Graves Disease

Thyroid
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© Mary Ann Liebert, Inc.

DOI: 10.1089/thy.2018.0165
1
Incidence of neonatal hyperthyroidism among newborns of
Graves’ disease patients treated with radioiodine therapy
This paper has been peer‐reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Ai Yoshihara1, Kenji Iwaku1, Jaeduk Yoshimura Noh1, Natsuko Watanabe1, Yo Kunii1, Hidemi
Ohye1, Miho Suzuki1, Masako Matsumoto1, Nami Suzuki1, Rie Tadokoro1, Chihiro
Incidence of neonatal hyperthyroidism among newborns of Graves’ disease patients treated with radioiodine therapy (DOI: 10.1089/thy.2018.0165)
Sekiyama1, Marino Hiruma1, Kiminori Sugino1, Koichi Ito1
1
Ito Hospital, Tokyo, Japan
Ai Yoshihara, M.D., Ph.D., E‐mail: a‐yoshihara@ito‐hospital.jp
Downloaded by Univ Of Virginia from www.liebertpub.com at 11/15/18. For personal use only.
Kenji Iwaku, M.D., Ph.D., E‐mail: k‐iwaku@ito‐hospital.jp
Jaeduk Yoshimura Noh, M.D., Ph.D., E‐mail: yoshimura@ito‐hospital.jp
Natsuko Watanabe, M.D., Ph.D., E‐mail: n‐watanabe@ito‐hospital.jp
Yo Kunii, M.D., Ph.D., E‐mail: y‐kidokoro@ito‐hospital.jp
Thyroid
Hidemi Ohye, M.D., Ph.D., E‐mail: h‐ohye@ito‐hospital.jp
Miho Suzuki, M.D., Ph.D., E‐mail: miho‐suzuki@ito‐hospital.jp
Masako Matsumoto, M.D., E‐mail: m‐matsumoto@ito‐hospital.jp
Nami Suzuki M.D., E‐mail: n‐suzuki@ito‐hospital.jp
Rie Tadokoro, M.D., E‐mail: r‐tadokoro@ito‐hospital.jp
Chihiro Sekiyama, M.D., E‐mail: c‐sekiyama@ito‐hospital.jp
Marino Hiruma, M.D., E‐mail: m‐morikawa@ito‐hospital.jp
Kiminori Sugino, M.D., Ph.D., E‐mail: k‐sugino@ito‐hospital.jp
Koichi Ito, M.D., Ph.D., E‐mail: k‐ito@ito‐hospital.jp
Running title: Incidence of neonatal hyperthyroidism
Key terms: neonatal hyperthyroidism, incidence, Graves’ disease, radioiodine therapy, TSH
receptor antibody
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Abstract
Background: The serum TSH receptor antibody (TRAb) titers of Graves’ disease (GD)
patients is known to increase after radioiodine (RAI) therapy and they can remain high for
years. The incidence of neonatal hyperthyroidism (NH) among newborns born to mothers
with GD who conceived after RAI therapy have not been reported in the past.
Objective: To investigate the incidence of NH among newborns born to mothers who
conceived within 2 years after RAI therapy, and to identify predictors of NH.
Patients: One hundred and forty‐five GD patients who conceived within 2 years after RAI
therapy were retrospectively reviewed, and information regarding their newborns was
collected.
Results: Fifty‐four of the 145 pregnant women (37%) were treated with anti‐thyroid drugs
(ATD) or potassium iodide (KI) for maternal hyperthyroidism during the first trimester.
There were 8 newborns with NH resulting in an incidence of 5.5%. Seven of the eight
Thyroid
mothers whose newborns had NH were treated with ATD or KI during their pregnancy. The
incidence of NH among the newborns born to mothers who conceived within 6 to 12
months after RAI therapy was 8.8%, 5.5% within 12 to18 months, and 3.6% within 18 to 24
months. Multivariate analysis revealed that the TRAb values in the third trimester were the
only risk factor for NH. The cut‐off TRAb value in the third trimester for predicting NH was
9.7 IU/L (reference values <2.0 IU/L).
Conclusion: The incidence of NH among the newborns born to mothers who conceived
within 2 years after RAI therapy was 5.5%. The fetuses of pregnant GD patients whose
TRAb value is high in the third trimester should be carefully followed by an obstetrician
during pregnancy, and the newborns should be carefully followed by a pediatrician after
birth.
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Introduction
Radioiodine (RAI) therapy is one of the therapeutic options for patients with Graves’
disease (GD). In general, for women with GD who desire a future pregnancy, pregnancy
should be postponed until a stable euthyroid state is reached. The serum TSH receptor
antibody (TRAb) levels of Graves’ disease (GD) patients is known to increase after RAI
therapy and then typically decrease to the pre‐RAI therapy level within a year, but in some
patients they can remain elevated for years (1‐4).
The fetal thyroid gland begins to synthesize thyroid hormones between weeks 10 to 12 of
gestation. Maternal TRAbs transferred to the fetus through the placenta may stimulate the
fetal thyroid gland starting as early as 18 weeks of pregnancy (5‐10). The incidence of fetal
and neonatal hyperthyroidism was reported to be between 1% and 5% in women with
active or a past history of Graves’ disease (8, 11). TRAb values of GD patients who
underwent RAI tend to be high, thus, there is a need to measure TRAbs during pregnancy
in women who underwent RAI before conception and to follow the fetus carefully for fetal
Thyroid
hyperthyroidism and neonatal hyperthyroidism if TRAb values are still present during
pregnancy.
The incidence of NH among newborns born to mothers with GD who conceived after RAI
therapy have not been reported in the past. We investigated the incidence of neonatal
hyperthyroidism (NH) among newborns born to mothers who conceived within 2 years
after RAI therapy, and we attempted to identify predictors of NH.
Subjects and Methods
We retrospectively reviewed the cases of 145 GD patients who conceived within 2 years
after RAI therapy, and gave birth between April 1, 2004 and December 31, 2015.
Information regarding their newborns was also collected. The diagnosis of GD was based
on the clinical findings, i.e., the presence of a goiter and/or ophthalmopathy, elevated free
triiodothyronine (FT3) and free thyroxine (FT4) levels, a suppressed thyroid‐stimulating
hormone (TSH) level, and a positive TSH receptor antibody (TRAb) test. Every newborn was
carefully followed in the hospital for at least 5 days after birth and was followed longer
when necessary. The diagnosis of neonatal hyperthyroidism (NH) was made based on
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clinical symptoms and TSH and FT4 levels of cord blood samples or of blood sampled from
the neonates within the first week after birth.
We investigated the overall incidence of NH. To investigate whether the incidence of NH
become lower when the interval between RAI therapy and conception is longer, we
investigated the incidence of NH among newborns born to mothers who conceived within
6 to 12 months, 12 to18 months, 18 to 24 months after RAI therapy.
To identify predictors of NH, we evaluated TRAb values at the time of RAI therapy and
TRAb values during pregnancy. We also collected information on each patient on the age
at the time of RAI therapy, thyroid volume at the time of RAI therapy, radioiodine
treatment activity, and days between RAI therapy and conception in order to identify
potential predictors of NH. Thyroid volume was evaluated by ultrasonography. This study
was approved by the Ethics Committee of Ito Hospital.
Laboratory methods
Thyroid
TSH, FT3, and FT4 levels were measured by electrochemiluminescence immunoassays
(ECLusys TSH, ECLusys FT3 and ECLusys FT4, respectively; Roche Diagnostics GmbH, Basel,
Switzerland). The manufacturers’ reference limits were: TSH 0.2‐4.5 mU/L, FT3 2.2‐4.3
pg/ml, and FT4 0.8‐1.6 ng/dl. The reference range for umbilical cord serum TSH was 0.09‐
18.0 mU/L, and for FT4 it was 1.04‐1.62 ng/dL. TRAb values were determined with an
electrochemiluminescence immunoassay kit (ECLusys TRAb; Roche Diagnostics GmbH,
Basel, Switzerland; reference values <2.0 IU/L).
Statistical analysis
Statistical analysis was performed with JMP software, version 11.0., (SAS Institute Inc.,
Cary, NC). Differences between the NH group and the non‐NH group were analyzed by the
Wilcoxon test. The data of treatment of GD mothers in the first trimester of pregnancy and
at delivery were statistically analyzed by using the Fisher’s exact test. P values <0.05 were
considered significant.
Multiple regression analyses (forward stepwise) were performed to identify possible
predictors of NH. Receiver operating characteristic (ROC) curve analysis was performed to
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assess the optimal cut‐off TRAb levels of GD mothers in the third trimester for predicting
NH in the newborn.
Results
Among the 145 GD patients, the median age at the time of RAI was 28 years old (range 19‐
38), and the median thyroid volume at the time was 48.8 ml (range 13.1–203.8). There
were 8 newborns with NH resulting in an incidence of 5.5%. Seven of eight mothers whose
newborns had NH were treated for maternal hyperthyroidism during their pregnancy.
Table 1 shows the characteristics of mothers whose newborns exhibited NH (NH group)
and mothers whose newborns did not develop NH (non‐NH group). The NH group had
higher TRAb values at the time of RAI therapy (median 40.0 IU/l vs. 9.7 IU/l, p=0.0034),
higher TRAb values in the first trimester (median 40.0 IU/l vs. 6.0 IU/l, p<0.0001), and
higher TRAb values in the third trimester than the non‐NH group (median 22.4 IU/l vs. 2.4
IU/l, p<0.0001). Thyroid volume at the time of RAI therapy, radioiodine dose, and number
of months between RAI therapy and conception did not differ significantly between the
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two groups. Detailed information regarding the eight hyperthyroid neonates is provided in
Table 2a, and detailed information regarding the mothers of the eight hyperthyroid
neonates is provided in Table 2b. The TRAb values in cord blood at delivery were high in all
neonates. Clinical goiter was apparent in two neonates at birth (No. 3 and No. 4). The cord
blood sample revealed hyperthyroidism in three neonates (Nos.3, 4, and 7) and
euthyroidism in 5 neonates (Nos. 1, 2, 5, 6, and 8), all of whom developed hyperthyroidism
after birth. As shown in Table 2b, 7 of the 8 mothers required treatment with antithyroid
drugs (ATDs) or potassium iodide (KI) to control their hyperthyroidism. Five neonates (No.
1, 2, 5, 6, and 8) developed hyperthyroidism after birth, because maternal ATD or KI is
cleared more rapidly than maternal TRAbs in the neonate.
Table 3 shows the treatment of GD mothers in the first trimester of pregnancy, second and
third trimester of pregnancy and at delivery, who conceived within 6 to 12 months, 12
to18 months, 18 to 24 months after RAI therapy. Treatment with ATD or KI was needed to
control maternal hyperthyroidism in 54 of 145 patients (37%). The GD patients who could
not tolerate any ATDs were treated with KI throughout their pregnancy to control
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maternal hyperthyroidism. In order to avoid the use of methimazole (MMI) in the first
trimester of pregnancy, KI was substituted for MMI in GD patients being treated with MMI
who could not tolerate propylthiouracil (PTU) because of adverse effects. When a patient
treated with KI remained hyperthyroid in the second trimester, MMI was added to KI, or
MMI was substituted for KI. When a patient was being treated with KI and thyroid function
was well controlled, the KI dose was continued or tapered. The percentage of GD patients
treated with ATD at delivery was significantly lower among patients who conceived within
18 to 24 months after RAI therapy, than in GD patients who conceived within 6 to 12
months after RAI (p<0.05). The incidence of NH among the newborns born to mothers who
conceived within 6 to 12 months after RAI therapy was 8.8% (3 out of 34; Figure 1), 5.5%
after 12 to18 months (3 out of 55; Figure 2), and 3.6% after 18 to 24 months (2 out of 56;
Figure 3). Although the incidence of NH among the newborns of mothers who conceived
within 18 to 24 months tended to be lower than among mothers who conceived within 6
to 12 months, comparisons by means of Fisher’s exact tests showed no statistically
significant differences between any of the three groups.
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The TRAb levels in the first trimester were negatively correlated with the number of days
between RAI therapy and conception (p=0.0011), but the correlation coefficient was low
(r2 = 0.065). There were no significant correlations between the TRAb values in the third
trimester and the number of days between RAI therapy and conception.
Multivariate analysis revealed that the TRAb values in the third trimester were the only
risk factor for NH. The ROC curve analysis showed that the cut‐off TRAb value in the third
trimester for predicting NH was 9.7 IU/L. A maternal TRAb value above 9.7 IU/L in the third
trimester predicted neonatal hyperthyroidism with 100% sensitivity and 88.3% specificity.
The area under the ROC curve was 0.94 (Figure 4). Based on these findings, we performed
an additional analysis to develop a model to predict a TRAb level in the first trimester that
would be expected to decline to less than 9.7 by the third trimester. The ROC curve
analysis showed that the optimal cut‐off TRAb value in the first trimester for predicting a
TRAb value below 9.7 IU/L in the third trimester was 28.0 IU/L. A maternal TRAb value
below 28.0 IU/L in the first trimester predicted a TRAb value below 9.7 IU/L in the third
trimester with 93% sensitivity and 76% specificity. The area under the ROC curve was 0.89.
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Discussion
Treatment decisions for hyperthyroid women with GD who desire future pregnancy is
sometimes difficult. Therapeutic options for GD include antithyroid drugs (ATDs), RAI
therapy and surgery. ATDs are associated with an increased rate of congenital
malformations in the newborns when they are used during the first trimester of pregnancy
(12‐15). The relapse rate of hyperthyroidism is high among patients treated with ATDs
compared to those treated with surgery or RAI (9). Moreover, ATDs can be associated with
adverse reactions (16). Surgery can achieve a high rate of remission in patients with GD,
but there are potential complications such as recurrent laryngeal nerve damage and
hypoparathyroidism, and there is as subsequent need for life‐long substitution therapy
with thyroid hormone. RAI therapy can also achieve high rate of remission in patients with
GD. However, in some patients there are considerable increases in TRAb values after RAI
therapy, usually with a peak at 3 months after treatment. In most patients, the TRAb
values then gradually decrease and return to pre‐RAI therapy values after a year, but
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average values remain well above the normal reference range throughout a 5‐year follow‐
up after treatment (3). During pregnancy, TRAb transfer to the fetus through the placenta
and may stimulate the fetal thyroid gland and cause goiter and hyperthyroidism as early as
18 weeks of pregnancy (5‐10). The American Thyroid Association and the Endocrine
Society recommend close follow‐up of the fetus of mothers who previously received RAI
therapy for GD and who have TRAb values more than two to three times the upper
reference limit (17‐23). A recent systematic review reported that intensive fetal
monitoring is recommended when maternal TRAb values are more than 3.7 times above
the upper limit of normal (24). Careful follow‐up of the fetus and the newborn is needed
when high TRAb values are detected in mothers with GD in the second and third trimester
(25‐27).
TRAbs interact with the TSH receptor and they can exert a stimulating action (TSAb), a
blocking action (TSBAb), or be neutral (26, 28‐30). TRAbs detected in hyperthyroid patients
obviously have a predominantly stimulating action. TSBAb are detected in a small
percentage of GD patients who develop hypothyroidism (31). Fetal hypothyroidism
sometimes develops when the TSBAb value of the mother is high during pregnancy (32,
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33). The TSBAb values of some GD patients who were not on ATD medication or who were
on low‐dose ATD medication during pregnancy have been reported to decrease (34) or to
increase, but there were no dramatic changes in the thyroid function of any of the patients
(35). It would be ideal to determine the bioactivity of TRAbs in GD patients after RAI
therapy, because the effect of maternal TRAb on the fetus cannot always be predicted on
the basis of maternal thyroid function (36). Since TSAb bioassays were performed in only 5
patients, and TSBAb bioassays in only 2 patients in our study, we did not include them in
the analysis. The TRAbs in the mothers with high TRAb values whose neonates did not
develop NH may have had an overall neutral effect.
The incidence of NH among the newborns born to mothers with GD who conceived after
RAI therapy had not been reported in the past. Based on the results of our study, the
incidence of NH was 8.8% among the newborns born to mothers with GD who conceived
within 6 to 12 months after RAI, and 3.6% among those who conceived within 18 to 24
month. Multivariate analysis revealed that the TRAb values in the third trimester were the
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only risk factor for NH. The TRAb values in the first trimester were negatively correlated
with the number of days between RAI therapy and conception, but the correlation
disappeared for TRAb values in the third trimester and the number of days between RAI
therapy and conception. It is difficult to predict the risk for NH at the time of RAI therapy.
Based on our data, the TRAb titer of pregnant women with a TRAb value below 28 IU/L in
the 1st trimester is likely to decline to less than 9.7 IU/L by the third trimester.
One of the limitations of this study is its retrospective nature, and we may have missed
some neonates who developed mild hyperthyroidism after discharge from the hospital.
However, all of the neonates in this study had been seen by a pediatrician at one month
after birth, and none of them required additional treatment. Another limitation is that the
number of subjects who conceived within 2 years after RAI therapy is small. The number of
cases of NH may have been insufficient to reach statistical levels that would show that the
incidence of NH is lower when conception occurred later after RAI.

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Conclusion
The incidence of NH among newborns born to mothers who conceived within 6 to 12
months after RAI was 8.8%, 5.5% within 12 to18 months and 3.6% within 18 to 24 months.
The fetuses of pregnant GD patients whose TRAb value is 9.7 IU/L (reference values <2.0
IU/L) or above in the third trimester should be carefully followed by an obstetrician during
pregnancy, and the newborns should be carefully followed by a pediatrician after birth.
Portions of this manuscript were presented at the 87th Annual Meeting of the ATA held in
Victoria, Canada in 2017.
Disclosure Statement
The author reports no conflicts of interest in this work.
Acknowledgments
We thank all the physicians, obstetricians and pediatricians who contributed to this study.
Thyroid
Corresponding author；
Ai Yoshihara M.D., Ph.D.
Ito Hospital, 4‐2‐6 Jingumae, Shibuyaku, Tokyo, Japan
Phone: +81‐3‐3402‐7447
Fax: +81‐3‐3402‐7455
E‐mail: a‐yoshihara@ito‐hospital.jpReferences

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mothers whose newborns did not develop NH (non‐NH group)
Table 1. Characteristics of mothers whose newborns exhibited NH (NH group) and of
15

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Table 2. (a) Characteristics of the 8 infants with neonatal hyperthyroidism
Table 2. (b) Characteristics of the 8 mothers of an infant with neonatal hyperthyroidism
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Table 3. Treatment of the GD patients in the first trimester of pregnancy and at delivery

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Figure legends
Figure 1
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TRAb value when RAI therapy was performed and during pregnancy after conception
within 6 to 12 months after RAI therapy in each patient. Incidence of NH was 8.8% (3/34).
Solid lines are TRAb values in each patient during pregnancy, and dashed lines connected
the TRAb value at RAI therapy and first TRAb value measurement in pregnancy.
Red line shows the mother of neonate who presented NH.

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Figure 2


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Figure 3


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Figure 4
and 88.3% specificity.

The receiver operating characteristic (ROC) curve analysis showed that the cut‐off TRAb
9.7 IU/L in the third trimester predicted neonatal hyperthyroidism with 100% sensitivity
value in the third trimester for predicting NH was 9.7 IU/L. A maternal TRAb value above
21

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Thyroid

radioiodine on stimulatory activity of Graves' immunoglobulins. Clin Endocrinol

changes in thyrotropin binding inhibitory immunoglobulins in Graves' disease

hyperthyroidism. Hormone and metabolic research Hormon‐ und

stimulating autoantibodies: potential mechanisms involved in the pendulum

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