Parameters of Thyroid Function Throughout and After
Pregnancy in an Iodine-Deficient Population
Maria Jose ´ Costeira,1,2Pedro Oliveira,1,3Susana Ares,4Susana Roque,1
Gabriella Morreale de Escobar,5,6and Joana Almeida Palha1
Background: The thyroid hormone milieu is of crucial importance for the developing fetus. Pregnancy induces
physiological changes in thyroid homeostasis that are influenced by the iodine status. However, longitudinal
studies addressing thyroid function during pregnancy and after delivery are still lacking in mild-to-moderate
iodine-deficient populations. Here we characterize the serum parameters of thyroid function throughout
pregnancy, and until 1 year after delivery, in a population of pregnant women whom we have previously
reported to be iodine deficient (median urinary iodine levels below 75mg/L).
Methods: One hundred eighteen pregnant women were studied. Clinical data were recorded and serum was
collected. Serum total and free thyroxine (T4) and triiodothyronine (T3), thyroid-stimulating hormone, thyroxine-
binding globulin, and thyroglobulin were measured.
Results: Mean total T4ranged from 159 at the start of gestation to 127nmol/L at 1 year after delivery, free T4
from 14.2 to 17.8pmol/L, total T3from 2.4 to 2.1nmol/L, free T3from 6.7pmol/L to 6.4pmol/L, thyroid-
stimulating hormone from 1.2 to 1.4mIU/L, T4-binding globulin from 62.0 to 26.9mg/L, and thyroglobulin from
11 to 10mg/L.
Conclusion: The pregnant women in this study had an absence of the usual free T4spike and a smaller than
expected increment in total T4, described during pregnancy in iodine-sufficient populations. A greater number of
women had subclinical hypothyroidism compared with iodine-sufficient populations. This hormonal profile,
most likely due to iodine insufficiency, may result in inadequate thyroid hormone supply to the developing
fetus. We conclude that care should be taken when reviewing the results of thyroid hormone tests in iodine-
insufficient populations and when no gestation-specific reference values have been established. In addition, we
recommend iodine supplementation in our population and populations with similar iodine status, particularly
during pregnancy and lactation.
binding globulin (TBG) due to elevated estrogen, elevated
levels of human chorionic gonadotropin that has thyroid-
stimulating hormone (TSH)-like activity, increased renal los-
ses of iodine due to increased glomerular filtration rate,
modifications in the peripheral metabolism of maternal thy-
regnancy is associated with profound modifications in
the regulation of thyroid function and economy. These
roid hormones, and iodine transfer to the placenta (1,2). The
for fetal development require adequate iodine intake. Iodine
is essential for the synthesis of the thyroid hormones needed
for the proper development of the central nervous system
(1,2). Therefore, interpretation of thyroid tests during preg-
nancy should consider these physiologic changes and the
iodine status of the population (2–4).
The fetus relies completely on maternal thyroid hormones
This work in part has been presented, in part, as an abstract in the Ninth Congress of the Portuguese Society of Endocrinology, Diabetes,
and Metabolism, Lisbon, Portugal, 2008.
1Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
2Centro Hospital Alto Ave-EPE, Guimara ˜es, Portugal.
3Department of Production and Systems Engineering, University of Minho, Braga, Portugal.
4Department of Neonatology, La Paz University Hospital, Madrid, Spain.
5Alberto Sols Biomedical Research Institute, Universidad Auto ´noma de Madrid, Madrid, Spain.
6National Research Council, Madrid, Spain.
Volume 20, Number 9, 2010
ª Mary Ann Liebert, Inc.
trimester; the mother continues to supply thyroid hormones
and iodine until birth, and iodine during lactation (1,2,5).
mental retardation, increasing evidence shows that maternal
hypothyroidism and maternal euthyroid hypothyroxinemia
are related to poorer psychomotor development of the new-
born (5–8). Therefore, recommendations on iodine supple-
mentation prior and throughout pregnancy and until the end
and developing countries are still considered iodine insuffi-
cient (9,10). Controversy exists, however, on whether to
monitor thyroid function throughout pregnancy (11,12). A
joint statement from the American Association of Clinical
Endocrinologists, American Thyroid Association, and the
Endocrine Society defends ‘‘routine screening for subclinical
those contemplating pregnancy’’ (13). The Endocrine Society
in their comments on management of thyroid dysfunction
during pregnancy and postpartum states that ‘‘universal
screening of pregnant women for thyroid disease is not yet
supported by adequate studies. . .’’ (14,15). Finally, the
American College of Obstetricians and Gynaecologists and
the United States Preventive Services Task Force suggests
‘‘performing testing only in women with personal history or
symptoms of thyroid disease and do not recommend univer-
sal testing’’ (16). A number of recent studies have been con-
cerned with the cost-effectiveness of universal screening in
pregnancy and the debate between ‘‘target high-risk case
finding’’ and ‘‘universal screening’’ (17,18). Many agree that
for proper monitoring it is necessary to establish reference
ranges for pregnancy and to choose the most informative
thyroid hormone parameters (3,4,12).
In the present study we characterized parameters of thy-
roid hormone function throughout pregnancy and after de-
livery in the same population of pregnant women we
previously found to be mild-to-moderately iodine insuffi-
cient (19), as defined by the World Health Organization
(WHO) criteria (20).
Materials and Methods
The study was carried out at the hospital Centro Hospitalar
do Alto Ave, EPE, Guimara ˜es, Portugal, between January
2003 and December 2005. Guimara ˜es is located 50km from
the sea, with both urban and rural populations, in a total of
about 1.2 million inhabitants. One hundred forty consecutive
pregnant women (without exclusion criteria, see below) en-
tering the antenatal clinic were invited to perform thyroid
function tests during and after pregnancy. Upon agreement,
demographic and clinical details were collected, including
age, gestational age, number of previous pregnancies,
breastfeeding 3 months after delivery, and Graffar socioeco-
nomic cultural state. A food-frequency questionnaire was
used to ascertain the number of weekly fish meals (a relevant
source of dietary iodine), the use of iodized salt or iodine-
containing multivitamin pills, and whether the eating regi-
men was vegetarian. Exclusion criteria were the use of drugs
or iodinated antiseptics, previous diabetes, assisted medical
reproduction, malformations of the fetus, autoimmune dis-
orders, thyroidal and other endocrine dysfunctions, and
heavy smoking (more than 10 cigarettes per day). Women
with multiple pregnancies or with antithyroidal antibodies
(antithyroglobulin [anti-Tg] and/or antiperoxidase [anti-
TPO]) were later excluded from the analysis. A total of 118
pregnant women thus remained in the study.
All women enrolled gave informed written consent and the
study was approved by the research ethical committee of the
Centro Hospitalar do Alto Ave. We have previously charac-
terized this population for iodine by measuring urine and
breast milk iodine levels (19).
Thyroid function measures
Blood was collected in each trimester of pregnancy (12?1,
24?1, and 32?1 weeks), when admitted to the hospital in
was centrifuged and serum was kept at ?808C until use. The
following serum parameters were measured: total thyroxine
(TT4), free T4(FT4), total triiodothyronine (TT3), free T3(FT3),
TSH, Tg, and anti-TPO and anti-Tg antibodies using the
DYNOtest radioimmunoassay reagents from Brahms Diag-
nostica GmbH (Berlin, Germany): DYNOtest FT4(SPART),
DYNOtest T4, DYNOtest T3, DYNOtest TSH, DYNOtest TgS,
normal reference ranges were TT458–154nmol/L, FT410–
25pmol/L, TT31.23–3.08nmol/L, FT33.4–8.5pmol/L, TSH
0.3–4.0mIU/L, Tg <70mg/L, anti-TPO <60U/mL, and anti-
Tg <60U/mL. For TBG the manufacturer provided a refer-
ence range for pregnancy of 16.4–64.4mg/L. Conversion
units used were as follows: FT3in pmol/L¼(pg/mL)/0.651;
Subclinical hypothyroidism was defined as a serum TSH
concentration abovethestatistically definedupper limitofthe
reference range (percentile [P] 97.5) when serum FT4con-
centration was within reference range, and overt hypothy-
roidism as serum TSH values >P97.5 and FT4 <P2.5.
Subclinical hyperthyroidism was defined as a serum TSH
concentration below the statistically defined lower limit of the
reference range (P2.5) when serum FT4concentration was
within reference range, and overt hyperthyroidism as TSH
values <P2.5 and FT4 >P97.5. Isolated hypothyroxinemia
when TT4or FT4values <P2.5 and TSH was normal (8).
Considering that some variables exhibited a much skewed
distribution (Tg and TSH), the median was used as the mea-
sure of central tendency together with the interquartile range
and percentiles. Correlations between variables were done
using the Pearson’s correlation or Spearman’s rank correla-
The comparison of several analytes throughout trimesters
was conducted using repeated measures. In some cases (TT3,
TSH, Tg), the log transformation was used so that the distri-
butions were approximately normal. The assumption of
sphericity was evaluated through the Mauchly’s test, and
when the test was significant, the degrees of freedom were
corrected using the Greenhouse-Geisser estimate of spheric-
ity. Pairwise comparisons were corrected with the Bonferroni
Statistical analyses were performed using the SPSS 15
significant when p<0.05. All tests were two sided.
996COSTEIRA ET AL.
From the initial pool of 140 pregnant women, 15 were ex-
cluded for being positive for either anti-TPO or anti-Tg, 1 of
these hadapregnancyloss,and7for multiplepregnancies (all
twins). The remaining 118 women had a medium age of 29.9
years (standard deviation: 7.0) and were pregnant for an
average of 2.3 times (standard deviation: 1.4), 55.9% belonged
to a medium-high socioeconomical status, and 51.4% ate fish
less than three times a week.
There was no difference between the thyroid function of
women with anti-TPO and anti-Tg antibodies (10.7% of the
study population) when compared with those without anti-
bodies (data not shown).
Thyroid function throughout pregnancy
and after delivery
Figure 1 represents the P10, P50, and P90 for all parameters
measured in pregnant women in the first, second, and third
trimesters, in the beginning of labor, and at 3 days, 3 months,
after delivery represent the basal levels, because the effects of
pregnancy should have disappeared (2,11,21). Because of the
absence of FT4surge and of the small increment of TT4, per-
centiles of these hormones were skewed to lower ranges. The
detailed numerical values (median and interquartile range) of
the thyroid function are presented in Table 1.
FT4levels during pregnancy were always lower than after
delivery, whereas TT4, TT3, and TBG levels were higher
during pregnancy than after delivery, although TT4increased
only 25% above the basal level compared with the expected
50% (1–3,21). The molar ratio TT3/TT4 remained steady
(0.016–0.017) throughout pregnancy.
Statistical analysis revealed significant differences across
trimesters, albeit the small changes in median values. TT4
values changed significantly between the first and the third
trimesters, and the second and the third trimesters, whereas
FT4, FT3, and TSH values changed significantly between all
three trimesters (first and second, second and third, and first
and third). TBG values changed significantly between thefirst
and the second trimesters and between the first and the third
between the second and the third trimesters.
In the first trimester of pregnancy two women had overt
hyperthyroidism and one had overt hypothyroidism. The
incidence of subclinical hypothyroidism changed according
to different thresholds: if defined by TSH >P97.5 (3.99mIU/L
in this population) it was 1.7%, but if the value of 2.5mIU/L
was considered it was 7.6%. The same occurred with sub-
clinical hyperthyroidism: 1.7% of the women had TSH val-
ues <P2.5 (0.08mIU/L in this population) and 7.6%
presented levels below the reference range provided by the
manufacturer. It should be noted that during the first tri-
mester of pregnancy, TSH levels are expected to decrease;
therefore, a cutoff of 2.5mIU/L may be still too high (3,4).
In that case, the percentage of pregnant women displaying
signs of subclinical hypothyroidism may be higher in our
Isolated hypothyroxinemia defined as TT4 levels <P2.5
(97.0nmol/L) was found in 1.7% of the pregnant women, but
whenthe absolute value ofTT4<100nmol/Lsuggested in the
universal absolute value of FT4to define hypothyroxinemia
(its value is dependent on the method and on the trimester
of gestation) (3,4). It should be emphasized that these abso-
lute reference values are for the nonpregnant population and
that in the first trimester TT4and FT4are expected to increase
while TSH is expected to decrease.
Table 2 shows the correlations between the various ana-
lytes studied. Of interest, the second trimester revealed fewer
correlations than anyother timepoint (TT4tended tocorrelate
with FT4, TT3, and FT3; TT3correlated with FT3), and in the
first trimester and 1 year after delivery there was a negative
correlation between TT3and FT4.
We also assessed correlations between thyroid function
and demographic characteristics, and no major correlations
were found (data not shown).
To respond properly to the pregnancy’s increased T4
demand, several adaptations are triggered during preg-
nancy (1,2,5). These should not pose a major problem to the
thyroid status of the pregnant women, and consequently to
the fetal development, in iodine-sufficient populations. The
present study focused on pregnant women (singleton and
negative for antithyroid antibodies) from a mild-to-moderate
iodine-insufficient area (19), as defined by the criteria es-
tablished by the WHO (20): median urinary iodine in the
three trimesters of pregnancy and milk iodine concentra-
tions of <75mg/L and <100mg/L, respectively (19). Of note,
this had an impact on the progeny of these women, because
median neonatal urinary iodine was low (71 and 97mg/L at
3 days and 3 months of age) (19). Here we have further
extended the study to characterize serum parameters of
thyroid function throughout pregnancy and up to 1 year
after delivery, selecting from the initial pregnant population
those singleton and negative for anti-TPO and anti-Tg an-
tibodies. TT4, TT3, and TBG levels were higher during
pregnancy than after delivery. However, the increase of TT4
in the first trimester was small (25%), when compared with
that expected (50%) in iodine-sufficient populations (1–3,21),
and further decreased throughout pregnancy rather than
remaining steady (21). The FT4 levels did not show the
termed ‘‘FT4 first trimester surge’’ (1–3,21), instead these
were always lower than basal levels throughout pregnancy
and lower than other reports in iodine-sufficient popula-
tions (8,9). Of note, the peak of TSH before labor preceded
that of Tg at 3 days after delivery, being exaggerated in
those women with some thyroid insufficiency (those with
TSH values in P90). In addition, if an absolute cutoff of
2.5mIU/L TSH is considered, 8% of women in the first
trimester of pregnancy are subclinically hypothyroid (3,22–
25). As TSH levels normally decreased in the first trimester
of pregnancy, the TSH cutoff of 2.5mIU/L defined for
nonpregnant women may still be too high for pregnant
women (3,4) and, therefore, even more women in our preg-
nant population may display subclinical hypothyroidism.
These observations are in accordance with the iodine
insufficiency previously described in this population (19).
THYROID FUNCTION AND PREGNANCY 997
(C), FT3(D), TSH (E), thyroglobulin (F), TBG (G) in the first, second, and third trimesters, in the beginning of labor, and at 3
days, 3 months, and 1 year after delivery. TT4, total thyroxine; FT4, free T4; TT3, total triiodothyronine; FT3, free T3; TSH,
thyroid-stimulating hormone; TBG, thyroxine-binding globulin.
Percentiles 10, 50, and 90 (P10, P50, P90) of thyroid analytes throughout and after pregnancy: TT4(A), FT4(B), TT3
Table 1. Measurements of Thyroid Function Throughout Pregnancy
and at 1 Year After Delivery (Median, P25, and P75)
Analyte First trimesterSecond trimesterThird trimester 1 year after
TT4, total thyroxine; FT4, free T4; TT3, total triiodothyronine; FT3, free T3; TSH, thyroid-stimulating hormone; Tg, thyroglobulin; TBG,
thyroxine-binding globulin; P, percentile.
Table 2. Correlation Coefficients (Spearman’s p) For Thyroid Analytes in Pregnant Women
1 year after delivery
aCorrelation is significant at the 0.01 level.
bCorrelation is significant at the 0.05 level.
THYROID FUNCTION AND PREGNANCY 999
We chose to recruit women from a public hospital for this
study because most women in Portugal attend the public
health system. However, caution should be taken when ex-
trapolating these results to the general population given the
small size of the studied population, the recruitment of wo-
that these women are iodine deficient.
We and other investigators have determined the parame-
ters of thyroid function at various moments throughout
pregnancy, both in populations considered iodine sufficient
(26,27) and insufficient (1,2,14,28). Nevertheless, to the best of
our knowledge, the present study is the first considering as
basal levels of thyroid function those at 1 year after delivery,
for the same women. In addition, it is correspondingly the
most extensive analysis for women for whom information on
urinary and milk iodine levels and thyroid gland volumes is
Iodine deficiency remains a problem worldwide (20). In
iodinated salt. This problem is twofold: (i) several countries,
including Portugal and other coastal countries, do not follow
the WHO recommendation on the use of household iodized
salt or iodine supplementation (10,29) and, therefore, (ii)
women are not knowledgeable of the importance of iodinated
salt in their diet and if they are this is not necessarily widely
available. Further, data about iodine sufficiency in pregnant
women are scarce worldwide and many countries report
urinary iodine values lower than the recommended (19,29), as
we also found in this study. The data presented here con-
tributes to the discussion on whether thyroid function should
be monitored before and/or throughout pregnancy, on which
thyroid function parameter is most appropriate for such
identifying hypothyroxinemia/hypothyroidism in pregnant
women that is distinct from the cutoff that defines normality
in the general population (24). When considering hypothyr-
oxinemia, our results confirm other findings (5,7,8,25) in
which, using the current reference range for TSH, measure-
ment of TSH alone is not sufficient. Screening is, however,
controversial, because scientific and clinical societies do not
agree on whether the available data are sufficient to provide
such recommendations (13–15). Although severe iodine in-
sufficiency is well recognized as the second major cause of
preventable mental retardation, after starvation (1,5,10), an
increasing body of evidence suggests that mild iodine insuf-
ficiency prevents children from fully achieving their intellec-
tual potential (5,7,8). Identification of hypothyroxinemia
during pregnancy, particularly in the first trimester, when
fetal thyroid hormones rely exclusively on the mother’s, is
important because it has been shown to result in poorer
pregnancy outcome (5,14), negatively impacting the psycho-
motor development and intelligence coefficient of the
progeny (1,5–8). For these reasons, the WHO and several in-
vestigators are recommending supplementation of iodine
before and during pregnancy, as well as the screening of
thyroid function before or in the beginning of pregnancy
(14,17,18). In conclusion, we recommend that a general policy
on salt iodization and iodine supplementation during preg-
nancy and lactation be implemented, and that when no
gestation-specific reference values are established, care
should be taken when analyzing the results of thyroid hor-
mone tests in iodine-insufficient populations.
The contributions of the authors were as follows: M.J.C.,
S.A., S.R., J.A.P., and G.M.E. planned and conducted the re-
search, discussed the data, and drafted the manuscript. P.O.
conducted the statistical analysis together with the other
authors. J.A.P. is the principal investigator of the project
that funded this research. This study was supported by
the Portuguese Science Foundation (FCT)-European Fund of
Regional Development (FEDER) grant POCTI_PSI_60948_
2004 and by the Integrated Actions for Exchange of Scientists
The authors declare that no competing financial interests
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Address correspondence to:
Joana A. Palha, Ph.D.
Life and Health Sciences Research Institute (ICVS)
School of Health Sciences
University of Minho
THYROID FUNCTION AND PREGNANCY 1001