Nutrition 50 (2018) 60–65

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Nutrition
journal homepage: www. nutritionjrnl . com

Applied nutritional investigation

Iodine deficiency in pregnancy: Still a health issue for the women of

Cassino city, Italy
Chiara Tuccilli Ph.D. a,1, Enke Baldini Ph.D. a,1, Elia Truppa B.S.N. b, Bruno D’Auria M.D. b,
Domenico De Quattro M.D. b, Giovanni Cacciola M.D. c, Tommaso Aceti M.D. d,
Giovanni Cirillo M.D. d, Antonio Faiola M.D. d, Patrizia Indigeno B.S.N. e, Lorella D’Aliesio B.S.N. e,
Fiorella Gazzellone B.S.N. e, Marco Bononi M.D. e,f, Eleonora D’Armiento M.D. g,
Giovanni Carbotta M.D. a, Daniele Pironi M.D. a, Antonio Catania M.D. a, Salvatore Sorrenti M.D. a,
Salvatore Ulisse Ph.D. a,*
aDepartment of Surgical Sciences, Sapienza University of Rome, Italy
b Department of Obstetrics and Gynecology, ASL Frosinone, Santa Scolastica Hospital, Cassino, Italy
c
UOC of Radiology, Department of Diagnostic, ASL Frosinone, Santa Scolastica Hospital, Cassino, Italy
d
Department of Clinical Pathology, ASL Frosinone, Santa Scolastica Hospital, Cassino, Italy
e f
Nursing School of Cassino, Sapienza University of Rome and University of Cassino and South Lazio, Cassino, Italy
Department of Surgery Pietro Valdoni, Sapienza University of Rome, Rome, Italy
g
Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy

ARTICLE INFO ABSTRACT

Article history: Objective: The World Health Organization, the United Nations Children’s Fund, and the International Council
Received 28 June 2017 for the Control of Iodine Deficiency Disorders recommend a median urinary iodine concentration (UIC) in
Received in revised form
pregnant women between 150 μg/L and 249 μg/L. In the present study, we evaluated whether in the urban
17 October 2017
area of Cassino (central Italy), after a national salt iodination program (30 mg/kg) was introduced in 2005, the
Accepted 5 November 2017
increased demand of iodine during pregnancy was satisfied.
Keywords:
Methods: Between January 2016 and April 2017, 99 pregnant women were enrolled to evaluate UIC in spot
Pregnancy
urine samples, serum level of thyrotropin, free thyroxine, antithyroglobulin and antithyroperoxidase
Goiter autoantibodies, and thyroid volume by ultrasonography. Eighty clinically healthy non-pregnant women were
Iodine supplementation evaluated as controls.
Iodine deficiency disorders Results: The median UIC was of 97.7 μg/L and 110.3 μg/L, respectively, in control and pregnant women. A
Thyroid hormones significant increase (P < 0.001) of median thyroid volume was found in pregnant women, relative to control
women, being, respectively, 10.4 mL (range 3.68–19.49 mL) and 7.16 mL (range 2.57–14.00 mL). A positive
correlation was found between thyroid volume and anthropometric parameters, and an inverse correlation was
identified between free thyroxine serum levels and anthropometric parameters.
Conclusions: This observational study found that the majority of pregnant women and their fetuses appear not
to be protected from the detrimental consequences of iodine deficiency. Therefore, the identifica-tion of new
strategies to increase the knowledge and awareness of the general population regarding the beneficial effects
of iodine supplementation during pregnancy is highly required.
© 2017 Elsevier Inc. All rights reserved.

Introduction rise of thyroxine binding globulin (TBG) and to increased pe-ripheral

Thyroxine (T4) requirement in pregnancy increases by ap-
proximately 50%, mainly as a result of the estrogen (E2)–induced
* Corresponding author. Tel.: +39 6 49970009; fax: +39 6 49972606.
E-mail address: Salvatore.ulisse@uniroma1.it (S. Ulisse).
1 The first two authors provided an equal contribution to the work.
https://doi.org/10.1016/j.nut.2017.11.007
0899-9007/© 2017 Elsevier Inc. All rights reserved.
T4 metabolism [1]. The appropriate maternal T4 levels at the onset of
pregnancy is important, because during the first trimester of gestation
the only source of fetal plasma T4 is rep-resented by the small
placental transfer of maternal T4 [2,3].
Iodine is an essential micronutrient required for the
appro-priate thyroid hormone biosynthesis, and the dietary
intake recommended by the World Health Organization, the
United
 C. Tuccilli et al. / Nutrition 50 (2018) 60–65
Table 1
Anthropometric parameters of control (n = 79) and pregnant (n = 96) women of Cassino, Italy expressed as median value and relative range in parenthesis
Control
Age (y) 33 (18–45)
Body weight (kg) 60 (45–91)
Body height (cm) 164 (150–175)
2
Body surface area (m ) 1.66 (1.38–1.99)
2
Body mass index (kg/m ) 22.06 (17.58–35.11)
Nations Children’s Fund, and the International Council for the Control
of Iodine Deficiency Disorders (WHO, UNICEF, and ICCIDD) is 150
μg/d for adults [4–6]. This amount of iodine should be in-creased
during gestation to 200 to 300 μg/d to sustain augmented maternal T 4
requirement and fetal thyroid function and to com-pensate for the
enhanced urinary iodide excretion occurring in pregnancy [4,6–8].
Urinary iodine concentration (UIC) is an ac-curate indicator of iodine
intake because 90% of ingested iodine is excreted in 24-h urine [8]. To
prevent iodine deficiency dis-orders (IDD), WHO/UNICEF/ICCIDD
established that for a given population median UIC must be between
100 μg/L and 199 μg/L in clinically healthy participants and between
150 μg/L and 249 μg/L in clinically healthy pregnant women [3–6,9–
13]. It is well known that inadequate iodine intake during pregnancy
may have detrimental effects of fetal development, including delayed
development and maturation of the fetal brain from mild intel-lectual
blunting to frank cretinism, which is the major preventable cause of
mental defects [10]. Furthermore, iodine deficiency in pregnancy is
responsible for maternal and fetal goiter, miscar-riages, stillbirths,
reduced fetal growth, neonatal hypothyroidisms, and impaired
reproduction in the adult life [9,10]. Studies from different European
and Asian countries still affected by moder-ate to mild iodine
deficiency have reported that the thyroid gland increases in volume
during gestation, and pregnant woman from these regions are at risk
of IDD [14,15]. Furthermore, some studies found that even in areas
with adequate iodide intake, a signifi-cant proportion of pregnant
women have UIC less than the recommended levels [4,5,15–18]. This
raises the issue of whether iodine supplementation should be
generalized in pregnant women, as recommended for the United
States and Canada by the Public Health Committee of the American
Thyroid Associa-tion [5,7].
In Italy, a national salt iodination program (30 mg/kg) was in-
troduced in 2005. The law required that all stores for direct
consumption should ensure the simultaneous availability of salt
enriched with iodine and common salt, the latter being provid-ed only
on a specific request from the consumer. The law also endorses the
use of iodine-enriched salt in the public catering sector.
In view of this, in the present observational study, we evalu-ated
whether in the urban area of Cassino (in central Italy), more than 10 y
after the introduction of the salt iodination program, the increased
demand of iodine during pregnancy was guaranteed.
Materials and methods
Participants
From January 2016 to April 2017, 99 pregnant women (7 in the first trimes-ter, 12
in the second trimester, and 80 at the third trimester) were consecutively enrolled on
presentation at the Department of Obstetrics and Gynecology of the Santa Scolastica
Hospital of Cassino, to evaluate UIC in randomly collected spot urine samples, serum
level of thyrotropin (TSH), free thyroxine (FT 4), antithyroglobulin (Ab-Tg),
antithyroperoxidase (Ab-TPO) autoantibodies, and thyroid size by ultrasonography.
The study protocol was approved by the ethical
61
Pregnant P value
33 (20–45) 0.905
73 (53–115) <0.001
165 (150–183) 0.388
1.80 (1.49–2.26) <0.001
26.95 (18.29–42.24) <0.001
committee of Policlinico Umberto I Hospital (Rif. 3827, protocol no. 2704/15) and by
the ethical committee (Comitato Etico Lazio 2) of the Regional Health System (Rif. 81-
15, protocol no. CE111479). Informed consent was obtained from all women included
in the study. Only pregnant women with a normal pregnancy and no personal history of
thyroid disease were included. As controls, 80 age-matched clinically healthy non-
pregnant women were included in the study. Controls and pregnant women were all
resident in the urban area of Cassino of central Italy. The mean age of control and
pregnant women were, respectively, 33.16 y and 32.94 y (Table 1). To all women a
questionnaire was provided to get information on their dietary habits. In particular, they
were asked whether they regularly use iodized salt and milk and whether they use
vitamin or mineral tablet supplements containing iodine. All women provided a spot
urine sample, which was frozen to −20°C until assayed as described later. After
hormonal assays, four women (one from the control group and three pregnant women,
of whom two were in the first trimester and one in the third trimester) were excluded
from the analysis being positive for the Ab-Tg and/or Ab-TPO autoantibodies. Anthro-
pometric parameters of control and pregnant women, which included age, body weight,
and height, were collected (Table 1). From the latter, body mass index (BMI), and body
surface area (BSA) [19,20] were calculated using the following formulas:
BMI kg m2  = Weight kg Height2 m
BSA m2 = Weight 0.425 × Height0.725 × 71.84 × 10−4
Some women of both groups, however, failed to provide anthropometric pa-
rameters or blood or morning urine samples or to perform the ultrasonography. For this
reason, the precise number of cases analyzed is reported in each figure of the Results
section.
UIC determination
The UIC determinations were performed on morning urine specimens by the
Sandell-Kolthoff method using a commercial colorimetric kit (Cell-Tech, Turin, Italy).
The intra-and interassay coefficients of variation were, respectively, 8.6% ( n = 10) and
11.9% (n = 10). The UIC values were reported as microgram per liter.
TSH, FT4, and thyroid autoantibody assays
Anti-Tg and anti-TPO autoantibodies, TSH, and FT 4 serum levels were ana-lyzed
on sera samples by chemiluminescence method using the Immulite 2000 assays
(Medical Systems, Genova, Italy). Reference range were as follows: Anti-Tg < 40
UI/mL; anti-TPO < 35 UI/mL; TSH 0.2 to 0.4 μUI/mL; FT4 8 to 20 pg/mL.
Thyroid ultrasound
Ultrasonography of the thyroid was performed with a Philips HDI4000 ul-
trasonogram equipped with a linear transducer. Longitudinal (Ld), transverse (Td), and
anteroposterior (APd) diameters, expressed in centimeters, of each thyroid lobe were
measured to estimate the volume of the gland through the formula of the ellipsoid
applied to each lobe: Thyroid volume (mL) = Ld × Td × APd × π/6. Ultrasound
examinations were performed by the same observer (G.C.). The intraobserver
variability, calculated as between-visit coefficient of variation, was determined by
multiple measurements (n = 6) performed on six different par-ticipants and ranged from
5.1% to 7.7%.
Statistical analysis
The non-parametric Mann-Whitney U test was used to compare UIC values
between experimental groups, and Spearman’s ρ correlation test was used to cor-
relate thyroid volume (TV), TSH, and FT4 values versus continuous variables such as
body weight, BMI or BSA. Statistical evaluation of the differences in the medians of
multiple groups was performed with the Kruskal-Wallis non-parametric H test
62 C. Tuccilli et al. / Nutrition 50 (2018) 60–65

and a post hoc test. All tests were performed using SPSS Statistics for Windows,
Version 22 (IBM Corp., Armonk, NY, USA). Values were considered statistically
significant when the pertaining P value was <0.05.

Results

In this study we analyzed 96 pregnant women and 79 age-

matched control women (Table 1). Control women had a median UIC
of 97.7 μg/L (ranging from 28.1–1154.3 μg/L) consistent with a mild
iodine deficiency, whereas in pregnant women it was 110.6 μg/L
(ranging from 15.8–491.3 μg/L), well below the rec-ommended 150
μg/L (Fig. 1).
The effects of iodized salt and/or milk consumption on UIC level
was analyzed for both control and pregnant women as a whole. The
analysis reported in Figure 2 indicated an increas-ing trend of UIC
from women not using either iodized salt or milk (median UIC, 79.8
μg/L), toward those using iodized salt (median UIC, 94.1 μg/L) or milk
(median UIC, 112.0 μg/L) or both (median UIC, 118.0 μg/L) (P =
0.054).
Fig. 1. Urinary iodine concentration (UIC) in non-pregnant control women and
pregnant women of Cassino, a city in central Italy.
Fig. 3. Thyroid volume in non-pregnant control women and pregnant women.
No correlation among UIC and thyroid volume, TSH, or FT 4 serum
levels were identified (data not shown). Pregnant women had a
significantly (P < 0.001) increased median TV (10.36 mL) compared
with control women (7.08 mL), as shown in Figure 3.
Thyroid volume had a moderate and significant correlation with
body weight (BW), BMI, and BSA (Table 2). A weak but sta-tistically
significant correlation remained also when control and pregnant
women were considered separately (Table 2).
In view of the significant correlation between TV and the an-
thropometric parameters, TV of control and pregnant women was
normalized against BW, BMI, or BSA. The results, reported in Figure
4, indicated that pregnant women had an increased TV even after
normalization for the BW, BMI, or BSA.
We next evaluated TSH and FT4 serum level in control and
pregnant women. Because TSH and FT4 levels fluctuate among the
different trimesters of pregnancy, pregnant women were grouped
based on the trimesters of pregnancy [21]. As shown in Figure 5,
women in the second and third trimester had FT 4 levels significantly
lower than those recorded in control women or in women in the first
trimester. On the other hand, we could not identify any statistically
significant differences in TSH levels among the different groups of
women.
Finally, a moderate inverse correlation was found between FT 4
serum levels and BW, BMI, and BSA, as shown in Table 2.
A weak but statistically significant correlation of FT4 with BW and
BMI remained statistically significant even when control and pregnant
women were considered separately. On the contrary,

Table 2
Spearman’s ρ correlation coefficients (r) among body weight (BW), body mass index
(BMI), and body surface area (BSA) with thyroid volume and serum free thyroxine
(FT4) level in non-pregnant control women and pregnant women

r P r P
FT4 Thyroid volume

All women
BW −0.45 0.001 0.46 0.001
BMI −0.45 0.001 0.47 0.001
BSA −0.39 0.001 0.42 0.001
Control
BW −0.24 0.05 0.259 0.05
BMI −0.23 0.05 0.234 0.05
BSA −0.22 0.055 0.236 0.05
Pregnant
BW −0.22 0.05 0.268 0.05
BMI −0.25 0.05 0.312 0.01
Fig. 2. Effect of dietary habits on urinary iodine concentration (UIC) in non-pregnant
control women and pregnant women as whole. Iod, iodine. BSA −0.17 0.102 0.219 0.05
 C. Tuccilli et al. / Nutrition 50 (2018) 60–65
Fig. 4. Normalized thyroid volume in non-pregnant control women and preg-
nant women. TV of control and pregnant women was normalized against BW,
BMI, or BSA. BMI, body mass index; BSA, body surface area; BW, body weight;
TV, thyroid volume.
the correlation of FT4 with BSA was lost when the two groups
of women were analyzed separately (Table 2).
Discussion
In the present study we found that the pregnant women of
Cassino, a city in central Italy, had, according to the WHO/UNICEF/
ICCIDD recommendations, an inadequate dietary iodine intake,
which in turn could be held responsible for the identified in-
creased median TV recorded with respect to control non-
pregnant women. In fact, because of the hormonal changes that
affect thyroid function and the increased urinary iodide excre-
tion during pregnancy, WHO/UNICEF/ICCIDD established that for
a given population median UIC for pregnant women should be
between 150 μg/L and 249 μg/L to prevent maternal-fetal
63
Fig. 5. TSH and FT4 level in non-pregnant control women and pregnant women.
disorders as a result of iodine deficiency [12,13]. In Italy, a law
introduced in 2005 a salt iodination program (30 mg/kg) to
prevent iodine deficient disorders. Despite the law, however, a
recent report found that, 10 years after the iodine prophylaxis
program, some regions are still characterized by mild iodine de-
ficiency, goiter, and other iodine deficiency disorders [22]. In a
previous study, performed in 2015 in the city of Cassino (in central
Italy), we reported that only 42% of the salt consumed was iodized.
Despite that, however, in the schoolchild population of this area
the median UIC value (133.9 μg/L) was consistent with an ade-
quate iodine intake [23]. This discrepancy could be explained by
the silent iodine prophylaxis deriving from the consumption of
iodine-rich foods, such as milk, or other iodine-enriched food,
which may compensate for the low consumption of iodized salt.
In the present observational study, we analyzed a case study of
96 pregnant women and 79 age-matched control women to eval-
uate whether the increased demand of iodine during pregnancy
was met. In control non-pregnant women, we found a median
UIC value of 97 μg/L, consistent with a mild iodine deficiency. In
pregnant women the median UIC was 110 μg/L, well below the
150 μg/L recommended by the WHO. We also attempted to cor-
relate UIC values with dietary habits of control and pregnant
women as a whole. The data obtained indicated an increasing
64 C. Tuccilli et al. / Nutrition 50 (2018) 60–65
trend of UIC value from women not using either iodized salt or milk,
toward those using iodized salt or milk or both. It has to be mentioned,
however, that the previously reported cutoffs for adequate UIC in
control women (100 μg/L) and pregnant women (150 μg/L) were
established by the WHO assuming a daily urinary volume of 1.5 L.
During pregnancy an increase in the glomeru-lar filtration rate may
take place, thus leading to an increased daily urinary volume, which
could make the previously reported UIC cutoff value non-reliable in
pregnant women. In this context, a recent study performed on
pregnant women in an iodine-adequate area in China reported that
UIC on spot urine sample could be inaccurate, increasing the
prevalence of iodine defi-ciency, and that UIC/creatinine ratio better
reflected the 24-h iodine excretion [24]. Thus, according to the latter, it
is possible that in the present study iodine deficiency found in
pregnant women could be overestimated. However, in agreement with
the insufficient iodine intake, we noticed a 46.3% increase in the
median TV in pregnant compared with control non-pregnant women.
This increase remained statistically significant even when thyroid
volume was normalized against anthropometric param-eters such as
body weight, body mass index, or body surface area. Previous studies
found that in iodine-replete areas, TV should not change during
pregnancy [14,21]. Therefore, this evidence sug-gests that in Cassino
mothers and their fetuses are at risk of iodine deficiency disorders,
including miscarriages, stillbirths, and in-adequate development and
maturation of fetal brains [11]. The hormonal FT4 and TSH levels in
control and pregnant women re-ported in this study resemble those
reported by Berghout et al.
[21] in an iodine-replete area. In this regard, however, the low
number of pregnant women in the first (n = 5) and second tri-mesters
(n = 12) analyzed in the present study must be noted. Thus, these
observations will need to be confirmed in larger case studies.
Finally, our data confirm previous findings indicating a pos-itive
correlation among TV and anthropometric parameters including BW,
BMI, and BSA [23,25–27]. Thus, we corroborate pre-vious
recommendations to use specific reference values for TV
as a function of BSA [26,27]. In addition, we have noticed a sta-
tistically significant inverse correlation among FT 4 serum level and
anthropometric parameters, including BW, BMI, and BSA. These
correlations remain statistically significant even when
control and pregnant women were considered separately, with the
only exception of the correlation between FT 4 and BSA, which was
lost when the two groups were analyzed separately. The latter may
result from the lower number of cases analyzed in each
group. In agreement with these findings, a negative association
between FT4, and BMI in adult normal-weight euthyroid indi-viduals
has been recently reported [28]. In addition, in pregnant women, it was
recently found that FT4 correlated negatively with BMI in the second
and third trimesters [29].
Iodine deficiency during pregnancy still represents a major health
issue worldwide, even in countries considered iodine suf-ficient [30–
35]. Greater attention by the major health care providers, including
obstetricians and gynecologists, is thought to play an important role in
solving this problem. In fact, in a recent study, it was reported that the
majority of U.S. obstetri-cians and midwives do not recommend
iodine-containing vitamins in women planning pregnancy, nor even
during pregnancy or lac-tation [36]. However, although main health
care providers may positively contribute to the eradication of iodine
deficiency in pregnancy, further research to identify new strategies to
in-crease the knowledge and awareness of the general population of
the beneficial effects of iodine supplementation program during
pregnancy is highly required [37].
Conclusions
We found that in the area of Cassino in central Italy iodine
deficiency during pregnancy is still a major health issue 10 years after
the introduction of the iodine prophylaxis program. We rec-ommend
that health care providers monitor iodine nutrition and the need for
iodine supplementation in pregnancy. Finally, our data warrant further
investigations to improve the knowledge and awareness of the
detrimental effects of iodine deficiency in the general population.
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