The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 12 4534-4537
Copyright © 2000 by The Endocrine Society
Parity as a Thyroid Size-Determining Factor in Areas with Moderate Iodine Deficiency
Mario Rotondi,
Giovanni Amato,
Bernadette Biondi,
Gherardo Mazziotti,
Andrea Del Buono,
Maria Rotonda Nicchio,
Simona Balzano,
Antonio Bellastella,
Daniel Glinoer and
Carlo Carella
Institute of Endocrinology (M.R., G.A., G.M., A.D.B.,
M.R.N., A.B., C.C.), II University of Naples, and Institute of
Endocrinology (B.B.) and Department of Mathematics and Statistics
(S.B.), University Federico II, 80121 Naples, Italy; and Department of
Internal Medicine (D.G.), Hospital Saint-Pierre, Université Libre
de Bruxelles, 1000 Brussels, Belgium
Address correspondence and requests for reprints to: Prof. Carlo Carella, Via Crispi, 44, 80121 Naples, Italy. E-mail:
Carlo.Carella{at}unina2.it
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Abstract
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Among the factors that may influence thyroid size, pregnancy and its
goitrogenic effect have been widely investigated, but thyroid volume
and pregnancy have never been compared retrospectively, and there are
no data on the possible relationship between thyroid size and parity.
The purpose of this work was to evaluate the effects of pregnancy on
thyroid volume in a moderate iodine deficiency area, to assess the
possibility of a relationship between thyroid size and parity status in
healthy females. A group of 208 nongoitrous healthy women underwent
thyroid volume estimation by ultrasound examination. All subjects were
euthyroid and negative for thyroid autoantibodies. They were assigned
to different groups, according to the number of completed pregnancies.
Five groups were formed (0, 1, 2, 3, 4 or more term pregnancies). Mean
thyroid volume increased progressively among the groups: group 0
(14.8 ± 0.7 mL); group I (16.0 ± 0.9 mL); group II
(17.1 ± 0.6 mL); group III (18.2 ± 0.6 mL); group IV
(20.3 ± 0.9 mL). The increment in thyroid volume was
statistically significant between group 0 and groups III
(P < 0.01) and IV (P <
0.001), and also between group I and group IV (P <
0.05). No independent effect of body weight and age on thyroid volume
was seen. Our results indicate that, in an area with moderate iodine
deficiency, the goitrogenic effect of pregnancy is not fully
reversible. Moreover, the statistically significant increase in thyroid
volume, observed in relation to parity, is the first clinical
demonstration of a cumulative goitrogenic effect of successive
pregnancies, providing a strong argument to increase the iodine supply
during pregnancy, even in conditions with moderate iodine deficiency.
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Introduction
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PREGNANCY CAN BE viewed as a prolonged
physiological condition stimulating the thyroid gland. The
physiological thyroid hormone’s steady-state equilibrium is markedly
modified during pregnancy because of high circulating levels of human
CG with its thyrotropic action, increase in serum
T4-binding globulin as a consequence of
high estrogen levels, and intense iodothyronine deiodination activity
of the placenta (1, 2). The pregnancy-induced changes in
maternal thyroid function may be achieved easily if iodine supply is
adequate. Instead, in areas with limited dietary iodine intake,
pregnancy may lead to a relative iodine-deficient state as assessed by
more intense relative hypothyroxinemia, preferential triiodothyronine
secretion with increased serum
T3/T4 ratio, and elevated
thyroglobulin levels (1, 2).
When a pregnancy takes place in iodine-sufficient conditions, the
thyroid gland adapts easily to the challenge of pregnancy and goiter
formation during gestation is not observed (3, 4). On the
contrary, pregnancies occurring in women with a restricted (or
deficient) iodine intake are frequently accompanied by goitrogenesis,
affecting both the mother and fetus (2, 3, 4, 5, 6). Furthermore,
changes in thyroid volume associated with gestation are directly
correlated to the degree of iodine deficiency (7). Most
studies have concluded that pregnancy-induced thyroid volume
alterations are reversible after the delivery (6, 8).
Even if parity has been proposed to be a factor influencing goiter
frequency during pregnancy (6, 9), there are presently no
existing reports in which thyroid volume has been evaluated in relation
with parity. Therefore, the purpose of the present work was to
investigate the effects of pregnancies in healthy females on the volume
of the thyroid, to assess a possible relationship between changes in
thyroid volume and the parity status.
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Patients and Methods
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Nongoitrous healthy females were selected from hospital staff
and their relatives, by means of a thyroid size physical examination
(by inspection and palpation), performed by two different
clinicians (C. C. and B. B.). After the initial
physical thyroid size estimation, all women who, according to the
grading scale proposed by Stanbury et al. (10),
were either grade 0A (thyroid not palpable, or if palpable no larger
than normal) or grade 0B (thyroid distinctly palpable but not visible
with the head in a normal or raised position) were enrolled. The study
group encompassed 208 healthy females. Their median age was 42 yr
(range, 22–75). All women lived in the city of Naples or the
surrounding areas, a region known to present moderate iodine
deficiency, with usual urinary iodine levels ranging from 40–100
µg/day (11). All subjects investigated underwent serum
free T3 (FT3), free
T4 (FT4), and TSH
determinations, as well as thyroglobulin antibody and thyroid
peroxidase antibody detection. All were clinically and
biochemically euthyroid and had no detectable thyroid autoantibodies.
Ultrasound examination of the thyroid gland was carried out, and
thyroid volume was calculated. Exclusion criteria were: 1) previous
history of thyroid disease of any kind; 2) thyroglobulin antibody
and/or thyroid peroxidase antibody positivity; 3) iodide prophylaxis;
4) presence of nodularity at ultrasound; 5) a pregnancy in the previous
18 months; 6) major physical illness; 7) iodide-containing or chronic
medication and/or oral contraceptives; and 8) for the nulliparous
women, any known endocrine cause of female infertility. All subjects
enrolled met these criteria. Women were assigned to five groups on the
basis of the number of completed pregnancies: group 0 (no pregnancy);
group I (one pregnancy); group II (two pregnancies); group III (three
pregnancies); and group IV: (four or more pregnancies). Women assigned
to group IV had a mean of 5 previous pregnancies (ranging from 4–12
pregnancies). A previous history of miscarriages and/or voluntary
pregnancy interruption were taken into account to exclude cases from
the study. All women gave informed consent to the study.
Hormone assay
Serum FT3, and FT4
(normal range, 3.84–7.68 and 10.3–23.2 pmol/L, respectively) were
assayed by RIA with Lysophase kits (Technogenetics, Milan, Italy).
Intra- and interassay variations and sensitivities were 2.9%, 4.7%,
and 0.8 pmol/L for FT3 and 3.0%, 5.7%, and 1.0
pmol/L for FT4, respectively. Serum TSH levels
(normal range within 0.3 and 3.5 mU/L) were investigated by an
ultrasensitive assay kit (DiaSorin, Inc., Saluggia,
Italy). Intra- and interassay variability was 3.9 and 5.4%,
respectively; sensitivity was 0.05 mU/L.
Ultrasound examination
The scanner used was a Toshiba 250 (Toshiba Sonolayer,
Japan), using a 7.5-MHz transducer. All subjects were examined
in the supine position, with the neck in hyperextension, by two
different operators (C. C. and G. A.) "blinded"
with regard to the group to which the patient belonged. The total
volume calculation was performed by a previously described method
(12), with intraobserver and interobserver variations of
4% and 6%, respectively.
Statistical analysis
Statistical analysis was performed using SPSS software
(SPSS, Inc., Evanston, IL). The effects of pregnancies,
age, and body weight on thyroid volume were analyzed separately by
one-way ANOVA. Post hoc analysis was performed when
appropriate by means of unpaired t test, applying the
Bonferroni’s correction. A P value less than 0.05 was
considered statistically significant. To test the independent effects
of age and parity on thyroid volume, multiple regression analysis was
used and partial correlation coefficients were computed. Data are
reported as the mean ± SEM, unless
otherwise noted.
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Results
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Age, body weight, and thyroid parameters of all groups are given
in Table 1
. As expected, the mean age of
women increased with the number of previous pregnancies (from 35 yr in
group 0 to 53 yr in group IV). There were no statistically significant
body weight differences between groups. Serum
FT3, FT4, and TSH were
within the normal range, and there was no statistically significant
difference between the groups. The one-way ANOVA was performed choosing
thyroid volume (expressed in mL) as a dependent variable and the number
of completed pregnancies, age, and body weight separately, as
independent variables. Considering the entire group of 208 subjects,
thyroid volume showed a significant increase, with both parity
(P < 0.001) and age (P < 0.05),
whereas no significant increase in thyroid size was found with body
weight. To discriminate the effects of previous pregnancies and of the
age on thyroid volume, partial correlation coefficients between thyroid
volume and number of term pregnancies (adjusted for the age) were
computed. The results indicated that the correlation between thyroid
volume and the number of term pregnancies was maintained and the
statistical power of this correlation was not reduced
(P < 0.001) after age adjustment. When a similar
partial correlation was evaluated between thyroid volume and age
(i.e. without the effect of completed pregnancies), the
correlation was no longer significant. Therefore, the number of
term-conducted pregnancies was identified as the variable that most
strongly correlated with thyroid size. To investigate a potential
additional effect of multiple term pregnancies, the ANOVA with
post hoc Bonferroni procedure for multiple comparisons was
performed (Fig. 1). The results clearly
indicated that the mean thyroid volume increased gradually with the
increasing number of gestations. Moreover, statistical significance was
only reached when comparing women whose differences as to the number of
completed pregnancies was greater than two.
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Figure 1. Progressive increase in thyroid volume
(mean ± SD in mL) [group 0 (14.8 ± 5.6); group
I (16.0 ± 4.5); group II (17.1 ± 4.4); group III (18.2
± 3.7); group IV (20.3 ± 3.8)] and statistical significance of
post hoc testing (Bonferroni) among groups.
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Discussion
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The mechanisms underlying the regulation of the thyroid gland
adaptation to the pregnant state have been recently reviewed, and the
physiopathological mechanisms leading to goiter formation during
pregnancy have been clarified (13).
Studies performed in iodine-sufficient areas have concluded that the
maternal thyroid gland is able to adapt to the new equilibrium state
associated with the gestation status, without significant modification
in thyroid volume (3, 4). In contrast, several studies
carried out in areas with variable degrees of iodine deficiency have
unequivocally shown that the pregnancy-induced metabolic adaptations
are compromised to different extents, related to the severity of the
iodine restriction (7, 8, 14).
The reversibility of the thyroid enlargement found in pregnancy has
been investigated in two studies, with opposite findings (6, 15). In the first study (6), the average increase
by 30% in thyroid volume during gestation was apparently normalized 12
months after delivery, whereas in the second study (15)
thyroid size increase averaged 55% and it was only partially reverted
12 months after parturition. The main difference between the two above
mentioned studies is that they were performed in areas with different
degrees of iodine deficiency, which is less pronounced in Copenaghen
(6) than in Bruxelles (15). Taking together
data obtained from iodine-sufficient or -deficient areas, it seems
reasonable to assume the existence of a continuum from physiology to
pathology driven, at least in part, by the environmental iodine supply
(16). Therefore, in iodine sufficiency, no or minimal
thyroid volume increase is observed during pregnancy; in iodine
deficiency, thyroid volume increases with gestation and reverts to the
initial size 12 months postpartum; and finally, when iodine deficiency
is more pronounced, the thyroid volume modifications induced by
pregnancy are only partially reversible. Thus, in such a condition,
pregnancy may act with a "ladder effect," in which each pregnancy
would represent one further step in "ladder climbing."
In previously published prospective studies, thyroid volume
modifications were investigated between early gestation and term or the
immediate postpartum period. In the present work, the aim was to
compare, for the first time, the effects of the number of previous
pregnancies on thyroid volume. Because this type of study cannot be
performed prospectively, we decided to analyze retrospectively the
number of full-term previous pregnancies in relation with the present
thyroid volume in a large group of women. The results clearly
demonstrated that, indeed, gestational goitrogenesis was not fully
reversible, at least in our area with a moderately iodine-deficient
status. For the first time, a correlation was shown between parity and
a larger thyroid volume with an additional effect related to multiple
pregnancies. This notion is particularly important because in the
present study, group IV comprised women having had between 4 and 12
previous pregnancies. Moreover, our results indicated that there was no
correlation between thyroid volume and age per se, in
accordance with some previous observations (16, 17) but in
contrast with one other (18). A positive correlation
between thyroid volume and body weight had been reported in the past
(18). This finding was not confirmed in the present study,
suggesting that it is most likely the lean body mass rather than the
whole body weight that represents the major determinant of thyroid size
(19).
In conclusion, the present study showed a significant association
between a larger thyroid size, in healthy women, that was correlated
with the number of their previous pregnancies. Although the design of
the present study was retrospective, the results constitute the first
clinical confirmation that the goitrogenic effect of pregnancy is
maintained in the long term, and it is related to the number of
pregnancies. This confirms the hypothesis that goiter formation during
pregnancy is not fully reversible after parturition, and the present
results provide an additional strong argument to indicate the need to
increase the iodine supply in pregnant women to an adequate level of
200 µg/day, as recommended by WHO (20, 21).
Received November 10, 1999.
Revised May 11, 2000.
Revised June 23, 2000.
Accepted August 17, 2000.
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Abstract
Introduction
