Endocrine Journal 2014, 61 (8), 751-758

Original

Management of hyperthyroidism during pregnancy in Asia

Fereidoun Azizi 1), Atieh Amouzegar 1), Ladan Mehran1), Shahram Alamdari 2), Imam Subekti3),
Bijay Vaidya4), Kris Poppe 5), Farzaneh Sarvghadi 1), Teofilo San Luis Jr 6) and Takashi Akamizu 7)
1)
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2)
Medical Research Development Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3)
Division of Endocrinology and Metabolism, Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
4)
Department of Endocrinology, Royal Devon and Exeter Hospital, Exeter, UK
5)
Department of Endocrinology and General Internal Medicine, University hospital Brussels, Free UZ Brussels(VUB), Brussels,
Belgium
6)
Faculty of Medicine and surgery, University of Santo Tomas, Manila, Philippines
7)
The First Department of Medicine, Wakayama Medical University, Wakayama, Japan

Abstract. Maternal hyperthyroidism in pregnancy is associated with adverse impacts on both mother and fetus. Recently,
the American Thyroid Association and the Endocrine Society have published guidelines for the management of thyroid
diseases in pregnancy. We aimed to disclose the impact of these guidelines in current practices of Asian members of the
Asia-Oceania Thyroid Association (AOTA) regarding the management of hyperthyroidism in pregnancy. Completed
questionnaire survey, based on clinical case scenarios, was collected from 321 Asian physician members of AOTA from 21
Asian countries in 2013. For a woman with Graves disease planning pregnancy, 92% of clinicians favored antithyroid
treatment, 52% with propylthiouracil (PTU) while 40% preferred methimazole (MMI). For a pregnant woman with newly
diagnosed overt hyperthyroidism, nearly all responders initiated PTU treatment. To monitor dosage of antithyroid drugs,
approximately 73% of responders used TSH and free T4 (FT4) levels without free T3 (FT3) (53%) or with FT3 (20%).
Majority of responders targeted achieving low serum TSH with FT4 (or total T4) in the upper end of the normal range. For
management of gestational thyrotoxicosis, 40% chose to follow up and 52% treated patients with PTU. Although timing
of TSH receptor antibodies measurement in pregnant hyperthyroid patients was variable, 53% of responders would check
it at least once during pregnancy. Nearly 80% of responders do not treat subclinical hyperthyroidism in pregnancy.
Therefore, despite wide variations in the management of hyperthyroidism during pregnancy in Asia, majority of Asian
physicians practice within the recommendations of major professional societies.

Key words: Hyperthyroidism, Management, Pregnancy

HYPERTHYROIDISM which occurs in 0.053.0% of birth, thyroid storm and maternal congestive heart fail-
pregnancies may pose various difficulties in diagnosis ure [3-7]; considering these impacts, optimal manage-
and treatment [1]. In addition, gestational transient thy- ment of maternal hyperthyroidism is of utmost impor-
rotoxicosis (GTT) or hypermesis gravidarum may com- tance [3]. Transient gestational thyrotoxicosis resulting
plicate its diagnosis and management during first half of from stimulation effect of HCG is less common and is
pregnancy [2]. Graves disease (GD), the most common not associated with poor pregnancy outcomes. As GTT
cause of hyperthyroidism in pregnancy, has adverse and GD have totally different approaches and risks, cor-
impacts in both mother and fetus including miscar- rect diagnosis should be confirmed. Antithyroid drugs
riage, pregnancy induced hyperthyroidism, prematurity, remain the mainstay of treatment of hyperthyroidism
low birth weight, intrauterine growth retardation, still in pregnant women, as radioiodine therapy is contra-
Submitted Mar. 31, 2014; Accepted Apr. 28, 2014 as EJ14-0145 indicated and thyroidectomy may be complicated by
Released online in J-STAGE as advance publication May 22, 2014 adverse effects of surgery [1, 8, 9].
Correspondence to: Ladan Mehran, M.D., Senior Research Two guidelines from the American Thyroid
Associate, Endocrine Research Centre, Research Institute for
Association (ATA) and the Endocrine Society (ES)
Endocrine Sciences, Shahid Beheshti University of Medical
Sciences, P.O. Box: 19395-4763 Tehran, I.R. Iran. have been published in 2011 and 2012 for the man-
E-mail: [email protected] agement of thyroid diseases including hyperthyroidism
The Japan Endocrine Society
752 Azizi et al.

[10, 11]. To what extent clinicians adopt these guide- analysis. Most of the responses received were from
lines in routine practice is unknown. We, therefore, Iran (n=44) followed by Indonesia (n=43), Philippines
surveyed the Asian members of the Asian- Oceania (n=40), Taiwan (n=38), Malaysia (n=23), Japan (n=14),
Thyroid Association (AOTA) to detect the current Singapore (n=12), India (n=11), Thailand (n=11) and
prevalent practices used for the management of hyper- Srilanka (n=10).
thyroidism during pregnancy in Asia.
Pre-pregnancy treatment of hyperthyroidism
Subjects and methods Physicians were asked about the treatment of thy-
This survey was performed in two phases. The first rotoxicosis in a 26 year old woman newly diagnosed
phase was done in March 2013; an electronic question- with Graves disease who wishes to become pregnant.
naire was emailed to the members of AOTA Council Responders suggested methimazole/ carbimazole (MMI/
and the presidents of Asian member endocrine societ- CMZ), propylthiouracil (PTU), surgery or radioiodine
ies, requesting them to distribute and have endocrinolo- treatment before surgery (Table 1). Only 8% of respond-
gists of the respective countries complete the question- ers recommended ablative treatment before pregnancy,
naires. A reminder was also sent in September 2013. 4% surgery and 4% radioiodine therapy. The remainder
The second phase of study was implemented during 92% would treat this case with antithyroid medications,
the meeting of Asian Federation of Endocrine Societies 52% propylthiouracil and 40% methimazole.
(AFES), held in November 13-16, 2013, in Jakarta,
Indonesia, where the survey questionnaires were dis- Treatment of hyperthyroidism in pregnancy
tributed for completion to endocrinologists, internists A 24 year old pregnant woman newly diagnosed
and general practitioners attending AFES 2013. Graves disease at 8 weeks of pregnancy was presented
The survey questionnaire composed of clinical case and the responders were questioned regarding the treat-
scenarios, posing questions related to clinical practice ment of her thyrotoxicosis. Of 96% who preferred
about the screening and management of hyper- and treatment with propylthiouracil, 38% chose this option
hypothyroidism in pregnancy. In this paper, the results only in the first trimester followed by change to methi-
concerning the diagnosis and treatment of hyperthy- mazole/ carbimazole in the second. Only 4% would
roidism during pregnancy are presented. The survey treat this hyperthyroid pregnant woman with methima-
questionnaire was a modification of instruments used zole/ carbimazole from the start.
by Vaidya et al. in a European survey [12]. There were
9 multiple choice questions on diagnosis and treatment Monitoring antithyroid treatment
of hyperthyroidism during pregnancy. The respond- There were inconsistencies in responders recom-
ers were allowed to provide their own response if the mendations on how to monitor the dose of antithyroid
option was not included in the questionnaire. drugs. More than half (53%) chose monitoring TSH
Analysis was performed by adjusting all frequencies and FT4 levels, 20% preferred TSH, FT4 and FT3,
to 100% basis, excluding the non-responders. All per- 9% FT4 alone, 9% TSH, total T4 and total T3 and 5%
centages were rounded up to a whole number in the chose TSH and total T4 measurements (Table 2).
text and tables.
Target thyroid test
Results When asked what results of target thyroid tests
would you aim to achieve with antithyroid drugs in preg-
Responders nancy?, sixty six percent of responders aimed to attain
Three hundred twenty one responses were received low serum TSH and FT4 (or total T4) in the upper end of
from 21 countries. Two responders that were not from the normal range (Table 3); however, 24% aimed to have
Asian countries (Australia) and 9 others that were not serum TSH and FT4 (or total T4) in the normal range.
involved in the management of thyroid diseases in
pregnancy were excluded. Therefore, data of responses Management of gestational thyrotoxicosis
from 310 responders in 21 Asian countries, including Responders were asked about the treatment of a 24
277 (89%) endocrinologists and 33 (11%) internists year old, 8 weeks pregnant woman with nausea, vom-
and general practitioners were included in the final iting, weight loss and palpitation, whose thyroid func-
 Pregnancy and hyperthyroidism 753

Table 1 Treatment preference in a woman diagnosed with Graves disease

seeking pre-pregnancy counseling
Responders
Recommendation
n (%)
Propylthiouracil 162 (52)
Methimazole/ carbimazole 123 (40)
Refer for definitive treatment with surgery before pregnancy 14 (4)
Refer for definitive treatment with radioiodine before pregnancy 12 (4)

Table 2 Different tests responders use to monitor antithyroid drugs dose in

pregnancy
Responders
Tests
n (%)
TSH and FT4 166 (53)
TSH, FT4 and FT3 62 (20)
FT4 alone 29 (9)
TSH, TT4, TT3 29 (9)
TSH and TT4 15 (5)
Others 12 (4)
FT4, free thyroxine; FT3, free triiodothyronine; TT3, total T3; TT4, total T4

Table 3 Target thyroid function tests in hyperthyroid pregnant women on

antithyroid drugs
Responders
Targets
n (%)
Low TSH and FT4(or TT4) in the upper end of normal range 197 (66)
TSH and FT4(or TT4) in the normal range 68 (24)
Low TSH and FT4(or TT4) in the normal range 16 (6)
Others 10 (4)
FT4, free thyroxine; FT3, free triiodothyronine; TT3, total T3; TT4, total T4

tion tests were in hyperthyroid range, with negative thy- up and 20% choose treatment.
roid antibodies. Nearly 40% of physicians chose follow
up, without treatment and 52% preferred treatment Fetal ultrasound monitoring
with propylthiouracil; of these 28% would change to Responders approaches to ultrasonography monitor-
methimazole/ carbimazole after first trimester (Table 4). ing of fetus in antithyroid treated women with Graves
disease varied. Nearly 55% of responders monitored the
Checking of TSH receptor antibodies fetus routinely using ultrasound scan; 20% would do so
Forty-three percent of responders did not rou- in only when the mother was positive for TRAb, while
tinely check TSH receptor antibodies (TRAb) in preg- 25% would not prescribe ultrasound monitoring.
nant women with Graves disease treated with antithy-
roid drugs (Table 5). Of around 53% who would check Management of postpartum hyperthyroidism
TRAb in the first trimester, 32% would repeat TRAb in There was inconsistency in responders recommenda-
the third trimester, only if positive in the first trimester. tions on how to manage a postpartum lactating woman
with relapse of Graves hyperthyroidism. Seventy-eight
Management of subclinical hyperthyroidism percent would start antithyroid medication (54%MMI
Physicians were then asked if they recommend treat- and 24% PTU) and continue lactation; however, the
ment or follow up of subclinical hyperthyroidism in remaining 22% would initiate antithyroid drugs (MM:
pregnancy. About 80% of responders preferred follow I6% and PTU: 6%) but would stop lactation (Table 6).
754 Azizi et al.

Table 4 Responders recommendations for treatment or follow up of an eight week

pregnant woman with gestational thyrotoxicosis
Recommendation Responders
n (%)
Follow up, no treatment 127 (40)
Propylthiouracil in first trimester, then change to methimazole/ carbimazole 86 (28)
Propylthiouracil 74 (24)
Methimazole/ carbimazole 7 (2)
Others* 23 (6)
*
Others include those who chose symptomatic therapy like as -blocker and hydration therapy

Table 5 Routine checking of TSH receptor antibodies (TRAb) in a pregnant hyperthyroid

woman
Responders
Response
n (%)
No 135 (43)
Yes, in the first trimester, and if positive in the third trimester 101 (32)
Yes, in each trimester 34 (11)
Yes, in the first and third trimesters 32 (10)
Others 21 (4)

Table 6 Responders recommendations to a postpartum lactating woman with Graves

hyperthyroidism
Responders
Recommendation
n (%)
Start methimazole/ carbimazole but continue lactation 169 (54)
Start propylthiouracil but continue lactation 76 (24)
Start methimazole/ carbimazole and stop lactation 53 (16)
Start propylthiouracil and stop lactation 23 (6)

Discussion of PTU has been recommended by both organizations

during the first trimester, followed by MMI from second
The present study reports, for the first time, current trimester onwards to the end of pregnancy. The greatest
clinical practices for management of hyperthyroidism concern in the use of MMI in the first trimester of preg-
during pregnancy in Asia. Guidelines from the ATA nancy is related to teratogenic effect called methima-
and ES published in 2011 and 2012 are alike in many zole embryopathy that induces choanal or esophageal
aspects, and no disagreement or controversy have been atresia, and dysmorphic faces [14-16]. On the other hand
found between the two guidelines [13]. Generally, PTU hepatotoxicity that may occur anytime during treat-
there was a high degree of consistency between clini- ment has caused concern regarding its use as the first line
cal practices of Asian physicians and guidelines, such drug for treatment of hyperthyroidism, limiting its use
as the initiation of antithyroid treatment in the first tri- to the first trimester of pregnancy [17-18]. Endocrine
mester, tests to monitor drug therapy and thyroid func- Society guidelines state that MMI may be administered
tion for a pregnant hyperthyroid woman, lack of treat- if patient has an adverse response or cannot tolerate PTU
ment of subclinical hyperthyroidism in pregnancy and or if this drug is not available. In addition, recommen-
management of postpartum hyperthyroidism. dations for change of PTU to MMI after first trimester
Maternal hyperthyroidism diagnosed during preg- has caused concerns for some thyroidologist; therefore
nancy should be corrected, because hyperthyroidism the ES recommends that practitioners should use their
has detrimental effects on both mother and fetal health clinical judgment in switching patients from one drug to
[3-7]. Based on current data, MMI and PTU have equal another [11]. In the present survey, 96% of responders
efficacy in the treatment of pregnant women. The use begin treatment of hyperthyroid pregnant women with
 Pregnancy and hyperthyroidism 755

PTU and almost one third (38%) of them will switch to pregnancy. Severe nausea, vomiting, weight loss and
MMI after the first trimester. palpitation, along with negative thyroid antibodies
For pre-conception counseling of a Graves, patient, favor gestational thyrotoxicosis, a self limiting condi-
92% of Asian clinicians advised antithyroid drugs (52% tion which is less severe than Graves disease [27, 2];
PTU and 40% MMI) and only 8% will ablate the thy- however, current clinical evidence of autoimmunity,
roid (radiation or surgery) before allowing the patient typical goiter, ophthalmopathy and TRAb supports the
to consider pregnancy, this is in agreement with ATA, diagnosis of Graves disease. In most cases of gesta-
which recommends the use of MMI/CMZ and change tional thyrotoxicosis no treatment is indicated; antithy-
to PTU once the pregnancy is confirmed [10]; how- roid drugs are not indicated as serum T4 returns to nor-
ever, it is not clear whether this approach would prevent mal around 14-18 weeks of pregnancy and the available
MMI/CMZ associated embryopathy. It is noteworthy evidence shows no improvement of pregnancy out-
that following treatment of hyperthyroidism with anti- comes in treated cases [28, 29]. This approach was
thyroid drugs or surgery, serum TRAb will decrease to selected only by 40% of responders, while 54% pre-
normal values in the majority of patients [19] and TRAb ferred treatment with antithyroid medications.
titers will increase during the first year after radioio- Increased serum TRAb is a risk for fetal and neona-
dine therapy followed by a subsequent gradual fall [20, tal hyperthyroidism and can be detected in up to 95%
21]; however, even 4-6 years after radioiodine therapy of hyperthyroid pregnant women with Graves dis-
many patients are still TRAb positive [22], an issue ease. The titer decreases with the progression of preg-
which is of utmost importance, as a high titer of TRAb nancy. Routine measurement of TRAb in a hyperthy-
is a risk factor for fetal and neonatal hyperthyroidism. roid pregnant woman under antithyroid drug therapy is
Therefore clinicians advise women to postpone preg- recommended by major professional endocrine organi-
nancy for more than 6 month after ablation with 131I. zations. Mothers with active hyperthyroidism, a his-
More than half of the clinicians monitor antithyroid tory of radioiodine therapy, thyroidectomy for hyper-
drug treatment by TSH and FT4 levels and another 20% thyroidism or delivery of a hyperthyroid infant should
with TSH, FT4 and FT3. Determination of serum TT3 undergo further evaluation [30-32]. The prevalence
levels used by 9% of physicians is not recommended as of fetal and neonatal hyperthyroidism ranges between
it has been reported that normalization of maternal TT3 1-5% in women with current or past history of Graves
leads to elevated serum TSH in infants [23]; in addition, disease and lack of treatment will increase morbidity
66% responders target achieving low TSH and FT4 (or and mortality in the fetus and infants [33, 34]. Serum
TT4) in the normal range during such therapy. This is TRAb titers increase following 131I therapy and may
also considered as good practice, since guidelines rec- remain high for many years thereafter. It is recom-
ommend TSH and FT4 assessment as the main tests mended to measure TRAb by 24-28 weeks of gesta-
for such monitoring and advise aiming for FT4 within tion to detect pregnancies at risk. A titer over 3 times
the upper end of normal range or just above the upper that of upper normal limits warrants close follows up
limit of normal, while utilizing the smallest possible of the fetus. It is worrying that 43% of clinicians sur-
dose of anti thyroid drugs during pregnancy [10, 11]. veyed indicated that they do not routinely check TRAb,
It was distressing to find that 24% of Asian clinicians mainly due to lack of availability of this test.
target normal range for serum TSH and FT4 concentra- Although there is not enough evidence to recom-
tions, an approach which could increase the chance of mend or advise against the use of thyroid ultrasound
fetal goiter and hypothyroidism [24]. Inconsistency in in differentiating the cause of hyperthyroidism in preg-
test combinations used by the responders (Table 2) for nancy, it has been recommended to use ultrasound scan
monitoring anti thyroid drugs doses during pregnancy for monitoring of fetus in women with Graves dis-
may to some extent be due to the availability of tests in ease under antithyroid drug therapy; ultrasonography
different settings. On the other hand, despite the con- should be performed in those with uncontrolled hyper-
troversy on the accuracy of FT4 assays during preg- thyroidism or with high TRAb titers, both of which can
nancy about 82% of physicians used FT4 alone or in compromise fetal well being [35]. Only 25% of Asian
combination with other tests [25, 26]. responders did not adhere to this recommendation.
Differentiation of Graves disease and gestational In this survey, for the management of hyperthy-
thyrotoxicosis may be difficult during the first half of roidism in a postpartum lactating woman, 78% of the
756 Azizi et al.

Table 7 Comparison of Asian and European responders in management of hyperthyroidism in pregnancy

Responders (%)
Variables
Asian European*
Pre-pregnancy approach for a newly diagnosed Graves disease
Propylthiouracil 52 42
Methimazole/ carbimazole 40 36
Surgery 4 9
Radioiodine 4 13
Treatment for Graves hyperthyroidism in first trimester
Propylthiouracil 58 53
Propylthiouracil in the first trimester then Methimazole/ carbimazole 38 34
Methimazole/ carbimazole 4 12
Tests to monitor antithyroid drugs dosage in pregnancy
TSH and FT4 53 27
TSH, FT4 and FT3 20 41
FT4 alone 9 8
TSH, TT4, TT3 9 4
Target thyroid function in treated hyperthyroidism
Low TSH and FT4(or TT4) in the upper end of normal range 66 64
TSH and FT4(or TT4) in the normal range 24 13
Low TSH and FT4(or TT4) in the normal range 6 19
Treatment for gestational thyrotoxicosis
Follow up, no treatment 40 50
Propylthiouracil, in first trimester, then methimazole/ carbimazole 28 17
Propylthiouracil 24 18
Methimazole/carbimazole 2 7
Checking TRAb in hyperthyroid pregnant
No 43 11
Yes, in the first trimester, and if positive in the third trimester 32 42
Yes, in each trimester 11 17
Yes, in the first and third trimester 10 15
Postpartum lactating woman with Graves hyperthyroidism
Methimazole/ carbimazole but continue lactation 54 38
Propylthiouracil but continue lactation 24 30
Methimazole/ carbimazole and stop lactation 16 21
Propylthiouracil and stop lactation 6 3
*
Ref no: [12]; Data derived from current survey

responders chose antithyroid therapy and continu- unfortunate, however that 22% of responder physicians
ing lactation; however, 24% of them preferred treat- surveyed recommended stopping lactation while treat-
ment with PTU. ATA and ES both recommended treat- ing the lactating mother with antithyroid medications.
ing lactating hyperthyroid women with MMI, because Compared to the survey reported management of
treatment with PTU may cause liver damage [17]. It hyperthyroidism in pregnancy in Europe [12], the
has been shown that MMI therapy up to 30 mg daily results of this study did not differ greatly in various
does not cause any alterations in thyroid function and aspects of management of hyperthyroidism during
mental or physical development of children, aged 48-86 pregnancy except for TRAb monitoring, which unfortu-
months, breast-fed by lactating hyperthyroid mothers nately most Asian physicians did not check it routinely
[36, 37]. Checking thyroid functions of breast-feed- in hyperthyroid pregnant women, contrary to European
ing infants of mothers taking antithyroid drugs is rec- clinicians who also assessed FT3 more in combination
ommended. Prescribing the treatment in divided doses with TSH and FT4 for monitoring the dose of anti thy-
immediately after breast feeding is also suggested. It is roid drugs (Table 7).
 Pregnancy and hyperthyroidism 757

There are several limitations that should be consid- considered in the strategic plans of continuing medical
ered in analyzing the results of this survey. First, the education in related professional societies of various
clinician responders were not randomly selected from countries of Asia.
all countries of this large continent (Asia) and may not
represent all physicians in Asia. The Asian Ocean Acknowledgement
Thyroid Association has over 4000 members of which
just 321 practitioners participated in this study which The authors thank all respondents for completing the
may not be representative of all; however we did not questionnaire, and the President and the Secretary of
receive responses from some of these practitioners. the Asia-Oceania Thyroid Association for giving us a
Our results are hence somewhat limited as regards gen- permission to carry out this survey amongst its mem-
eralization. Second, variations in the clinical prac- bers. The authors are indebted to the assistance of
tices of different countries especially, those with larger Merck-Serono Co., particular Gernot Beroset, Prafira
number of responders, could have influenced the over- Kuswardhani and Wiwi Feriyanti for distribution and
all results of this study. Third, majority of participants collection of survey questioners during the AFES-2013
of this survey were endocrinologists, and the approach meeting in Jakarta. The authors wish to acknowledge
of other healthcare professionals for management of Ms. Niloofar Shiva for critical editing of English gram-
hyperthyroidism in pregnancy, may differ from that of mar and syntax of the manuscript.
the endocrinologists surveyed; on the other hand, none
of the responders were obstetricians, although some Declaration of Interest
of them do manage these patients in multidisciplinary
settings. We believe that this survey with participants The authors declare that there is no conflict of inter-
from 21 Asian countries may provide a snapshot of cur- est that could be perceived as prejudicing the impartial-
rent practices in the management of hyperthyroidism in ity of the research reported.
Asia, however larger surveys are clearly warranted.
It is concluded that although most Asian clinicians Funding
adhere to the clinical practice guidelines recommended
by major professional organizations, the lack of adher- This research did not receive any specific grant from any
ence of a considerable number of physicians should be funding agency in the public, commercial profit sector.

References
1. Azizi F, Amouzegar A (2011) Management of hyper- pregnancy. Am J Obstet Gynecol 160: 63-70.
thyroidism during pregnancy and lactation. Eur J 8. Mandel SJ, Cooper DS (2001) The use of antithyroid
Endocrinol 164: 871-876. drugs in pregnancy and lactation. J Clin Endocrinol
2. Tan JY, Loh KC, Yeo GS, Chee YC (2002) Transient Metab 86: 2354-2359.
hyperthyroidism of hyperemesis gravidarum. BJOG 9. Azizi F (2006) The safety and efficacy of antithyroid
109: 683-688. drugs. Expert Opin Drug Saf 5: 107-116.
3. Stagnaro-Green A (2009) Maternal thyroid disease and 10. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F,
preterm delivery. J Clin Endocrinol Metab 94: 21-25. Mestman J, et al. (2011) American Thyroid Association
4. Mestman JH (1997) Hyperthyroidism in pregnancy. Taskforce on Thyroid Disease During Pregnancy
Clin Obstet Gynecol 40: 45-64. and Postpartum. Guidelines of the American Thyroid
5. Papendieck P, Chiesa A, Prieto L, Gruneiro-Papendieck Association for the diagnosis and management of thy-
L (2009) Thyroid disorders of neonates born to mothers roid disease during pregnancy and postpartum. Thyroid
with Graves disease. J Pediatr Endocrinol Metab 22: 21: 1081-1125.
547-553. 11. De Groot L, Abalovich M, Alexander EK, Amino
6. Krassas GE, Poppe K, Glinoer D (2010) Thyroid func- N, Barbour L, et al. (2012) Management of Thyroid
tion and human reproductive health. Endocr Rev 31: Dysfunction during Pregnancy and Postpartum: An
702-755. Endocrine Society Clinical Practice Guideline. J Clin
7. Davis LE, Lucas MJ, Hankins GD, Roark ML, Endocrinol Metab 97: 2543-2565.
Cunningham FG (1989) Thyrotoxicosis complicating 12. Poppe K, Hubalewska-Dydejczyk A, Laurberg P,
758 Azizi et al.

Negro R, Vermiglio F, et al. (2012) Management of of propylthiouracil in a pregnant woman with Graves
Hyperthyroidism in Pregnancy: Results of a Survey hyperthyroidism. Thyroid 9: 1111-1114.
among Members of the European Thyroid Association. 25. Lee RH, Spencer CA, Mestman JH, Miller EA, Petrovic
Eur Thyroid J 1: 34-40. I, et al. (2009) Free T4 immunoassays are flawed during
13. Alamdari S, Azizi F, Delshad H, Sarvghadi F, pregnancy. Am J Obstet Gynecol 200: 260.
Amouzegar A, et al. (2013) Management of hyperthy- 26. Anckaert E, Poppe K, Van Uytfanghe K, Schiettecatte J,
roidism in pregnancy: comparison of recommendations Foulon W, et al. (2010) FT4 immunoassays may display
of American thyroid association and endocrine society. a pattern during pregnancy similar to the equilibrium
J Thyroid Res 2013: Article ID: 878467. dialysis ID-LC/tandem MS candidate reference mea-
14. Clementi M, Di Gianantonio E, Pelo E, Mammi I, Basile surement procedure in spite of susceptibility towards
RT, et al. (1999) Methimazole embryopathy: delinea- binding protein alterations. Clin Chim Acta 411: 1348-
tion of the phenotype. Am J Med Genet 83: 43-46. 1353.
15. Barbero P, Valdez R, Rodrguez H, Tiscornia C, Mansilla 27. Goodwin TM, Montoro M, Mestman JH (1992)
E, et al. (2008) Choanal atresia associated with maternal Transient hyperthyroidism and hyperemesis gravi-
hyperthyroidism treated with methimazole: a case-con- darum: clinical aspects. Am J Obstet Gynecol 167: 648-
trol study. Am J Med Genet A 146A: 2390-2395. 652.
16. Clemanti M, Di Gianantonio, E, Cassina M, Leoncini 28. Verberg MF, Gillott DJ, Al-Fardan N, Grudzinskas JG
E, Botto LD, et al (2010) SAFE-Med study Group. (2005) Hyperemesis gravidarum, a literature review.
Treatment of hyperthyroidism in pregnancy and birth Hum Reprod Update 11: 527-239.
defects. J Clin Endocrinol Metab 95: E337-341. 29. Bouillon R, Naesens M, Van Assche FA, De Keyser L,
17. Russo MW, Galanko JA, Shrestha R, Fried MW, De Moor P, et al. (1982) Thyroid function in patients
Watkins P (2004) Liver transplantation for acute liver with hyperemesis gravidarum. Am J Obstet Gynecol
failure from drug induced liver injury in the United 143: 922-926.
States. Liver Transpl 10: 1018-1023. 30. McKenzie JM, Zakarija M (1992) Fetal and neonatal
18. Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee hyperthyroidism and hypothyroidism due to maternal
CM, et al. (2009) The Role of Propylthiouracil in the TSH receptor antibodies. Thyroid 2: 155-159.
Management of Graves Disease in Adults: report of 31. Mitsuda N, Tamaki H, Amino N, Hosono T, Miyai K,
a meeting jointly sponsored by the American Thyroid et al. (1992) Risk factors for developmental disorders
Association and the Food and Drug Administration. in infants born to women with Graves disease. Obstet
Thyroid 19: 673-674. Gynecol 80: 359-364.
19. Laurberg P, Bournaud C, Karmisholt J, Orgiazzi J (2009) 32. Peleg D, Cada S, Peleg A, Ben-Ami M (2002) The rela-
Management of Graves hyperthyroidism in pregnancy: tionship between maternal serum thyroid-stimulating
focus on both maternal and foetal thyroid function, and immunoglobulin and fetal and neonatal thyrotoxicosis.
caution against surgical thyroidectomy in pregnancy. Obstet Gynecol 99: 1040-1043.
Eur J Endocrinol 160: 1-8. 33. Zimmerman D (1999) Fetal and neonatal hyperthyroid-
20. Atkinson S, McGregor AM, Kendall-Taylor P, Peterson ism. Thyroid 9: 727-733.
MM, Smith BR (1982) Effect of radioiodine on stim- 34. Polak M, Le Gac I, Vuillard E, Guibourdenche J, Leger
ulatory activity of Graves immunoglobulins. Clin J, et al. (2004) Fetal and neonatal thyroid function in
Endocrinol (Oxf) 16: 537-543. relation to maternal Graves disease. Best Pract Res
21. Teng CS, Yeung RT, Khoo RK, Alagaratnam TT (1980) Clin Endocrinol Metab 18: 289-302.
A prospective study of the changes in thyrotropin bind- 35. Cohen O, Pinhas-Hamiel O, Sivan E, Dolitski M, Lipitz
ing inhibitory immunoglobulins in Graves disease S, et al. (2003) Serial in utero ultrasonographic mea-
treated by subtotal thyroidectomy or radioactive iodine. surements of the fetal thyroid: a new complementary
J Clin Endocrinol Metab 50: 1005-1010. tool in the management of maternal hyperthyroidism in
22. Laurberg P, Wallin G, Tallstedt L, Abraham-Nordling pregnancy. Prenat Diagn 23: 740-742.
M, Lundell G, et al. (2008) TSH-receptor autoimmunity 36. Azizi F, Hedayati M (2002) Thyroid function in breast-
in Graves disease after therapy with anti-thyroid drugs, fed infants whose mothers take high doses of methima-
surgery, or radioiodine: a 5-year prospective random- zole. J Endocrinol Invest 25: 493-496.
ized study. Eur J Endocrinol 158: 69-75. 37. Azizi F, Bahrainian M, Khamseh ME, Khoshniat M
23. Hamburger JI (1992) Diagnosis and management of (2003) Intellectual development and thyroid function
Graves disease in pregnancy. Thyroid 2: 219-224. in children who were breast-fed by thyrotoxic mothers
24. Ochoa-Maya MR, Frates MC, Lee-Parritz A, Seely EW taking methimazole. J Pediatr Endocrinol Metab 16:
(1999) Resolution of fetal goiter after discontinuation 1239-1243.