UNIVERSITY OF PISA
PhD Program in
Clinical and Translational Science
Iodine Intake, Thyroid Function and
Pregnancy Outcome in a Tuscan Cohort
of Women Living in an Area with
Moderate Iodine Deficiency
Candidate
Tutor
Elena Gianetti, MD
Massimo Tonacchera, MD, PhD
1 INDEX
• Abstract
• Introduction
o Maternal thyroid function during pregnancy
o Fetal thyroid function
o Hypothyroidism during pregnancy
o Hyperthyroidism during pregnancy
o Thyroid autoimmunity and pregnancy
• Aim
• Patients
• Materials and methods
• Results
o Cohort description
o Iodine intake
o Thyroid hormones modifications during pregnancy
o Thyroid function and iodine intake
o Thyroid volume and iodine intake
o Thyroid autoimmunity during pregnancy
o LT4 treatment during pregnancy
o Thyroid autoimmunity and risk of miscarriage
• Discussion
• Conclusions
• References
2 ABSTRACT
Thyroid hormones are crucial for fetal development. Pregnancy leads to multiple changes in thyroid function.
Aim of the study was to evaluate iodine intake, thyroid function and thyroid autoimmunity impact on pregnancy outcome.
Thyroid function, anti-thyroid antibodies, thyroid ultrasound, urinary iodine
[UI], and pregnancy complications were analyzed at 10th, 15th, 20th, 25th and 35th
weeks of pregnancy and 3-6 months after delivery in 902 women living in Tuscany, an area of moderate iodine deficiency.
Chronic autoimmune thyroiditis [CAT] was found in 414 women (45.9%). Of these, only 261 (63%) were aware of their disease before our evaluation. Similarly, a nodular disease was found in 138 women (15.3%), but only 89 (64%) knew about that before pregnancy.
At the first evaluation, iodized salt alone [S] was assumed by 31% of women, multivitamins containing iodine [M] by 20%, both [B] by 24% and none [N] by 25%. While a significantly higher UI and a higher number of women with UI over the desirable 150 µg/L value was measured in M and B groups, median UI was below 150 µg/L in all groups, both considering all women and only women not assuming any thyroid therapy.
A significant correlation between FT4, FT3 or TSH and UI was not found in either healthy women or women affected by a thyroid disease, but women with UI below 50 µg/L had a significantly lower FT3/FT4 ratio.
Thyroid volume significantly increased throughout pregnancy, this increase depending on both TSH and UI.
In women affected by autoimmune thyroiditis, both thyroglobulin and anti-thyroperoxidase antibodies decreased during pregnancy and rebounded 3 months after delivery.
3 Analyzing the previous pregnancy history of recruited women (n=492 pregnancies), a miscarriage was reported in 51.4% of cases, without differences between healthy women and women affected by CAT (miscarriage prevalence being 53.9% and 49.9% respectively). No difference between women affected by CAT and healthy ones was found when considering the 902 pregnancies included in this study, although the prevalence in both groups was about 10%. LT4 dose in women already treated at the beginning of pregnancy required an
increase in57% of women under suppressive therapy (mean increase 52%), 72%
of women with autoimmune hypothyroidism (mean increase 33%) and 92% of thyroidectomized women (mean increase 34%). Moreover, 50 women affected by CAT and 5 with thyroid nodules initiated LT4 therapy during pregnancy, mean final dose being 64.2±31.1 µg/die and 55.0±27.4 µg/die respectively. In conclusion, almost a half of women affected by a thyroid disease were not aware of their disease at the beginning of pregnancy, suggesting that a universal screening could be useful. While S seems to be not enough a supplementation during pregnancy, M are able to increase UI but the majority of women continue to have an insufficient iodine uptake. Moreover, M are assumed by a minority of women, suggesting an improvement in supplementation programs is needed. This is crucial when considering that FT3/FT4 ratio increased in women with very low UI, suggesting a role of UI in isolated hypothyroxinemia, which has been previously correlated with children cognitive abilities. While an increase in LT4 therapy is often required, this is not true for all women and varies in different thyroid diseases, so that any change in the dose should follow an early, frequent and personalized thyroid function evaluation.
4 INTRODUCTION
Maternal thyroid function during pregnancy
Pregnancy leads to multiple hormonal modifications impacting on thyroid function. Human chorionic gonadotropin (hCG) stimulates thyroid function because of its structural homology with TSH, leading to a reduction in TSH serum levels especially during the first trimester. Moreover, placenta contains type 2 and type 3 deiodinases that convert T4 to T3. During pregnancy estradiol increases, stimulating TBG hepatic production, which leads to a transient decrease of free thyroid hormones. Through a positive feedback, this stimulates hypothalamus-hypophysis-thyroid axis, leads to an increase in thyroid hormones production. Because of all these modifications, TSH values decreases in the very first weeks of pregnancy and increases later on (figures 1, 2). Thyroid stimulation during pregnancy has an effect on thyroid volume as well, which increases of 10% in iodine sufficient areas and 20-40% in iodine deficient areas. During pregnancy, iodine requirement increases of near 50% because of higher glomerular filtration and renal iodine clearance, accelerated thyroid hormones synthesis and placental transfer of thyroid hormones from the mother to the fetus, especially during the third trimester. When iodine is not enough, thyroid is not able to adapt the increased hormone synthesis requirement, possibly causing hypothyroidism and goiter. For these reasons, iodine intake is crucial during pregnancy. According to OMS data, in 2007 nineteen European nations had an adequate iodine intake, which is much more than 1993, when only 2 were iodine
sufficient areas1. However, of 40 evaluated nations, 13 had persistent iodine
deficiency. Moreover, in 2004 about 43% of European children between 6 and 12 years old showed iodine deficient status, and in a British study of 2010, 51% of
school girls were iodine deficient2. In a Spanish study iodine intake was evaluated
in 2104 women during first trimester and 1322 in second and third trimester, showing that urinary iodine (UI) median were below the adequate values (88 µg/
5 during first trimester and 140 µg/l during second trimester), confirming the presence of iodine deficiency but lacking to show a correlation with either maternal thyroid hormones or neonatal TSH. In particular, only 14.4% of women during first trimester and 26.8% during second trimester had and adequate
iodine intake (likely due to iodine supplementation)3. According to OMS, iodine
intake during pregnancy should remain between 250 µg and 500 µg. Iodine supplementation with multivitamins containing 150-250 µg of iodine as
potassium iodide is recommended since before the beginning of pregnancy4.
Thyroid function changes at different times during pregnancy, so that normal ranges of TSH and FT4 are trimester-specific. In particular, TSH normal range is 0.1-2.5 mU/l during first, 0.2-3.0 mU/l during second and 0.3-3/3.5 mU/l during
third trimester5-7. Moreover, some women present with TSH values below the
detectable (<0.01 mU/l) without being affected by any thyroid disease. A small but significant ethnicity-related difference has been demonstrated: Asian and Black women present with lower mean TSH respect to Caucasian ones during
the whole pregnancy8. Because of TBG increase and albumin reduction
concentration due to dilution, FT4 values interpretation depends on the dosage method (it should be done using dialyzed serum or ultrafiltration by
chromatography/spectrography9). Trimester specific FT4 values have not been
reported in the literature. Some authors have proposed to use TT4 (multiplying non-pregnancy values by 1.5), FT4 index (immunoassay) or T3 uptake, but none of these methods are routinely used.
Fetal thyroid function
Thyroid hormones are crucial during embryogenesis, particularly for nervous system development. Fetal thyroid starts as a simple midline thickening and develops to form the thyroid diverticulum, between the first and second pouches. Later, it descends through the thyroglossal duct reaching its definitive
6
increasing up to 36th week. Thyroid is able to modify iodine uptake on the basis
of iodine intake and TSH values only once it is completely developed. Therefore, maternal thyroid function and iodine intake are essential to maintain the adequate fetal thyroid hormones needs, especially during the first weeks that
are the most important for embryogenesis10.
Hypothyroidism during pregnancy
Hypothyroidism during pregnancy is defined by TSH values greater than 2.5 mU/l during the first trimester and 3 mU/l during second and third trimesters associated to decreased FT4 values, or TSH greater than 10 mU/l independently from FT4 values. Subclinical hypothyroidism is characterized by TSH values between 2.5 mU/ml and 10 mU/ml associated to normal FT4. Finally, in isolated
hypothyroxinemia TSH is normal and FT4 is below the 5th-10th centile.
Reported prevalence of hypothyroidism in fertile women is 0.3-0.5%, while subclinical hypothyroidism is 2-2.5%. The first cause of hypothyroidism is chronic autoimmune thyroiditis (CAT), followed by radiometabolic therapy and thyroidectomy. Maternal complications of gestational hypothyroidism can be gestational hypertension (with or without preeclampsia), anemia, placental breakdown and post-partum bleeding. From a fetal point of view, possible complications are miscarriage, perinatal death, fetal suffering, low birth weight, transient congenital hypothyroidism (caused by blocking TSH receptor antibodies) and cognitive alterations. All this maternal and fetal problems have been associated with overt hypothyroidism, but not as much is known on possible consequences of subclinical hypothyroidism. However, a recent meta-analysis has confirmed an increased risk of miscarriage, preterm labor, gestational diabetes, gestational hypertension and preeclampsia, although
association with neurological damage is less clear11. Isolated hypothyroxinemia
has not been associated with obstetrical problems or neurological development so far.
7 Treatment of hypothyroidism consists in oral LT4 replacement. American
Thyroid Association (2017)5and Endocrine Society (2012)7 recommend to start
LT4 therapy in presence of subclinical hypothyroidism and anti-thyroperoxidase
antibodies (TPOAb), while European Thyroid Association (2014)6, 12 advices to
treat all women with subclinical hypothyroidism. None of these recent guidelines recommends treatment for isolated hypothyroxinemia, except during the first trimester (because of the unclear association with neurological problems).
Once the treatment is started, thyroid hormones should be measured after 30-40 days. Later on and in not treated women with CAT, thyroid function should be checked every 4-6 weeks.
Women already assuming LT4 when the pregnancy begins usually need a
dosage increase of 30% since the 4th-6th weeks. For women who start LT4
treatment during pregnancy, initial dose should be 1.8-2 µg/kg/die in overt
hypothyroidism and 1.0-1.5 µg/kg/die in subclinical hypothyroidism13. Thyroid
function should be checked 6 weeks after delivery. At that time, although women usually need to go back to pre-pregnancy dose, it has been recently showed that 50% of the ones affected by CAT require a post-partum dose that is
higher than before conception14, suggesting a persisting effect of pregnancy in
presence of thyroid autoimmunity.
Hyperthyroidism during pregnancy
The first cause of hyperthyroidism during pregnancy is Graves’ disease (GD). Independently from autoimmune etiology, gestational hyperthyroidism can be caused by the increased thyroid stimulation by hCG (gestational transient
thyrotoxicosis)15. This happens more often in hydatiform mole or
choriocarcinoma16, but it can be found in other conditions as well, such as twin
pregnancies17, rare TSH receptor mutations leading to increase sensitivity to
8 gravidarum. Once neoplastic etiology is excluded, this form of hyperthyroidism usually does not require treatment since it is usually mild, with no or little
symptoms, and thyroid function spontaneously normalizes by 20th week.
Differently, untreated GD can lead to important maternal and fetal consequences. Differential diagnosis is based on clinical signs (goiter, serious hyperthyroidism, ophtalmopathy) and on the presence of TSH receptor antibodies (TRAb).
Hyperthyroidism treatment is based on thioamides (methimazole [MMI] and
propylthiouracil [PTU]) and rarely on surgery (only during 2nd trimester).
Thioamides are able to cross the placenta, leading to a risk of fetal hypothyroxinemia in case of too high dosage. For the same reason, they could
be teratogenic when used between the 6th and the 10th week. "Methimazole
embryopathy" is a combination of congenital malformations (choanal atresia, esophageal atresia, omphalocele, aplasia cutis, facial dimorphism) that has been described in association with MMI administration during the first trimester, although clear evidence is lacking. For this reason PTU use is preferred during the first trimester of pregnancy, although recently the possibility of a teratogenic effect has been suggested as well. Anyways, for the well known
hepatotoxicity of PTU, MMI should be used during second and third trimester19.
Most recent guidelines7 recommend verifying the presence of TRAb starting at
20th week of pregnancy (in particular between 22th and 26th week) in women
affected by GD. In women under treatment and showing TRAb levels 2-3 times over the upper limit, maternal FT4 and fetal biometry should be checked
between 18th and 22nd week and every 4-6 weeks thereafter. Signs of fetal
hyperthyroidism are fetal goiter, intrauterine growth restriction, hydrocephalus, increased bone age, tachycardia (>160 bmp), cardiac failure. Right after delivery, these newborns should undergo to a TRAb levels evaluation on cord blood and FT4, FT3 and TSH measurement on neonatal serum by 24-48h of life, one week later and at two months of life.
9 Thyroid autoimmunity and pregnancy
Thyroid autoimmunity is the main cause of hypothyroidism and the most common autoimmune disease in fertile women, with a prevalence of 5-10%. The association between this condition and infertility has been evaluated in several studies (table 1).
In studies where the cause of infertility were either polycystic ovary syndrome
(PCOS)20 or endometriosis21 a significant association has been found. In
particular, in PCOS thyroid autoimmunity was found in 27% of women vs. 8% of control group, probably due to the increased estrogen/progesterone ratio: lower progesterone levels would lead to a prevalence of Th1 lymphocytes vs. Th2, leading to an inflammatory pattern with increased gamma-IFN.
However, a meta-analysis of 53 studies on the association between thyroid autoimmunity and pregnancy has demonstrated that, although a mild association exists, women affected by CAT were older and presented with a slightly but significantly higher TSH, so that a clear cause-effect correlation
10 AIMS
Aims of this study were to evaluate:
• Prevalence of thyroid diseases during pregnancy
• Iodine intake adequacy during pregnancy
• FT4, FT3 and TSH modifications during pregnancy
• Correlation between iodine intake and thyroid function
• Correlation between iodine intake and thyroid volume
• Thyroid autoantibodies changes during pregnancy
• L-thyroxine treatment requirement during pregnancy
11 Nine hundred and two consecutive not-selected pregnant Tuscan women were included in the study. Women were referred by their ObGyn to a clinic practice that was especially established in the Department of Clinical and Experimental Medicine - U.O. Endocrinology I. Women were evaluated throughout the whole pregnancy and until 3-6 months after delivery.
12 MATERIALS AND METHODS
Women were evaluated at 10th, 15th, 20th, 25th and 35th week of pregnancy and 3-6 months after delivery. At each timepoint TSH, FT4, FT3, TPOAb, Antithyroglobulin antibodies (TgAb) and UI were measured. In selected cases TSH-receptor antibodies (TRAb) and calcitonin (CT) were evaluated as well. Moreover, a thyroid ultrasound was performed at each timepoint.
TSH, FT4, FT3 TPOAb and TgAb where measured by enhanced chemioluminescence (Immulite®2000, by Medical Systems Genova). Normal ranges in general non pregnant general population are:
o TSH = 0.4-3.4 mU/L o FT3= 2.7-5.7 pg/ml o FT4 = 7-17 pg/ml o TPOAb < 10 UI/ml o TgAb < 30 UI/ml o CT < 10 pg/ml o TRAb < 2 UI/L
Consistently with the most recent guidelines, subclinical hypothyroidism was defined by TSH values over 2.5 mU/l during the first trimester of pregnancy and by TSH values over 3 mU/l during second and third trimester.
UI was determined on a single urine sample by Autoanalyser 3 (Bran-Luebbe). Consistently with international guidelines, during pregnancy we defined:
Iodine deficiency: UI < 100 μg/l
Mild iodine deficiency: UI 101-150 μg/l
Adequate iodine intake: UI 151-250 μg/l,
13 Thyroid volume, echogenicity, presence of nodules and morphologic changes throughout pregnancy were measured by thyroid ultrasound. All ultrasounds were performed by the same physician using an ESAOTE machine and a 7 MHz linear probe.
14 RESULTS
902 pregnancies were analyzed in this study. Mean age of women was 33±5.3 years. Eight hundred and seventy-five women (97.0%) were Caucasian, 10 (11.1%) African, 10 (11.1%) Hispanic and 5 (5.5%) Asian. Mean BMI at first
evaluation was 22.7±3.9 Kg/cm2. In particular, 77% of women presented with a
normal weight (BMI <24.9 Kg/cm2), 17% overweight (25<BMI>29.9 Kg/cm2) and
6% obese (BMI>30 Kg/cm2, max BMI 36 Kg/cm2).
Cohort description
At first evaluation, 494 women (54.8%) were not aware of any thyroid disease, 261 (28.9%) knew to be affected by CAT, 89 (9.9%) by thyroid nodules, 37 (4.1%) by GD, 10 (1.1%) by thyroid carcinoma. Moreover, 4 women were affected by other forms of hypothyroidism (2 congenital, 1 post-radiotherapy for lymphoma and 1 for Rathke pouch cyst) (figure 3). After evaluation of the 902 women, 297 (32.9%) resulted to be healthy, 414 (45.9%) presented with CAT, 138 (15.3%) with nodular goiter, 42 (5.8%) by GD and 11 by thyroid carcinoma (plus, the diagnosis was confirmed for the four women with not-autoimmune hypothyroidism) (figure 4). This means that of the 494 women who did not know of any thyroid disease, only 297 (60.1%) were actually healthy, while 154 (31.1%) presented with CAT, 49 (9.9%) with nodular goiter, 15 (3.0%) by GD and 1 (0.2%) by thyroid carcinoma (figure 5).
About 75% of women affected by CAT presented with adequate TSH values independently from the time of their first evaluation. In particular, when the initial visit was:
- before 12th week of pregnancy, 74% presented with TSH below 2.5 µU/ml (euthyroidism), 23% with TSH over 2.5 µU/ml and normal FT4 and FT3 (subclinical hypothyroidism) and 3% with TSH over 2.5 µU/ml with decreased FT4 and FT3 (overt hypothyroidism).
15 - between 13th and 17th week of pregnancy, 75% presented with euthyroidism (TSH below 2.5 µU/ml), 25% with subclinical hypothyroidism and none with overt hypothyroidism.
- between 18th and 22nd week of pregnancy, all presented with TSH below 3 µU/ml (euthyroidism).
- between 23th and 30th week of pregnancy, 75% presented with TSH below 3 µU/ml (euthyroidism) and 25% with TSH over 3 µU/ml and normal FT4 and FT3 (subclinical hypothyroidism).
- after 31st week of gestation, all were euthyroid (TSH below 3 µU/ml).
Women were divided into three groups on the basis of UI: Iodine intake
- poor iodine intake (P): <150 µg/l
- adequate iodine intake (A): 150-250 µg/l - excessive iodine intake (E): >250 µg/l
Women were interrogated on their use of iodized salt, multivitamins containing iodine or both. At the first evaluation, 25.1% did not assume any iodine supplementation (N), 31.0% was using iodized salt (S), 20.2% multivitamins (M) and 23.7% both (B).
Median UI was poor in all groups, but UI increased and number of women with poor iodine intake decreased with iodine supplementation (median UI was 46 µg/L in N, 55 µg/l in S, 98 µg/l in M and 141 µg/l in B; women with poor iodine intake were 92% in N, 88% in S, 67% in M and 65% in B). Although iodized salt use increases UI, when it is assumed alone it does not lead to a statistically significant difference respect to women without iodine supplementation. The difference becomes significant between N and M (p-value [0.014]) and between
16 N and B (p-value [0.041]). Results are similar when considering only women not assuming thyroid therapy (table 2).
Throughout pregnancy, UI levels significantly increased (ANOVA p-value < 0.001) and decrease after delivery (figure 6).
Analyzing all untreated women, mean TSH statistically increased during pregnancy (p-value = 0.007), remaining adequate at all timepoints. Mean FT4 and FT3 gradually and statistically significantly decreased throughout pregnancy (test one way ANOVA p-value<0.001), but remained in the normal range (figure 7).
FT4, FT3 and TSH changes during pregnancy
Similar results were found including only women without a thyroid disease: mean TSH statistically increased during pregnancy (p-value = 0.007), remaining adequate at all timepoints, and mean FT4 and FT3 gradually and statistically significantly decreased throughout pregnancy (test one way ANOVA p-value<0.001), but remained in the normal range (figure 8).
A correlation between UI and FT4, FT3, TSH and FT3/FT4 ratio was sought. In women without a thyroid disease, no significant correlation was found at any of the timepoints, with the only exception of a statistically significant correlation
between UI and FT4 at the 20th week (p-value 0.049). In women affected by CAT
no significant correlation was found at any of the timepoints. Thyroid function and iodine intake
However, analyzing the whole cohort and classifying women on the basis of UI below or over 50 µg/l (to underline severe iodine deficiency), a statistically significant correlation between UI and FT3/FT4 ratio was found (p-value 0.045).
17
Analyzing the whole cohort, mean thyroid volume at 10th week was 11.4 ± 4.9
ml and it was 12.6 ± 5.1 ml at 35th weeks, gradually and significantly increasing
throughout pregnancy (ANOVA p-value 0.02; t-test p-value between 10th and
35th week 0.007) (figure 9). When adjusting for TSH, UI or both the correlation
was not present anymore, so that both TSH and UI are responsible for thyroid volume increase throughout pregnancy.
Iodine intake and thyroid volume
Similar results were obtained when analyzing only women not affected by any
thyroid disease (11.4 ± 2.9 ml at 10th week and 13.8 ± 3.4 ml at 35th week - t-test
p-value 0.01) or women affected by CAT (11.5 ± 4.5 ml at 10th week and 12.5 ±
5.1 ml at 35th week - t-test p-value 0.01).
In women affected by CAT, TgAb and TPOAb were measured at all timepoints. Both autoantibodies decreased throughout pregnancy, although this difference was statistically significant only for TgAb (test one way ANOVA p-value <0.001). Three months after delivery thyroid autoantibodies increased, in particular TPOAb, which become higher than before pregnancy (figure 10).
Thyroid autoimmunity evaluation
Two hundred and seventeen women assumed L-thyroxine treatment during pregnancy, 162 of them since before conception. Twenty-three out of these 217 were under suppressive therapy for a nodular goiter and the others under replacement therapy, in particular 23 were hypothyroid after total thyroidectomy and 171 were affected by CAT with hypothyroidism.
L-thyroxine treatment during pregnancy
57.1% of women under suppressive therapy had to increase LT4 dose during pregnancy, mean increase being 52.2% of initial dose. 92.3% of women under
18 replacement therapy after thyroidectomy had to increase LT4 dose during pregnancy, mean increase being 34.4% of initial dose. 71.9% of women under replacement therapy for autoimmune hypothyroidism had to increase LT4 dose during pregnancy, mean increase being 33.0% of initial dose (table 3).
Moreover, 50 women affected by CAT and 5 women with thyroid nodules initiated LT4 therapy during pregnancy, mean final dose being 64.2±31.1 µg/die and 55.0±27.4 µg/die respectively.
At the first visit women were interrogated about previous pregnancies and miscarriages. Of all previous pregnancies occurred in women included in the study (#492), 253 (51.4%) ended with a miscarriage, with no significant difference (analyzed by chi-square) between healthy women (53.9%) and women affected by CAT (49.9%) (table 4).
Thyroid autoimmunity and miscarriages
Data regarding the outcome are available for 251 of the 902 pregnancies included in the study. Of these, 27 (10.8%) ended with a miscarriage, with no significant difference (analyzed by chi-square) between healthy women (11.1%) and women affected by CAT (9.6%) (table 5).
19 DISCUSSION
In this study, 902 consecutive pregnant women were evaluated. At first evaluation, 54.8% of women were not aware of any thyroid disease, while 28.9% knew to be affected by CAT, 9.9% by thyroid nodules, 4.1% by GD and 1.1% by thyroid carcinoma. It is well known that thyroid diseases are more frequent in women, with a female/male ratio of 4-10/1. In areas with adequate
iodine intake, autoimmunity is the most common etiology23. When autopsy data
were analyzed, 27% of adult women resulted affected by CAT, although only 20% could be diagnosed on the basis of ultrasound pattern and presence of TPOAb. On the other hand, an important study on the prevalence of thyroid diseases in areas with iodine deficiency has been conducted in Pescopagano (Italy), where 1148 subjects were evaluated basally in 1995 and after 15 years of supplementation with iodized salt. Iodine supplementation led to modifications of thyroid diseases prevalence, with a decrease in goiter and functional autonomy in young subjects and a reduction in not-autoimmune
hyperthyroidism in olders. CAT was found in 18.4% of young adult women24
consistent with anamnestic data of our study. Interestingly however, after evaluation we found that only 60.1% of the 494 women who did not know of any thyroid disease were actually healthy, while 31.1% presented with CAT, 9.9% with nodular goiter, 3.0% with GD and 1 by thyroid carcinoma. Current
guidelines7, 25 recommend thyroid disease screening during pregnancy only
when risk factors are present (age > 30 years, family history, goiter, thyroid antibodies, signs or symptoms of thyroid dysfunction, other autoimmune diseases, infertility, previous miscarriages, previous radiotherapy on the neck, iodine deficiency). Our data suggest that a universal screening should be performed, with particular attention to thyroid autoimmunity and possible resulting thyroid function modifications, to avoid maternal and fetal complication during pregnancy and delivery.
20 Iodine, essential for thyroid hormones synthesis, is assumed with diet. According to literature, about 29% of world population lives in an area with
iodine deficiency, which modifies prevalence of thyroid diseases26, 27. The most
used kind of iodine supplementation is iodized salt. In 2005 the Italian Parliament approved a law planning to add 30 mg of iodized potassium to every
kilogram of salt, which must be available everywhere (Law March 21th, 2005, n.
55, “Disposizioni finalizzate alla prevenzione del gozzo endemico e di altre
patologie da carenza iodica", published on Gazzetta Ufficiale n. 91, April 20th,
2005).
Iodine intake
During pregnancy, iodine requirement increases of about 50%, so that WHO advices for a daily iodine intake between 250 µg and 500 µg during pregnancy
and lactation1, 4. In this case, iodine supplementation with supplements
containing 150/250 µg of iodine are the first choice, to be started months before conception.
In our study, about 25% of women did not assume any iodine supplementation, 31% used iodized salt, 20% multivitamins and 24% both. In Italy, the Istituto Superiore di Sanità reports that iodized salt is used by 40% of population, which is far from countries with adequate iodine intake (where 90% of people assume it), suggesting that a better information and communication by persons and institutions in charge is needed.
In our study, iodine supplementation led to an increase of UI, despite iodized salt use alone was not able to significantly modify it: the percentage of women with poor iodine intake decreased when both iodized salt and multivitamins were assumed. UI significantly increased during pregnancy and decreased after delivery. This is likely due to the use of multivitamins during pregnancy that are often discontinued after delivery.
21 Importantly, even in presence of iodine supplementation, median UI was not adequate at any timepoint. This could be due to a too short supplementation time: it has been described that it takes at least two years to restore normal
thyroid iodine deposits28. Therefore, it would be importance to initiate
adequate iodine supplementation way before conception.
In this study, during pregnancy a gradual FT4 and FT3 reduction and TSH increase occurred, both in women affected by CAT and in healthy women,
consistently with data in the literature1. For this reason, it would be important
to check thyroid function at least once every trimester in all women, to verify all values remain into the normal range.
Thyroid hormones changes during pregnancy
Although a linear correlation between UI and thyroid function was not found (possibly because of the size of the cohort), in our study a significant difference in FT3/FT4 ratio was described between women with very low UI (< 50 µg/l) and the others, suggesting that iodine deficiency can lead to isolated hypothyroxinemia.
Thyroid function and iodine intake
Several studies have been conducted to evaluate the role of isolated hypothyroxinemia on fetal neurological development. Data on animal models suggest that low FT4 values are able to modify fetal neurogenesis and neuronal
migration29, consistently with human data suggesting that isolated
hypothyroxinemia negatively impacts on fetal cognitive development30. In 1971
the first prospective study was conducted on 1394 women with hypothyroxinemia during pregnancy: newborns were evaluated at 8 moths, 4 years and 7 years demonstrating that children born to not-treated mothers
22
showed that women with hypothyroxinemia at 12th-13th week of pregnancy had
babies with a higher risk of psychomotor skills32 and language alterations33. In
another study on 27 Sicilian women, 7 out of 8 children from mother with low FT4 during pregnancy and iodine deficiency presented with attention deficit and
hyperactivity disorder at 7-8 years34. In a cohort of 1761 Spanish women,
hypothyroxinemia at 13th week was associated to a lower Bayley scale score at
14 months, indicating an impaired neurological development35.
On the other side, the only randomized study in the literature has been conducted on 21846 pregnant women, 794 of whom with increased TSH and/or decreased FT4 values at 15th week: 390 were treated with LT4 and 404 were not treated. Data did not show any significant difference in IQ between 3 years old children from the two groups. The results did not change when evaluating
only women with FT4 reduction, independently from TSH36. Therefore, clear
data on the role of hypothyroxinemia in neurological development are lacking.
Currently, the American Thyroid Association5 advices not to treat isolated
hypothyroxinemia, while the European Thyroid Association6 recommends to
treat only women during the first trimester and the Endocrine Society7 does not
mention this issue.
Thyroid volume and iodine intake
In our study we showed an increase in thyroid volume during pregnancy, which
was correlated to TSH and UI modifications. In a previous paper, Romano et al.37
evaluated 35 pregnant women assuming either iodized salt or placebo: not-supplemented women presented with a 16% increased thyroid volume,
although TSH did not change. Later, Pedersen et al.38 analyzed data from 54
women daily assuming 200 µg of iodine, confirming that iodine supplementation led to a lower increase in thyroid volume and lower TSH and thyroglobulin values during pregnancy, despite no effects on FT4 and FT3
23
10840 women respectively. On the other side, when 66 women with positive
TPOAb were evaluated, the results showed that multivitamins containing 150 µg of iodine led to an increased UI with no significant effects on FT4, thyroglobulin
or TSH41. Later on, an Italian study analyzed the effect of different iodine doses,
evaluating women assuming 50 µg/day vs. 200 µg/day: UI increased only with
the higher dose, despite no effect of thyroid volume and thyroid function42.
Overall, the cited studies suggest that in mild/moderate iodine deficient areas maternal thyroid is able to adjust to the increased thyroid synthesis which is required during pregnancy. Moreover, it is possible that iodine supplementation during pregnancy is able to limit the increase in thyroid volume and in TSH values, consistently with our data.
In women affected by CAT, we demonstrated a reduction in TgAb and TPOAb throughout pregnancy, consistently with gestational general autoimmunity decrease which prevents from maternal rejection of the fetus, and a rebound 3 months after delivery. For this reasons, even women with negative antithyroid antibodies during pregnancy should re-measure them 3-6 months after delivery to exclude the presence of CAT, especially when thyroid ultrasound is suggestive of an autoimmune thyroid disease. The increase of thyroid autoantibodies 3 months after delivery is responsible of post-partum thyroiditis
and is consistent with the timing of this disease as described in the literature43.
Thyroid autoantibodies during pregnancy
L-thyroxine treatment during pregnancy
In the prospective THERAPY (Thyroid Hormone EaRly Adjustment in PregnancY)
study44, 48 women were divided in two groups: the first increased the dose of
29% and the second of 43% as soon as pregnancy was confirmed. These changes led to TSH values below 5 mU/l in the first trimester for both groups,
24 but 32% of the first group and 65% of the second showed TSH values below 0.5 mUI/l, requiring a reduction of the dose. Authors concluded that the dose should be increased of 29% at the beginning of pregnancy (doubling the pre-pregnancy dose on two days per week) and thyroid function should be monitored monthly to obtain TSH modifications similar to physiologic ones. The different dose increase requirement in hypothyroid women seems to depend on the cause of hypothyroidism. Verga et al. monthly evaluated 185 pregnant women, 155 of whom were assuming LT4 since before conception: 86% of women required an increase in the dose, which was higher in women who started treatment because of a subclinical hypothyroidism (mean increase 70%, ranging between 14% and 300%), respect to overt (mean increase 45%) and post-ablative hypothyroidism (mean increase 49%). Moreover, usually the main increase was required during the first trimester, although some women needed further adjustments, so that authors recommended to monitor thyroid
function once a month up to delivery45. The European Society of Paediatric
Endocrinology46 advices to increase the dose of 25-30% as soon as the
pregnancy is confirmed and verify thyroid function every 4-6 week later on. In our study, of 162 women already assuming LT4 at the beginning of pregnancy, an LT4 dose increase was required by 57% of women under suppressive therapy (mean increase 52%), in 72% of women with autoimmune hypothyroidism (mean increase 33%) and in 92% of thyroidectomized women (mean increase 34%). Moreover, 50 women affected by CAT and 5 women with thyroid nodules initiated LT4 therapy during pregnancy, mean final dose being 64.2±31.1 µg/die and 55.0±27.4 µg/die respectively. This data confirm that the management of LT4 therapy during pregnancy should be early, frequent and differentiated on the basis of different thyroid diseases.
25 Thyroid diseases and miscarriages
Spontaneous miscarriage is the most common complication of pregnancy. According to SIdR (Società Italiana della Riproduzione), 15% of clinically recognized pregnancies hesitate in a miscarriage, but it is believed that actually 50% of total pregnancies (including biochemical ones, diagnosed only on the
basis of hCG measurement and ended by the 5th week, when there are not
symptoms or ultrasound signs of pregnancy yet) undergo this fate. The risk of miscarriage seems to increase after a previous one (14-17% after the first and 38% after the second failure), although about 90% of women with a previous miscarriage have a normal pregnancy at a further attempt.
Several studies aimed to verify the association between thyroid autoimmunity and risk of miscarriage (table 6), which would have a strong clinical impact considering the prevalence of this diseases in fertile women. Some of these studies found this association, although others demonstrated that when thyroid function is normal, women affected by CAT are as fertile as healthy ones. In a recent meta-analysis, a significant association between CAT and miscarriages
has been found22, despite no causal effect has been demonstrated since other
risk factors were present in the cohorts as well. In particular, the higher risk could be due to a general modification of immune system with a prevalence of cell-mediated response in the endometrial tissue, CD5/20+ B lymphocytes and Th1 response, in association with cross reactivity between thyroglobulin and placental antigens. CAT would then indicate a predisposition to general autoimmunity which would be the real cause of the miscarriage. For instance, anti-phospholipids syndrome is associated to multiple miscarriages with a risk of 15-90% (varying among different studies), which is due to protrombotic factors (increased thromboxane A2 and decreased prostacyclin), interference with embryo implantation, cytochemical alterations and complement pathway activation. Similarly, systemic lupus erythematosus is known to be associated with an increased risk of precocious miscarriage. Moreover, others endocrine-metabolic diseases such as diabetes mellitus and hyperprolactinemia may
26 increase the risk of miscarriage. Another hypothesis is that CAT, even when associated to euthyroidism, could have an increased risk of developing mild or overt hypothyroidism in presence of the usual gestational thyroid changes. This risk would be higher in women with pre-pregnancy TSH values > 2.5 mU/l. Negro et al. reported that in euthyroid women with positive TPOAb, LT4 therapy decreased the risk of miscarriage. However, the treated group started with higher TSH values, so that it is impossible to establish whether this difference is
due to autoimmunity or thyroid function47. Lastly, in these studies mean age of
women affected by CAT was higher than controls, and the association between infertility/miscarriage and age is well known.
In our study, anamnestic data on women included in this study indicate that a half of their previous pregnancies ended with a miscarriage, without differences between healthy women and the ones affected by CAT. Consistently, no differences were found on the basis of thyroid autoimmunity when prospectively analyzing the pregnancies included in this study, although the prevalence decreased around 10%. The striking difference between the first (retrospective) and the second (prospective) analysis is most likely due to the high percentage of miscarriages occurring at the very beginning of pregnancy (including biochemical ones), which are lacking in the second analysis since
women were first evaluated after the 10th week.
In conclusion, since currently there is not clear demonstration that thyroid autoimmunity would be associated with increased risk of miscarriage or that L-thyroxine treatment in presence of euthyroidism would prevent this risk, when
27 CONCLUSIONS
In conclusion, a screening for thyroid diseases should be performed universally, with particular attention to thyroid autoimmunity and possible consequent thyroid function modifications, to avoid maternal and fetal complication during pregnancy and delivery. A better national information program on iodine supplementation during pregnancy is needed, including adequate supplementation methods (salt, multivitamins), doses (at least 150/250 µg) and timing (beginning before conception). Since thyroid function varies throughout pregnancy, it would be important to measure thyroid hormones at least once every trimester in all women, to verify that all values remain into the normal range. Thyroid volume increases during pregnancy, depending upon TSH and UI values, further underlying the importance of iodine supplementation. Thyroid autoantibodies decrease throughout gestation and increase after labor, so that women who had not been evaluated before pregnancy should measure antithyroid antibodies 3-6 months after delivery, especially when thyroid ultrasound suggests the presence of CAT. In women assuming L-thyroxine therapy at the time of conception, an early evaluation of thyroid function is crucial to assess when a dose increase is needed. Later on, an intensive thyroid function monitoring throughout the whole pregnancy is necessary to set any further adjustment. Lastly, currently there is not clear demonstration that thyroid autoimmunity would be associated with increased risk of miscarriage or that L-thyroxine treatment in presence of euthyroidism would prevent this risk, therefore when thyroid function is normal no treatment is needed.
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34 FIGURES
Figure 1: estradiol effects on thyroid function during pregnancy.
35 Figure 3: anamnestic diagnosis of women included in the study.
Figure 4: diagnosis after evaluation of women included in the study.
36 Urinary iodine Weeks 0 10 20 30 40 50 m c g/ l (m edi an) 0 100 200 300 400
37 Figure 7: FT4, FT3, TSH throughout pregnancy in untreated women.
FT4 Weeks 5 10 15 20 25 30 35 40 p g/ m l 0 5 10 15 20 FT4 FT3 Weeks 5 10 15 20 25 30 35 40 p g/ m l 0 2 4 6 FT3 TSH Weeks 5 10 15 20 25 30 35 40 mc U /ml 0 1 2 3 4 TSH
38 Figure 8: FT4, FT3, TSH throughout pregnancy in healthy women.
FT4 Weeks 5 10 15 20 25 30 35 40 p g/ m l 0 2 4 6 8 10 12 14 FT4 FT3 Weeks 5 10 15 20 25 30 35 40 p g/ m l 0 1 2 3 4 5 FT3 TSH Weeks 5 10 15 20 25 30 35 40 p g/ m l 0 1 2 3 4 TSH
39 Weeks 5 10 15 20 25 30 35 40 ml 6 8 10 12 14 16 18 20
40 AbTg Weeks 0 10 20 30 40 50 U I/ m l 0 100 200 300 400 500 AbTPO Weeks 0 10 20 30 40 50 U I/ m l 0 200 400 600 800
41 TABLES
Table 1: studies analyzing the correlation between thyroid autoimmunity and fertility.
42
Group All women Only untreated women
# women UI (µg/l) % # women UI (µg/l) % N 25.1% 46 R 88.4% 12.9% 32 R 92.9% A 5.8% A 0% E 5.8% E 7.1% S 31.0% 55 R 88.7% 22.9% 48 R 93.5% A 9.7% A 6.5% E 1.6% E 0% M 20.2% 98 R 72.9% 25.8% 109 R 68.3% A 8.3% A 9.8% E 18.8% E 21.9% B 23.7% 141 R 54.2% 28.6% 132 R 52.6% A 18.7% A 18.4% E 27.1% E 29.0% p-value OneWay ANOVA <0,001 <0,001
Table 2: UI at 10th week in all women, and in not-treated women. N no iodine supplementation, S iodized salt, M multivitamins, B both.
43 Table 3: Changes in LT4 treatment during pregnancy.
Replacement therapy Suppressive therapy
Tx TCA Thyroid nodules
Women treated throughout the
whole pregnancy (#) 23 121 18
Women who started LT4
treatment during pregnancy (#) 0 50 5
% of women increasing the
dose 92.30% 71.90% 57.10%
% of women not increasing the
dose 7.70% 28.10% 42.90%
Final dose in women who
started LT4 during pregnancy - 64.2±31.1 55.0±27.4 Dose in women not modifying
LT4 therapy during pregnancy (mean, SD)
125 78.9±45.4 79.2±50.5
Initial dose in women
increasing LT4 (mean, SD) 109.3±26.8 83.7±32.0 71.9±41.3 Final dose in women increasing
44 Newborns Miscarriages Total
Healthy 88 103 191
CAT 151 150 301
Total 239 253 492
Table 4: Previous pregnancies and miscarriages of women included in the study.
Newborns Miscarriages Total
Healthy 40 5 45
CAT 132 14 146
Total 224 27 251
45 Table 6: risk of miscarriage in euthyroid women either healthy or affected by CAT.
