el
Contenido en yodo desarrollo fetal y posnatal.
en yodo frente a
150 µg /día*
Siempre debe tenerse en cuenta la gran diferencia
existente entre las cantidades mínimas necesarias y las
Sal yodada 60 µg/1 g 0,4 x
Amiodarona 7.500 µg/ 50 x
cantidades de yodo potencialmente nocivas. Considére-
comprimido se que las cantidades mínimas necesarias se expresan en
Desinfectantes cientos de µg de yodo (200-300 µg en la embarazada).
Solución de Lugol 126.000 µg/ml 840 x La cantidad de povidona yodada en 1 ml de Betadine®
Betadine (povidona
yodada) 10.000 µg/ml 67 x
es de 100 mg (!!), lo que equivale a unos 100.000 µg. En
Yoduro sódico al 10% 85.000 µg/ml 570 x cualquier aplicación de povidona yodada se emplea un
Vioformo/clioquinol 12.000 µg/ml 80 x volumen de desinfectante muy superior a 1 ml. Lo mis-
Enterovioformo 120.000 µg/ 800 x mo ocurre cuando se usan contrastes yodados (tabla 3).
comprimido
Contrastes radiológicos Cualquier neonato, sobre todo si es prematuro, que
Hexabrix 320.000 µg/ml 2.100 x inevitablemente tiene que someterse a pruebas diagnós-
Oragrafin 308.000 µg/ 2.050 x ticas o quirúrgicas que hagan imprescindible la adminis-
cápsula
tración de contrastes yodados, puede padecer un blo-
Lipiodol 380.000 µg/ml 2.500 x
Renografin 370.000 µg/ml 2.500 x queo de la función tiroidea como consecuencia de la in-
Telepaque 333.000 µg/ml 2.200 x tervención, y entrar en un estado de hipotiroidismo. Por
*150 mg/día suele ser la ingesta diaria mínima considerada adecuada para eso, y por el frecuente retraso en el pleno funciona-
jóvenes y adultos, excluyendo mujeres embarazadas y lactantes. miento de los mecanismos de retroalimentación negati-
va hipófisis-tiroides característicos de esa edad, se reco-
de escape”, pero sí se sabe que aún no son plena- mienda que no sólo se envíen al Centro de Detección
mente operativos en el recién nacido, y lo son tanto Precoz de Hipotiroidismo Congénito las muestras de
menos cuanto menor sea su edad gestacional. Éste es sangre tomadas a los pocos días del nacimiento, sino ca-
el motivo de la gran frecuencia con que se bloquea la da vez que se hayan administrado contrastes yodados.
glándula tiroidea del niño prematuro, al enfrentarse a No debe darse el alta al paciente sin tener pruebas bio-
cantidades de yodo que son toleradas perfectamente químicas de que no padece hipotiroidismo, aunque sea
por un adulto. adquirido y transitorio.
El riesgo de un bloqueo de la glándula del neonato no Las cantidades de yodo de la mayoría de los contras-
sólo aumenta en el caso de que haya nacido prematu- tes yodados son incluso superiores a las mencionadas
ramente, sino que depende también en gran medida de para la povidona yodada (tabla 3). A veces no se tiene
la ingesta de yodo materna. Cuando ésta ha sido insufi- conciencia de que el recién nacido está recibiendo esta
ciente, el aclaramiento de yoduro por la glándula tiroi- sobredosis: la mera inserción de catéteres (no radioopa-
des del niño, así como su tamaño, aumentan rápida- cos) para alimentación parenteral conlleva la inyección
mente y de forma considerable. Pero al volver a llegar de contraste en cantidades muy pequeñas, pero sufi-
yodo en cantidades adecuadas, o altas, no disminuye cientes para bloquear la función tiroidea18, por lo que
rápidamente la excesiva vascularización de la glándula, deben sustituirse por catéteres radioopacos.
ni la captación aumentada de yodo. Hay un desfase tem- En resumen, en el caso de la mujer embarazada, el
poral importante, por lo que al llegarle una cantidad ex- lactante y el neonato (sea éste prematuro o a término),
cesiva de yodo, la glándula acumula una proporción hay que tener presente que:
mayor que en el caso de un recién nacido sin carencia
anterior de yodo. Esto contribuye a que se observe un 1. Tienen derecho a que se le asegure el yodo nece-
bloqueo de la glándula con dosis de yodo que no re- sario para el desarrollo óptimo de su cerebro.
sultan excesivas cuando la población está bien nutrida. 2. Es sumamente improbable que reciba un exceso
Los efectos bloqueadores del yodo se ven potenciados nocivo de yodo a través de la alimentación y el uso de
cuando se superponen una cierta deficiencia de yodo y suplementos polivitamínicos y minerales que lo con-
la inmadurez de la glándula del prematuro. Por eso, en tengan.
muchos países europeos (España incluida) el hipotiroi- 3. Puede ser el personal sanitario el primer responsa-
dismo neonatal por exceso de yodo es mucho más fre- ble de que se vean expuestos a dosis excesivas, que
cuente que en Japón y en los Estados Unidos, donde la provienen siempre del uso de diferentes medicamentos,
ingesta de yodo de la población es más alta. desinfectantes yodados y contrastes radiológicos.

4 ANALES ESPAÑOLES DE PEDIATRÍA. VOL. 53, N.o 1, 2000


BIBLIOGRAFÍA
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ANALES ESPAÑOLES DE PEDIATRÍA. VOL. 53, N.o 1, 2000 5
European Journal of Endocrinology (2004) 151 U25–U37 ISSN 0804-4643

Role of thyroid hormone during early brain development

Gabriella Morreale de Escobar, Marı́a Jesús Obregón and Francisco Escobar del Rey
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Cientı́ficas (CSIC) y Universidad Autónoma 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 develop-
ment, 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 corti-
cogenesis 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 neuro-
logical 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 hypothyroidism (CH). This success was interpreted as

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 phys-
icians usually adhered to the idea that maternal thyroid
hormones did not play a role in early neurodevelop-
ment, an idea apparently supported by the good
results obtained with prompt treatment of congenital
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 hor-
mone 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

q 2004 Society of the European Journal of Endocrinology Online version via www.eje.org
U26 G Morreale de Escobar and others
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 simi-
larity between man and rat with respect to placent-
ation, 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 differ-
ence that is often forgotten when postnatal findings in
hypothyroid rat models are extrapolated to the third tri-
mester 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
www.eje.org
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151
tube closure and are likely to mediate biological effects
of the T3 that has been locally generated from T4 trans-
ferred 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, serum-
derived 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 cer-
ebral 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 irre-
versible 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 con-
firmed – 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 permitted
their purification and determination by sensitive and
specific RIAs. Most commercially available methods
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151 Maternal thyroxine and fetal brain U27

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 ade-
quate, 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 some-
what 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 concen-
tration 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 concen-
trations 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. Concen-
trations 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 ultra-
sound-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) con-
tains 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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U28 G Morreale de Escobar and others
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) Concen-
trations 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.
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151
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 concen-
trations of maternal T4 or FT4 that have escaped the
placental ‘barrier’. The T4-binding capacity of the pro-
teins in fetal fluids 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 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 hypothyr-
oxinemic women, even if they are clinically euthyroid.
The results explained why an efficient ‘barrier’ to
maternal thyroid hormone transfer is actually necess-
ary. If total T4 and T3 reached the same concentrations
in fetal fluids 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 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 concen-
trations 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 onto-
genic 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
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151 Maternal thyroxine and fetal brain U29

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 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 develop-
mental 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 gener-
ated 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 mid-
gestation. 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 gener-
ates 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 down-
regulation 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 fac-
tors 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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U30 G Morreale de Escobar and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151

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 summar-
ize 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 onto-
genic 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 par-
ameters 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 hypothala-
mic –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 intrau-
terine 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 neuroendo-
crine 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 regard-
ing 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 Figure 4 (A–C) The ontogenic changes in different parameters
and human astrocytes in primary culture (28). This of thyroid hormone status from 12 weeks PMA until birth,
receptor mediates extrathyroidal cAMP-independent obtained in vivo by cordocentesis, without interfering with the
biological effects of TSH, among which is, quite inter- normal connections between mother and conceptus. The
estingly, the stimulation of D2 in astroglial cells. The shaded areas enclose the values reported by Thorpe-Beeston
et al. (25). (A and B) Show that fetal serum FT4 values reach
possible cAMP-independent ‘extrathyroidal’ actions of maternal concentrations shortly after midgestation, whereas
TSH throughout human fetal development are most those of FT3 are low throughout pregnancy. (C) Draws attention
intriguing, especially if acting in brain development as to the very high levels of fetal TSH, most of which were higher
a growth factor. Equally intriguing is why the high than those of the mother. (A) Also shows the FT4 levels found
intrauterine TSH concentrations plummet with birth. in sera from premature babies (B, preterm) (30, 31) as com-
pared with those in utero (25).
Sudden severance from the placenta might be playing
a role, as the placenta produces high amounts of
thyrotropin-releasing hormone-like peptides that Fetal circulating T4 and FT4 are already increasing
might be stimulating extrapituitary synthesis of TSH steadily in utero before the fetal thyroid is likely to be
or TSH-like proteins. able to maintain such concentrations when deprived

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151
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 signifi-
cantly 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 con-
tinues until the umbilical cord is severed was conclus-
ively 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 syn-
thesize 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.
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 pro-
grammed expression of the iodothyronine deiodinase iso-
enzymes, 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 chan-
ging 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 rel-
evant 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
Maternal thyroxine and fetal brain U31
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 recep-
tors, 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 inter-
relationships. 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 sul-
fotransferases, glucuronidases and sulfatases, and of
recently identified specific iodothyronine plasma mem-
brane 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 inter-
ruption 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 ethi-
cal constraints.
In the rat, changes in maternal thyroid hormone avail-
ability 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 neur-
ons 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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U32 G Morreale de Escobar and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151

the cells generated during this period was aberrant, with TSH is suppressed. Plotting mean maternal serum
neurons appearing in layers of the somatosensory cortex hCG levels as a function of gestational age shows peak
and hippocampus where they are never found in pups concentrations at the end of the first trimester,
from normal dams. The cytoarchitectures of the barrel with TSH levels falling in a mirror image (Fig. 5).
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 abnormal-
ities 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 suscepti-
bility 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.

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

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151
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 preg-
nancy 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 hypo-
thalamic –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 ‘nor-
malize 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.
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
Maternal thyroxine and fetal brain U33
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 autoimmu-
nity features, with normal FT4, normal TSH with thyr-
oid 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 evalu-
ations, 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 approxi-
mately 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 trimester-
specific 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 iodine-
sufficient, 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 hypothyr-
oxinemia 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 fre-
quent than primary thyroid failure and thyroid autoim-
munity. It has been amply documented that iodine
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U34 G Morreale de Escobar and others
deficiency is, worldwide, the most frequent cause of
reproductive failure, decreased mental and motor func-
tions, 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, constitu-
tes an important handicap in our increasingly competi-
tive 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 indus-
trialized societies, receiving so little attention in medical
practice? We should like to point out a few of the poss-
ible reasons.
Unchanged serum TSH
Regulation of thyroid function through the hypothala-
mic –pituitary– thyroid negative feed-back is so
ingrained in our thinking, that a low T4 is automatic-
ally 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 over-
looked 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 circulat-
ing iodide triggers very efficient autoregulatory mech-
anisms 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 hypo-
physectomized 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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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151
secretion of thyroid hormones is switched towards a pre-
ferential 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 individ-
uals from areas with iodine deficiency alone, with
increased Tg concentrations being a much more fre-
quent 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 adap-
tation 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 indi-
cated 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).
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151 Maternal thyroxine and fetal brain U35

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 autoregula-
tory 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 hypothyr-
oidism. This is in conceptual agreement with the obser-
vation 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 summar-
ized here supports the hypothesis that an inappropriate
first trimester surge in maternal FT4, whatever the cir-
culating 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 preg-
nancy 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 con-
siderable logistic problems in large countries such as
the United States, but ought to be implemented in Euro-
pean 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 Figure 6 Possible timing in man of cerebral developmental events
cut-off points of laboratory data for its definition. This is that are sensitive to maternal thyroid hormones in the rat (9)
the bad news. But the good news is that most cases of (lower panel), with respect to timing of first trimester events in
maternal hypothyroxinemia are related to a relative maternal thyroid physiology controlled by the conceptus, such as
iodine deficiency during pregnancy that can be so the surge in maternal FT4 (middle panel), despite the suppression
of circulating TSH (upper panel).
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 extensively promoted, whether or not folate deficiency is
learning disabilities of new generations by promoting: confirmed.
(i) the use of iodized salt throughout life, possibly by In the early 1920s, David Marine, a precursor of
universal salt iodization (41); and (ii) the use of iodine present programs for the worldwide elimination of
supplements, both as vitamin – mineral mixtures that IDDs expressed his views that ‘simple goiter is the
contain potassium iodide, or as potassium iodide tablets, easiest to prevent of all known diseases. It can be
where available, from the onset of pregnancy – or earlier excluded from the list of human diseases as soon as
if pregnancy is planned – just as folate supplements are society decides to undertake the necessary effort’

www.eje.org
U36 G Morreale de Escobar and others
(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
www.eje.org

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.
1 Especialista en endocrinología y nutrición. FEA del complejo hospitalario de Jaén; 2 Especialista en medicina fa-
miliar 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 Ser-
vicio de endocrinología en el Hospital Carlos Haya de Málaga.
DÉFICIT DE YODO Y COCIENTE INTELECTUAL
Objetivo: comprobar la relación que pueda existir entre el grado de yo-
duria 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 (ni-
vel 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).
Resultados: Los resultados muestran diferencias estadísticamente sig-
nificativas 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 sig-
nificativas en el CI en función del sexo, del curso o del municipio. Tam-
poco 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 dife-
rencias no son estadísticamente significativas.
Conclusiones: Una vez más, y de acuerdo con estudios anteriores, se con-
firma que el bajo grado de yoduria en una zona de endemia bociosa leve/
moderada, se relaciona con una menor inteligencia general en la niñez (hi-
pótesis 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 inte-
lectual, 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 psicomo-
tor; 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
13
Santiago Fernández P, et al - DÉFICIT DE YODO Y COCIENTE INTELECTUAL
CORRELATION BETWEEN IODINE DEFICIT AND INTELLIGENCE
QUOTIENT
Goal: To determine the possible correlation between iodine excre-
tion levels and children’s overall intelligence quotients.
Design: Descriptive study.
Setting: 14 towns located in the province of Jaen, all with a popu-
lation 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 chil-
dren 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 concentra-
tion of iodine than the group with a high IQ. No statistically signifi-
cant 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 coun-
ty were also found to have an above average IQ when compared to
the rest of the children included in the study, although the differen-
ces were not statistically significant.
Conclusions: This study again confirms the results of earlier stu-
dies showing that low levels of iodine excretion in an area where
endemic goiter is low to moderate correlate to lower general intelli-
gence 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 pos-
sibility 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.
129
Medicina de Familia (And) Vol. 5, N.º 3, noviembre 2004
Introducción
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 cretinis-
mo 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 cri-
bado neonatal mediante la determinación de TSH en san-
gre 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 defi-
ciencia de yodo permanente, como son: bajo rendimien-
to en las habilidades visual-motoras, en destreza moto-
ra, habilidades perceptuales y neuromotoras y bajo co-
ciente 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 psi-
cométricos utilizados con una puntuación media por de-
bajo de una desviación estándar que la puntuación obte-
nida en escolares de una zona control. Sin embargo, son
escasos los estudios realizados en zonas de endemia
bociosa moderada o leve. Además, los trabajos realiza-
dos con relación al efecto beneficioso sobre la capacidad
intelectual de la administración de yodo, no son concor-
dantes: mientras que algunos encuentran un efecto be-
neficioso en la suplementación con yodo de niños entre
6-8 años 11, otros no consiguen encontrarla en niños en-
tre 5-12 años 1, 12. Diferencias en el tipo de test psicomé-
trico 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 discordan-
cias 1, 3, 10, 13.
Por otro lado, las recomendaciones internacionales so-
bre ingesta de yodo estiman una ingesta mínima de 150
µg/d de yodo para cubrir las necesidades y esto se tra-
duciría 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 asocia-
ción poblacional de la ingesta de yodo, medida por la yo-
duria, con la maduración intelectual (medida por determi-
nados test psicológicos).
130
Material y métodos
El estudio se ha realizado en los colegios públicos de 14 municipios meno-
res de 5000 habitantes de la provincia de Jaén, previa cita de los investi-
gadores con los profesores y los padres de los escolares.
El muestreo se ha realizado multietápico para garantizar la representativi-
dad, teniendo como unidades de muestreo, en orden decreciente, la comar-
ca (n = 5), el pueblo (n = 14), el colegio (n = 14) y los niños (n = 1209).
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 ali-
mentos.
2. Test psicométrico para la medida del CI. En esta investigación se ha uti-
lizado el test del Factor G de Cattell 16, 17. Todas las evaluaciones psi-
cométricas han sido realizadas por el mismo evaluador. El test de Ca-
tell 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 técni-
ca 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 com-
paraciones, o ANOVA de una o varias vías, en el caso de comparacio-
nes 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 regre-
sión 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 Kleim-
baun 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 estadísti-
co a los escolares que han sido tratados con desinfectan-
tes yodados, es de 70 µg/l.
Hay diferencias significativas en la distribución de la yo-
duria en función de las comarcas variando entre una me-
dia 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
14

94’18 µg/l respectivamente; p < 0,01); también es estadís-
ticamente 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 es-
colares 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 con-
trario el CI ha sido significativamente menor en los niños
que tuvieron yodurias < 100 µg/L (p = 0,01) (Tabla 2). Es-
tas diferencias de CI en función de los niveles de yodu-
ria se mantienen en un modelo de ANOVA (p = 0,02) des-
pués 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 aso-
ció 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 aso-
ciación entre los niveles de yoduria con el CI. (Tabla 3)
Así mismo el CI se relacionó con la ingesta de sal yoda-
da y con la frecuencia en el consumo de lácteos, pues los
escolares que tomaban sal yodada y lácteos más frecuen-
temente, 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 distri-
bución 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 asocia-
ción (Tabla 4).
Discusión
Si bien no hay muchos estudios que contemplen los as-
pectos 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
15
Santiago Fernández P, et al - DÉFICIT DE YODO Y COCIENTE INTELECTUAL
de los niños 2, 25. En el presente trabajo se confirma esta
asociación en una muestra representativa de una pobla-
ción escolar, étnica y socialmente homogénea, de un país
desarrollado del sur de Europa, sin problemas nutriciona-
les 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 deficien-
te 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 te-
ner 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 cau-
sas. Por otra parte, un sesgo propio de las pruebas co-
lectivas administradas en un aula escolar por una perso-
na 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 prevalen-
cia de los distintos tipos de retraso mental con los esta-
blecidos en el DSM-IV (APA, 1995): el 83% de los niños
con CI inferior a 70 podría clasificarse como Retraso Men-
tal Leve (un CI entre 50 y 70), el 14% como Retraso Men-
tal 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 yo-
duria 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 po-
tencia) 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 men-
tal (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.
131
Medicina de Familia (And) Vol. 5, N.º 3, noviembre 2004
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 dé-
ficit 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 sue-
len diferenciarse no sólo en el grado de déficit de yodo,
sino que la zona más deficitaria en yodo suele ser tam-
bién la más deprimida económica y socioculturalmente,
mientras que la zona no deficiente en yodo suele ser más
desarrollada y coincide mejor con las poblaciones mues-
trales 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 diferen-
cias 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 yodo-
deficiente han padecido, en algún momento de su desa-
rrollo, ese déficit (aunque en la actualidad pudiera haber-
se paliado). Lo que se mide son los efectos de la caren-
cia de yodo a largo plazo. No obstante, con esta metodo-
logía, se corre el riesgo de incluir dentro de la zona ca-
rente de yodo a un número indeterminado de sujetos que,
por cualquier causa (movilidad geográfica, hábitos de
consumo saludables…), nunca hayan sufrido dicho défi-
cit, o bien al contrario, considerar como no carentes de
yodo a personas que sí lo sean pese a vivir en la actua-
lidad 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 presen-
tan los sujetos, se evitan los problemas anteriores, si bien,
se corre el riesgo de tomar como algo estable (la inges-
ta de yodo), lo que puede ser el reflejo de algo coyuntu-
ral. 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 yodu-
ria sería, en la mayoría de los casos, el reflejo de un há-
bito de consumo estable 32.
Finalmente, el grupo de alta yoduria en el presente estu-
dio se compone de sujetos que conviven en las mismas
132
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 norma-
tivo 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 signifi-
cativas 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 comporta-
miento que el grupo de mayor yoduria. Este tipo de com-
portamiento 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 di-
ficultades para seguir el curso de las clases como lo ha-
cen sus compañeros con un CI más elevado. Estas difi-
cultades pueden llevar a que el niño no entienda la tota-
lidad de lo que se explica en el aula con lo que, proba-
blemente, 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 dé-
ficit de yodo el causante directo de la conducta disrupti-
va en el niño, sino la disminución de las habilidades in-
telectuales que dicho déficit conlleva.
Podemos concluir, por tanto, que en la provincia de Jaén
existe un grado de endemia bociosa leve que puede lle-
gar a moderada en algunos municipios. La ingesta de sal
yodada no se adecua a las recomendaciones internacio-
nales 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 man-
tenga en una deficiencia económica y social con respec-
to al resto del país.
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27. Azizi F, Kalani H, Kimiagar M, Ghazi A, Sarshar A, Nafarabadi M, et al.
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133
Medicina de Familia (And) Vol. 5, N.º 3, noviembre 2004

TABLA 1. COCIENTE INTELECTUAL (CI) DE TODA LA POBLACIÓN ESCOLAR ESTUDIADA Y SU DISTRIBUCIÓN POR PERCENTILES.

CI
Total (media ± SD) 97,2 ± 17,1
Percentiles de CI:
P-5 65,1
P-10 74
P-25 87,3
P-50 99
P-75 109
P-90 117
P-95 121

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

Variable de clasificación CI P
Sexo:
Niños 96,34 ± 17,44 NS
Niñas 98,17 ± 16,73
Curso:
1.º Primaria 97,73 ± 14,58
NS
5.º Primaria 96,27 ± 19,34
2.º E.S.O. 97,78 ± 16,69
Bocio:
No 97,36 ± 17,11
NS
IA 96,10 ± 17,10
IB 100,48 ± 17,22
Yoduria:
= 100 µg/L 96,40 ± 17,46 0,01
> 100 µg/L 99,03 ± 15,81

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 *** % niños con CI ≤ p-25 β β

EEβ OR ** IC 95 % P*
> 150 16,5 1
> 100 y ≤ 150 22,5 0,39 0,28 1,48 0,85-2,56 0,16
> 50 y ≤ 100 26,4 0,6 0,25 1,83 1,12-2,97 0,01
> 25 y ≤ 50 26,7 0,63 0,31 1,89 1,02-3,45 0,04
≤ 52 30,1 0,83 0,31 2,31 1,25-4,21 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.

134 18
 Santiago Fernández P, et al - DÉFICIT DE YODO Y COCIENTE INTELECTUAL

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 referen-
cia= 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.

Modelos Variable β β
EEβ OR IC 95 % P
dependiente
Sal:
Modelo 1 2 vs 3 0,33 0,18 1,39 0,98-1,98 0,07
1 vs 3 0,53 0,22 1,7 1,10-2,61 0,01
Lácteos:
Modelo 2 1 vs 0 -0,12 0,18 0,88 0,62-1,26 0,5
2 vs 0 0,45 0,2 1,57 1,06-2,32 0,02
Sal:
2 vs 3 0,32 0,18 1,38 0,97-1,96 0,08
1 vs 3 0,53 0,22 1,74 1,10-2,61 0,01
Modelo 3
Lácteos:
1 vs 0 -0,1 0,18 0,89 0,63-1,29 0,55
2 vs 0 0,43 0,2 1,54 1,04-2,27 0,03
Sal:
2 vs 3 0,31 0,18 1,36 0,96-1,94 0,09
1 vs 3 0,45 0,21 1,75 1,04-2,37 0,01
Lácteos:
Modelo 4
1 vs 0 -0,09 0,18 0,91 0,64-1,30 0,61
2 vs 0 0,45 0,21 1,58 1,04-2,37 0,03
Sexo 0,3 0,16 1.35 0,99-1,85 0,06
Edad 0,0013 0,027 1 0,95-1,06 0,96

19 135
ARTÍCULO ESPECIAL
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 ex-
tendida en nuestras maternidades. La aplicación de anti-
sépticos yodados tanto a la madre en los momentos pre-
vios al parto como al recién nacido provoca una sobre-
carga 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 le-
che hasta 10 veces en los días inmediatamente posterio-
res 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 yo-
do, esta sobrecarga yodada puede provocar un bloqueo
transitorio del tiroides neonatal que tiene repercusiones
negativas sobre el programa de detección del hipotiroi-
dismo congénito, aumentando el número de falsos posi-
tivos, y sus inmediatas consecuencias: ansiedad de los pa-
dres y un importante aumento de los costes del progra-
ma. Más graves son las consecuencias que este bloqueo
puede producir en el desarrollo del recién nacido.
Parece ineludible realizar una llamada de atención so-
bre las alteraciones que provocan los antisépticos yoda-
dos y desaconsejar su uso en el período perinatal.
Palabras clave:
Povidona-yodada. Yodo. Hormonas tiroideas. Hipoti-
roidismo. Recién nacido.
IODINE ANTISEPTICS ARE NOT HARMLESS
The use of iodine-containing antiseptics is still com-
mon in obstetrics and neonatology. Topical iodine gi-
ven both to the mother before delivery and to the neo-
nate 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.
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 breast-
fed. 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: paren-
tal 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 pe-
riod should be avoided.
Key words:
Providone-iodine. Iodine. Thyroid hormones. Hypothy-
roidism. Newborn.
INTRODUCCIÓN
La aplicación de antisépticos yodados a la madre ges-
tante y al recién nacido es un ejemplo de actividades
médicas o sanitarias que, pese a ser aparentemente ino-
cuas, pueden provocar alteraciones fisiológicas impor-
tantes.
Actualmente, la utilización de antisépticos yodados en
el período perinatal es casi la norma, no sólo en nues-
tro país sino en gran parte de las maternidades de las
que se conocen sus protocolos.
Hoy en día, sabemos que su aplicación cutánea o mu-
cosa 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 hipotiroi-
dismo congénito: aumenta el número de falsos positi-
vos, aumenta el gasto por la necesidad de repetir la
ANALES ESPAÑOLES DE PEDIATRÍA. VOL. 53, N.o 1, 2000 25
ARTÍCULO ESPECIAL. J. Arena Ansotegui y J.I. Emparanza Knörr
3,5
3,0
2,5
p < 0,001
2,0
1,5
1,0
0,5
0,0
Recién nacidos Recién nacidos
no tratados tratados
Hipertirotropinemia transitoria
Hipotiroidismo transitorio
Figura 1. Frecuencia, en porcentaje, de hipotiroidismo
transitorio e hipertirotropinemia.
prueba, provoca ansiedad en los padres por lo que com-
porta 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 neona-
tal, como consecuencia de una sobrecarga yodada de la
que no puede desembarazarse, produce el llamado efec-
to de Wolf-Chaikoff, y ha sido demostrado en numero-
sas publicaciones1-41. La afectación del tiroides feto-neo-
natal 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 nutri-
cional de yodo en la madre. La utilización de antisépti-
cos 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 tiroi-
dea5,39,42. Nuestra experiencia al respecto fue de interés
y no ha perdido actualidad a pesar de los años transcu-
rridos1,2.
APLICACIÓN DE YODO AL RECIÉN NACIDO
En el año 19842 pudimos comprobar, en un estudio
retrospectivo, que la aplicación diaria de Betadine® (po-
vidona yodada al 10%) en el muñón umbilical de 356 re-
cién 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 re-
cibieron povidona yodada (PVP-I), tal y como se refleja
en la figura 1.
26 ANALES ESPAÑOLES DE PEDIATRÍA. VOL. 53, N.o 1, 2000
La alarma la dio un incremento brusco de las altera-
ciones transitorias de la función tiroidea reconocidas en
el cribado neonatal del hipotiroidismo congénito, y la
asociación estadísticamente significativa de estos trastor-
nos 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 en-
tonces se eliminaron los antisépticos yodados de nues-
tra 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, obser-
vamos que las alteraciones transitorias de la función ti-
roidea afectaban casi exclusivamente a los recién naci-
dos alimentados al pecho, con una tasa del 0,82% com-
parada con el 0,10% de los que se alimentaban con
fórmula, lo que nos hizo pensar en una iatrogenia liga-
da a la lactancia materna.
APLICACIÓN DE YODO A LA MADRE
Al descubrir que la PVP-I se utilizaba sistemáticamen-
te en nuestra maternidad, tanto para la preparación pe-
rineal de la madre y las curas diarias de la episiotomía
en el parto vaginal, como para preparar el campo qui-
rúrgico y las curas de la herida en el caso de una cesá-
rea, 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 impor-
tante 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 distri-
buidas 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 ma-
terna inicial similar en ambos grupos, pero inferior a
100 µg/l, con un incremento progresivo y muy impor-
tante en los días siguientes al parto, que reflejaba la so-
brecarga 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.
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)
 Los antisépticos yodados no son inocuos

La yodemia elevada de forma significativa en la san- TABLA 2. Yoduria materna y concentración de yodo
gre de cordón de los recién nacidos del grupo PVP (ta- en la leche materna (µg/l)
bla 3) sólo puede explicarse por una rapidísima absor-
CLHX PVP-I
ción y distribución del yodo aplicado a la piel de la ma-
dre pocos minutos antes de obtener la muestra del Orina
Anteparto 96 61
cordón, pero son exclusivamente los recién nacidos que 24 h 176 1.427*
lactan, y a cuyas madres se les sigue curando la episio- 48 h 135 1.881*
tomía con PVP-I, los que sufren una sobrecarga yodada 96 h 76 2.171*
suficientemente importante y mantenida como para pre- Leche (96 h) 105 1.216*
sentar un bloqueo tiroideo. *p < 0,001. CLHX: clorhexidina; PVP-I: povidona yodada.
Estos resultados sugieren que: a) la piel del adulto es
muy permeable al yodo de la PVP-yodada, y que la uti- TABLA 3. Iodemia y ioduria en el recién nacido (µg/l)
lización de antisépticos yodados para la preparación pe-
CLHX PVP-LM PVP-LA
rineal de la madre y las curas diarias de la episiotomía
produce una importante sobrecarga yodada a la madre, Sangre de cordón 68* 100
y b) la excreción elevada de yodo por la leche materna, Orina
como expresión de su yodemia también elevada, es res- 24 h 65* 270 620
48 h 69* 283 395
ponsable de la sobrecarga yodada de los recién nacidos 96 h 579 8.326** 374
que lactan y explica el incremento de los trastornos tran-
CLHX: clorhexidina; PVP-LM: povidona yodada-lactancia materna;
sitorios de su función tiroidea. 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 an-
tisépticos yodados, no sólo en el recién nacido sino tam-
bién 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 ha-
bitual en el período perinatal.
En la CAV existe un déficit nutricional de yodo, consi-
derado 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 Cri-
bado Endocrino-Metabólico de la CAV). Este déficit pue-
de 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 ge-
neral que se lleva a cabo en la CAV. Sin embargo, las
ventas de sal yodada en nuestra comunidad apenas al-
canzan el 55% del total de ventas de sal (Servicio de In-
formación al Consumidor de Eroski; abril 2000).
Una vez eliminados los antisépticos yodados en el pe-
ríodo perinatal, nuestro objetivo será erradicar los tras-
tornos 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 mu-
jer embarazada con 250-300 µg de yodo al día durante
toda la gestación.
La deficiencia nutricional de yodo es un problema ge-
neralizado en Europa, y España no es una excepción. De
ahí que las políticas de yodación de la sal y la elimina-
ción de los antisépticos yodados en el período perinatal
sean dos acciones sanitarias de absoluta necesidad55.
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