Incidence of Neonatal Hyperthyroidism Among Newborns of Graves' Disease Patients Treated with Radioiodine Therapy

Abstract

Background:

The serum thyrotropin receptor antibody (TRAb) titers of Graves' disease (GD) patients are known to increase after radioiodine (RAI) therapy, and they can remain high for years. The incidence of neonatal hyperthyroidism (NH) among newborns of mothers with GD who conceived after RAI therapy has not been previously reported. The aims of this study were to investigate the incidence of NH among newborns of mothers who conceived within two years after RAI therapy, and to identify predictors of NH.

Methods:

GD patients (n = 145) who conceived within two years after RAI therapy were retrospectively reviewed, and information regarding their newborns was collected.

Results:

Of the 145 pregnant women, 54 (37%) were treated with antithyroid drugs or potassium iodide for maternal hyperthyroidism during the first trimester. There were eight newborns with NH, resulting in an incidence of 5.5%. Seven of the eight mothers whose newborns had NH were treated with antithyroid drugs or potassium iodide during their pregnancy. The incidence of NH among the newborns of mothers who conceived within 6–12 months after RAI therapy was 8.8%, within 12–18 months was 5.5%, and within 18–24 months was 3.6%. Multivariate analysis revealed that the TRAb values in the third trimester were the only risk factor for NH. The cutoff TRAb value in the third trimester for predicting NH was 9.7 IU/L (reference value <2.0 IU/L).

Conclusions:

The incidence of NH among newborns of mothers who conceived within two 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.

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 thyrotropin receptor antibody (TRAb) levels of 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 and 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 (NH) was reported to be between 1% and 5% in women with active or a past history of GD (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 undergo RAI before conception and to follow the fetus carefully for fetal hyperthyroidism and NH if TRAb values are still present during pregnancy.

The incidence of NH among newborns of mothers with GD who conceived after RAI therapy has not been previously reported. This study investigated the incidence of NH among newborns of mothers who conceived within two years after RAI therapy, and it attempted to identify predictors of NH.

Methods

The cases of 145 GD patients who conceived within two years after RAI therapy who and gave birth between April 1, 2004, and December 31, 2015, were retrospectively reviewed. Information regarding their newborns was also collected. The diagnosis of GD was based on the clinical findings, that is, the presence of a goiter and/or ophthalmopathy, elevated free triiodothyronine (fT3) and free thyroxine (fT4) levels, a suppressed thyrotropin (TSH) level, and a positive TRAb test. Every newborn was carefully followed in the hospital for at least five days after birth and was followed longer when necessary. The diagnosis of NH was made based on clinical symptoms and TSH and fT4 levels of cord blood samples or of blood sampled from the neonates within the first week after birth.

The overall incidence of NH was investigated. To investigate whether the incidence of NH becomes lower when the interval between RAI therapy and conception is longer, the incidence of NH was investigated among newborns of mothers who conceived within 6–12, 12–8, and 18–24 months after RAI therapy.

To identify predictors of NH, TRAb values were evaluated at the time of RAI therapy and during pregnancy. Information was also collected on each patient, including 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, Tokyo, Japan.

Laboratory methods

TSH, fT3, and fT4 levels were measured by electrochemiluminescence immunoassays (ECLusys TSH, ECLusys fT3, and ECLusys fT4, respectively; Roche Diagnostics GmbH, Basel, Switzerland). The manufacturer's reference limits were: TSH 0.2–4.5 mIU/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 mIU/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; reference value <2.0 IU/L).

Statistical analysis

Statistical analysis was performed with JMP v11.0 (SAS Institute, Inc., Cary, NC). Differences between the NH group and the non-NH group were analyzed by the Wilcoxon test. The data of the treatment of GD mothers in the first trimester of pregnancy and at delivery were statistically analyzed by using Fisher's exact test. p-Values of <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 assess the optimal cutoff TRAb levels of GD mothers in the third trimester for predicting NH in newborns.

Results

Among the 145 GD patients, the median age at the time of RAI was 28 years (range 19–38 years), and the median thyroid volume was 48.8 mL (range 13.1–203.8 mL). There were eight 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 two groups. Detailed information regarding the eight hyperthyroid neonates is provided in Table 2, and detailed information regarding the mothers of the eight hyperthyroid neonates is provided in Table 3. 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 five neonates (nos. 1, 2, 5, 6, and 8), all of whom developed hyperthyroidism after birth. As shown in Table 3, seven of the eight mothers required treatment with antithyroid drugs (ATDs) or potassium iodide (KI) to control their hyperthyroidism. Five neonates (nos. 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 1.

Characteristics of Mothers Whose Newborns Exhibited NH (NH Group) and of Mothers Whose Newborns Did Not Develop NH (non-NH Group)

	Non-NH (n = 137), median (range)	NH (n = 8), median (range)	p-Value
Age when RAI was performed, years	29 (19–38)	25.5 (20–37)	NS
Thyroid volume when RAI was performed, mL	47.7 (13–203.8)	62.0 (36.9–110.3)	NS
¹³¹I dose, MBq	223.3 (11.9–1110)	320.1 (74.7–1110)	NS
Days between RAI and conception, days	479 (182–718)	392 (222–712)	NS
Age at delivery	31 (21–40)	27.5 (22–38)	NS
TRAb when RAI was performed	9.75 (0.3–40)	40 (10.2–40)	0.0034
TRAb at 1st trimester	6.0 (0.3–40)	40 (30.6–40)	<0.0001
TRAb at 3rd trimester	2.4 (0.3–40)	22.4 (9.7–40)	<0.0001

NH, neonatal hyperthyroidism; RAI, radioactive iodine; TRAb, thyrotropin receptor antibody; NS, not significant.

Table 2.

Characteristics of the Eight Infants with NH

				Cord
No.	Gestation length (weeks)	Birth weight (g)	Neonatal goiter	fT3 (pg/mL)	fT4 (ng/dL)	TSH (μIU/mL)	TRAb (IU/L)	TSAb (%)	Treatment for NH	Thyroid function test results after birth
1	40.5	3410	No	1.3	1.27	3.71	22.2	1745	None	Day 7 fT4 2.15 ng/dL, TSH 0.36 μIU/mL
2	38.6	3161	No	1.28	1.16	2.80	11.2		None	Day 5 fT4 2.99 ng/dl, TSH 0.434 μIU/mL
3	34.5	2494	Yes	2.69	3.50	<0.01	37.6		Antithyroid drugs
4	36.5	2368	Yes	3.6	4.79	<0.01	40.0	1995	Antithyroid drugs
5	40.4	3196	No	1.73	1.25	2.35	9.9		None	Day 12 fT4 1.66 ng/dL, TSH 0.1 μIU/mL, TRAb 6.5 IU/L
6	40.4	3154	No	1.5	1.33	2.88	13.7		None	Day 13 fT4 2.44 ng/dL, TSH 0.272 μIU/mL
7	40.4	3585	No	2.6	2.35	0.35	18.5		Antithyroid drugs
8	40.2	2950	No	1.61	1.27	0.29	19.4	801	Antithyroid drugs	Day 8 fT4 3.51 ng/dL, TSH 0.01 μIU/mL

fT3, free triiodothyronine; fT4, free thyroxine; TSH, thyrotropin; TSAb, thyroid-stimulating antibody.

Table 3.

Characteristics of the Eight Mothers of an Infant with NH

			TRAb (IU/L)					Maternal treatment
No.	Age at delivery (years)	Days between RAI and conception (days)	When RAI was performed	1st trimester	3rd trimester	At delivery	TSAb (%)	In the 1st trimester	At delivery
1	32	222	16.2	40.0	14.3	14.3	920	Antithyroid drugs	Potassium iodide
2	38	224	40.0	40.0	14.4	10.2		Levothyroxine	Potassium iodide
3	26	291	40.0	40.0	40.0	40.0		Potassium iodide	Potassium iodide
4	25	363	40.0	40.0	40.0	39.6		Levothyroxine	No medication
5	29	421	11.5	30.6	9.7	9.4		Antithyroid drugs	Antithyroid drugs
6	28	439	40.0	40.0	14.2	14.2		Potassium iodide	Potassium iodide
7	27	658	40.0	40.0	28.4			Potassium iodide	Antithyroid drugs
8	23	712	10.2	40.0	22.4	18.4	1143	Potassium iodide	Potassium iodide

Table 4 shows the treatment of GD mothers in the first trimester of pregnancy, in the second and third trimesters of pregnancy, and at delivery, who conceived within 6–12 months, 12–18 months, and 18–24 months after RAI therapy. Treatment with ATD or KI was needed to control maternal hyperthyroidism in 54/145 (37%) patients. The GD patients who could not tolerate any ATDs were treated with KI throughout their pregnancy to control 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 18–24 months after RAI therapy than it was in GD patients who conceived within 6–12 months after RAI (p < 0.05). The incidence of NH among the newborns of mothers who conceived within 6–12 months after RAI therapy was 8.8% (3/34; Fig. 1), 5.5% after 12–18 months (3/55; Fig. 2), and 3.6% after 18–24 months (2/56; Fig. 3). Although the incidence of NH among the newborns of mothers who conceived within 18–24 months tended to be lower than among mothers who conceived within 6–12 months, comparisons by means of Fisher's exact tests showed no statistically significant differences between any of the three groups.

FIG. 1.

Thyrotropin receptor antibody (TRAb) value when radioactive iodine (RAI) therapy was performed and during pregnancy after conception within 6–12 months after RAI therapy in each patient. Incidence of neonatal hyperthyroidism (NH) was 8.8% (3/34). Solid lines are TRAb values in each patient during pregnancy, and dashed lines connect the TRAb value at RAI therapy and first TRAb value measurement in pregnancy. The red line shows the mother of neonate who presented with NH.

FIG. 2.

TRAb value when RAI therapy was performed and during pregnancy after conception within 12–18 months after RAI therapy in each patient. Incidence of NH was 5.5% (3/55).

FIG. 3.

TRAb value when RAI therapy was performed and during pregnancy after conception within 18–24 months after RAI therapy in each patient. Incidence of NH was 3.6% (2/56).

Table 4.

Treatment of the GD Patients in the First Trimester of Pregnancy and at Delivery

	Months between RAI and conception
	6–12 months	12–18 months	18–24 months
	n = 34	n = 55	n = 56
Treatment in the first trimester
Antithyroid drugs	2 (6%)	9 (16%)	7 (13%)
Antithyroid drug (MMI)→potassium iodide	1 (3%)	1 (2%)	0
Potassium iodide	14 (41%)	7 (13%)	13 (23%)
No medication	7 (21%)	12 (22%)	20 (36%)
Levothyroxine	10 (29%)	26 (47%)	16 (29%)
Treatment in the 2nd and 3rd trimesters
Antithyroid drugs	4 (12%)	8 (15%)	3 (5%)
Potassium iodide	8 (24%)	7 (13%)	4 (7%)
No medication	11 (32%)	7 (13%)	18 (32%)
Levothyroxine	11 (32%)	33 (60%)	31 (55%)
Treatment at delivery
Antithyroid drugs	4 (12%)	6 (11%)	2 (4%)
Potassium iodide	8 (24%)	7 (13%)	4 (7%)
No medication	11 (32%)	9 (16%)	19 (34%)
Levothyroxine	11 (32%)	33 (60%)	31 (55%)

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 (r ² = 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 cutoff TRAb value in the third trimester for predicting NH was 9.7 IU/L. A maternal TRAb value >9.7 IU/L in the third trimester predicted NH with 100% sensitivity and 88.3% specificity. The area under the ROC curve was 0.94 (Fig. 4). Based on these findings, an additional analysis was performed to develop a model to predict a TRAb level in the first trimester that would be expected to decline to <9.7 by the third trimester. The ROC curve analysis showed that the optimal cutoff TRAb value in the first trimester for predicting a TRAb value <9.7 IU/L in the third trimester was 28.0 IU/L. A maternal TRAb value <28.0 IU/L in the first trimester predicted a TRAb value <9.7 IU/L in the third trimester with 93% sensitivity and 76% specificity. The area under the ROC curve was 0.89.

FIG. 4.

The receiver operating characteristic (ROC) curve analysis showed that the cutoff TRAb value in the third trimester for predicting NH was 9.7 IU/L. A maternal TRAb value >9.7 IU/L in the third trimester predicted NH with 100% sensitivity and 88.3% specificity.

Discussion

Treatment decisions for hyperthyroid women with GD who desire a future pregnancy are sometimes difficult. Therapeutic options for GD include ATDs, RAI therapy, and surgery. ATDs are associated with an increased rate of congenital malformations in 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 lifelong substitution therapy with thyroid hormone. RAI therapy can also achieve a 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 three months after treatment. In most patients, TRAb values then gradually decrease and return to pre-RAI therapy values after a year, but average values remain well above the normal reference range throughout a five-year follow-up after treatment (3). During pregnancy, TRAbs 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 >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 trimesters (25 –27).

TRAbs interact with the TSH receptor and they can exert a stimulating action (TSAb) or a blocking action (TSBAb), or they can be neutral (26,28 –30). TRAbs detected in hyperthyroid patients obviously have a predominantly stimulating action. TSBAbs 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 (32,33). 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 five patients and TSBAb bioassays in only two patients in this study, they were not included 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 of mothers with GD who conceived after RAI therapy had not been previously reported. Based on the results of this study, the incidence of NH was 8.8% among the newborns of mothers with GD who conceived within 6–12 months after RAI, and 3.6% among those who conceived within 18–24 months. Multivariate analysis revealed that the TRAb values in the third trimester were the 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 the current data, the TRAb titer of pregnant women with a TRAb value <28 IU/L in the first trimester is likely to decline to <9.7 IU/L by the third trimester.

One of the limitations of this study is its retrospective nature, and some neonates who developed mild hyperthyroidism after discharge from the hospital may have been missed. 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 two 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.

Conclusion

The incidence of NH among newborns of mothers who conceived within 6–12 months after RAI was 8.8%, 5.5% within 12–18 months, and 3.6% within 18–24 months. The fetuses of pregnant GD patients whose TRAb value is ≥9.7 IU/L (reference value <2.0 IU/L) 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.

Footnotes

Acknowledgments

We thank all the physicians, obstetricians, and pediatricians who contributed to this study. Portions of this manuscript were presented at the 87th Annual Meeting of the American Thyroid Association held in Victoria, Canada, in 2017.

Author Disclosure Statement

The authors report no conflicts of interest in this work.

References

Atkinson

, McGregor

, Kendall-Taylor

, Peterson

, Smith

. 1982. Effect of radioiodine on stimulatory activity of Graves' immunoglobulins. Clin Endocrinol (Oxf), 16:537–543.

Hamada

, Momotani

, Ishikawa

, Yoshimura Noh

, Okamoto

, Konishi

, Ito

. 2011. Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism. Endocr J, 58:55–58.

Laurberg

, Wallin

, Tallstedt

, Abraham-Nordling

, Lundell

, Torring

. 2008. TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol, 158:69–75.

Teng

, Yeung

, Khoo

, Alagaratnam

. 1980. A prospective study of the changes in thyrotropin binding inhibitory immunoglobulins in Graves' disease treated by subtotal thyroidectomy or radioactive iodine. J Clin Endocrinol Metab, 50:1005–1010.

Burrow

, Fisher

, Larsen

. 1994. Maternal and fetal thyroid function. N Engl J Med, 331:1072–1078.

Fisher

, Klein

. 1981. Thyroid development and disorders of thyroid function in the newborn. N Engl J Med, 304:702–712.

Zakarija

, McKenzie

. 1983. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab, 57:1036–1040.

Zimmerman

. 1999. Fetal and neonatal hyperthyroidism. Thyroid, 9:727–733.

Smith

, Hegedus

. 2016. Graves' disease. N Engl J Med, 375:1552–1565.

10.

Donnelly

, Wood

, Casey

, Hobbins

, Barbour

. 2015. Early severe fetal Graves disease in a mother after thyroid ablation and thyroidectomy. Obstet Gynecol, 125:1059–1062.

11.

Levy-Shraga

, Tamir-Hostovsky

, Boyko

, Lerner-Geva

, Pinhas-Hamiel

. 2014. Follow-up of newborns of mothers with Graves' disease. Thyroid, 24:1032–1039.

12.

Andersen

, Olsen

, Wu

, Laurberg

. 2013. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab, 98:4373–4381.

13.

Clementi

, Di Gianantonio

, Cassina

, Leoncini

, Botto

, Mastroiacovo

. 2010. Treatment of hyperthyroidism in pregnancy and birth defects. J Clin Endocrinol Metab, 95:E337–341.

14.

Yoshihara

, Noh

, Yamaguchi

, Ohye

, Sato

, Sekiya

, Kosuga

, Suzuki

, Matsumoto

, Kunii

, Watanabe

, Mukasa

, Ito

. 2012. Treatment of Graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab, 97:2396–2403.

15.

Andersen

, Olsen

, Wu

, Laurberg

. 2014. Severity of birth defects after propylthiouracil exposure in early pregnancy. Thyroid, 24:1533–1540.

16.

Otsuka

, Noh

, Chino

, Shimizu

, Mukasa

, Ito

, Taniyama

. 2012. Hepatotoxicity and cutaneous reactions after antithyroid drug administration. Clin Endocrinol, 77:310–315.

17.

Alexander

, Pearce

, Brent

, Brown

, Chen

, Dosiou

, Grobman

, Laurberg

, Lazarus

, Mandel

, Peeters

, Sullivan

. 2017. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid, 27:315–389.

18.

De Groot

, Abalovich

, Alexander

, Amino

, Barbour

, Cobin

, Eastman

, Lazarus

, Luton

, Mandel

, Mestman

, Rovet

, Sullivan

. 2012. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 97:2543–2565.

19.

Abeillon-du Payrat

, Chikh

, Bossard

, Bretones

, Gaucherand

, Claris

, Charrie

, Raverot

, Orgiazzi

, Borson-Chazot

, Bournaud

. 2014. Predictive value of maternal second-generation thyroid-binding inhibitory immunoglobulin assay for neonatal autoimmune hyperthyroidism. Eur J Endocrinol, 171:451–460.

20.

Besancon

, Beltrand

, Le Gac

, Luton

, Polak

. 2014. Management of neonates born to women with Graves' disease: a cohort study. Eur J Endocrinol, 170:855–862.

21.

Kamijo

. 2007. TSH-receptor antibodies determined by the first, second and third generation assays and thyroid-stimulating antibody in pregnant patients with Graves' disease. Endocr J, 54:619–624.

22.

Uenaka

, Tanimura

, Tairaku

, Morioka

, Ebina

, Yamada

. 2014. Risk factors for neonatal thyroid dysfunction in pregnancies complicated by Graves' disease. Eur J Obstet Gynecol Reprod Biol, 177:89–93.

23.

Clavel

, Madec

, Bornet

, Deviller

, Stefanutti

, Orgiazzi

. 1990. Anti TSH-receptor antibodies in pregnant patients with autoimmune thyroid disorder. Br J Obstet Gynaecol, 97:1003–1008.

24.

van Dijk

, Smits

, Fliers

, Bisschop

. 2018. Maternal thyrotropin receptor antibody concentration and the risk of fetal and neonatal thyrotoxicosis: a systematic review. Thyroid, 28:257–264.

25.

Kurtoğlu

, Özdemir

. 2017. Fetal neonatal hyperthyroidism: diagnostic and therapeutic approachment. Turk Pediatri Ars, 52:1–9.

26.

Bucci

, Giuliani

, Napolitano

. 2017. Thyroid-stimulating hormone receptor antibodies in pregnancy: clinical relevance. Front Endocrinol (Lausanne), 8:137.

27.

van der Kaay

, Wasserman

, Palmert

. 2016. Management of neonates born to mothers with Graves' disease. Pediatrics, 137.

28.

Morshed

, Davies

. 2015. Graves' disease mechanisms: the role of stimulating, blocking, and cleavage region TSH receptor antibodies. Horm Metab Res, 47:727–734.

29.

Takasu

, Yamashiro

, Ochi

, Sato

, Nagata

, Komiya

, Yoshimura

. 2001. TSBAb (TSH-stimulation blocking antibody) and TSAb (thyroid stimulating antibody) in TSBAb-positive patients with hypothyroidism and Graves' patients with hyperthyroidism. Horm Metab Res, 33:232–237.

30.

Michalek

, Morshed

, Latif

, Davies

. 2009. TSH receptor autoantibodies. Autoimmun Rev, 9:113–116.

31.

McLachlan

, Rapoport

. 2013. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa . Thyroid, 23:14–24.

32.

Ohira

, Miyake

, Kobara

, Kikuchi

, Osada

, Ashida

, Hirabayashi

, Nishio

, Kanai

, Shiozawa

. 2010. Fetal goitrous hypothyroidism due to maternal thyroid stimulation-blocking antibody: a case report. Fetal Diagn Ther, 28:220–224.

33.

Ueta

, Fukui

, Murakami

, Yamanouchi

, Yamamoto

, Murao

, Santou

, Taniguchi

, Mitani

, Shigemasa

. 1999. Development of primary hypothyroidism with the appearance of blocking-type antibody to thyrotropin receptor in Graves' disease in late pregnancy. Thyroid, 9:179–182.

34.

Amino

, Izumi

, Hidaka

, Takeoka

, Nakata

, Tatsumi

, Nagata

, Takano

. 2003. No increase of blocking type anti-thyrotropin receptor antibodies during pregnancy in patients with Graves' disease. J Clin Endocrinol Metab, 88:5871–5874.

35.

Kung

, Lau

, Kohn

. 2001. Epitope mapping of TSH receptor-blocking antibodies in Graves' disease that appear during pregnancy. J Clin Endocrinol Metab, 86:3647–3653.

36.

Balucan

, Morshed

, Davies

. 2013. Thyroid autoantibodies in pregnancy: their role, regulation and clinical relevance. J Thyroid Res, 2013:182472.