|
Kérdezz-felelek
PM tultengesem van, a T3 szintem a merheto ertek felett van, tobb, mint 46.
Kaptam Propycil-t, mert jelenleg szoptatok, demeg nem kezdtem el szedni, mert elotte probaltam utana olvasni az interneten.
Irtam az FDA-nek is, hogy megtudjam mi az allaspontjuk a Propycillel kapcsolatban, es a valaszuk
Propylthiouracil should be reserved for patients who can not tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism
Because of the risk of fetal abnormalities associated with methimazole, propylthiouracil may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy
Irtak meg a sulyos majkarosodasrol is, mint lehetseges mellekhatas.
Kicsit el vagyok veszve a sok informacio kozott, es szeretnem a legjobb megoldast valasztani, mind a kisbabam, mind magam szamara.
Hajlok arra is, hogy inkabb a methimazole-t szedjem es abbahagyjam a szoptatast.
Szeretnem megkerdezni, mi a velemenye errol, melyik gyogyszert javasolja.
Illetve meg azt szeretnem tudni, hogy ha a methimazole mellett dontok, akkor a szoptatas egyaltalan nem javasolt, vagy esetleg megtarthatok napi 1 v 2 szoptatast a gyogyser szedes mellett?
elore is koszonom a valaszat
Udvozlettel
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1. Mindenek előtt tisztázni kellene, hogy mi okozza a túlműködést. Az irányelevekt, az FDA-t és a NICE-t ismerem és ennek megfelelően járok , jártam el és azt javaslom:el
Hindawi Publishing Corporation International Journal of Endocrinology
Volume 2010, Article ID 910636, 5 pages
doi:10.1155/2010/910636
Case Report
Propylthiouracil-Induced Acute Liver Failure:
Role of Liver Transplantation
Andres F. Carrion,1 Frank Czul,1 Leopoldo R. Arosemena,2
Gennaro Selvaggi,3 Monica T. Garcia,4 Akin Tekin,3 Andreas G. Tzakis,3
PaulMartin,5 and Ravi K. Ghanta6
1Department of Medicine, University of Miami Leonard M. Miller School of Medicine, 185 SW 7th Street, Unit 1510, Miami,
FL 33130, USA
2Division of Hepatology, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami,
FL 33130, USA
3Division of Liver and Gastrointestinal Transplantation, Department of Surgery, University of Miami
Leonard M. Miller School of Medicine, Miami, FL 33130, USA
4Department of Pathology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33130, USA
5Divisions of Hepatology and Liver and Gastrointestinal Transplantation, Department of Medicine, University of Miami
Leonard M. Miller School of Medicine, Miami, FL 33130, USA
6Division of Gastroenterology, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami,
FL 33130, USA
Correspondence should be addressed to Andres F. Carrion, acarrionmonsalve@med.miami.edu
Received 21 July 2010; Accepted 30 November 2010
Academic Editor: Furio M. Pacini
Copyright © 2010 Andres F. Carrion et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from
asymptomatic elevation of transaminases to fulminant hepatic failure and death.We describe two cases of acute hepatic failure due
to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant
management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction
is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may
prevent progression to liver failure or even death.
1. Introduction
Propylthiouracil (PTU) has been implicated in drug-induced
liver injury (DILI) in patients with hyperthyroidism treated
with this medication. Reported injury has ranged from mild
asymptomatic elevation of aminotransferases to acute liver
failure (ALF). Although asymptomatic elevations in hepatic
enzymes have been described in patients with untreated
hyperthyroidism, recognition of hepatic dysfunction in a
patient taking PTU requires immediate discontinuation of
the drug and close followup.
2. Case Presentations
Case 1. A 29-year-old African American woman with
Graves’ disease unsuccessfully treated with methimazole was
prescribed propylthiouracil (PTU) 50 mg PO every 8 hours.
Aminotransferase levels were normal before therapy was
started; however, mild elevations of these enzymes were
initially noticed by the fourth week of therapy (AST:
64 U/L, ALT: 94 U/L, alkaline phosphatase: 170 U/L) and
continued to progressively increase by week eight. By week
ten of treatment, she reported jaundice, fatigue, epigastric
2 International Journal of Endocrinology
abdominal pain, nausea, and vomiting. She denied the
use of over-the-counter or herbal medications. Her past
medical history and family history were not contributory.
She denied excessive alcohol consumption and recreational
drug use. Upon subsequent transfer to our institution,
initial laboratory workup revealed a prothrombin time of
39.1 seconds, INR 3.9, total bilirubin 19.3mg/dL, direct
bilirubin 12.1mg/dL, AST 503 U/L, ALT 443 U/L, alkaline
phosphatase 509 U/L, TSH 0.013 μIU/ml, and free-T4
0.7 ng/dL. Serum markers for viral hepatitis A, B, and C
were negative. Antinuclear antibodies, antismooth muscle
antibodies, and antimitochondrial antibodies were negative.
PTU was discontinued, but the coagulopathy worsened,
and she subsequently developed hepatic encephalopathy.
She underwent orthotopic liver transplantation (OLT) eight
days following admission. Histologic examination of the
explanted liver revealed submassive, confluent necrosis with
parenchymal hemorrhage, bile duct proliferation, intracellular
and canalicular cholestasis, bile plugging, and severe lymphoplasmacytic
and eosinophilic infiltrates. Immunostain
for IgG4 was positive (Figure 1, microphotographs (a) and
(b)). The patient was discharged home in stable condition on
postoperative day twelve. Her liver function become normal
6 months following OLT.
Case 2. A 34-year-old African American woman with Graves’
disease and without an antecedent history of liver disease
was prescribed PTU 150 mg PO twice daily. Baseline levels
of aminotransferases were normal at the time PTU was
started. Six weeks later she started to complain of malaise
and generalized weakness followed by progressive jaundice,
but she did not seek medical care until two weeks later when
she had developed confusion, nausea, and vomiting. Blood
tests at that time were INR 4.3, total bilirubin 22.8mg/dL,
direct bilirubin 10.8mg/dL, AST 1081 U/L, ALT 1227 U/L,
alkaline phosphatase 272 U/L, TSH 61.2 μIU/ml, and free-
T4 0.6 ng/dL. Serum markers for autoimmune and viral
hepatitis A, B, and C were negative. PTU was discontinued;
however, her mental status continued to deteriorate with
progression to severe hepatic encephalopathy. A transjugular
liver biopsy revealed extensive parenchymal necrosis, collapse
of the lobular architecture, bile duct proliferation,
and periportal inflammation. Two days after admission,
she was listed for OLT and received a liver transplant
three days later. Histological examination of the native
liver showed submassive confluent necrosis with prominent
eosinophilic, neutrophilic, and lymphoplasmacytic infiltrate
with canalicular and intracellular cholestasis and numerous
lobular acidophilic bodies (Figure 1, microphotographs (c)
and (d)). The allograft was retrieved from a 77-year-old
deceased donor, due to the recipient’s critical status. The
posttransplant course was complicated by the development
of graft dysfunction due to severe rejection, which did not
improve with aggressive immunosuppressive therapy. The
patient was relisted for OLT two weeks after the initial
transplant and received a second allograft 6 days later.
The postoperative course after the second transplant was
complicated by a biliary leak that required reconstruction
of the biliary anastomosis, as well as multiple episodes
of rejection which were treated with antilymphocyte antibodies,
plasmapheresis, and administration of rituximab.
The patient eventually recovered. She was discharged on
postoperative day 155 from the first liver transplant and is
currently at home doing well 6 months after the second liver
transplant.
3. Discussion
PTU is a thioamide derivative widely used for the treatment
of hyperthyroidism which exerts its pharmacologic effects
by two different mechanisms. It inhibits reactions catalyzed
by the enzyme thyroid peroxidase expressed in the thyroid
follicles and blocks iodine organification, and it also inhibits
the enzyme 5-deiodinase accountable for the peripheral
conversion of T4 into the active T3 moiety.
PTU-induced hepatitis was first reported by H. J. Livingston
and S. F. Livingston in 1947 [1], shortly after the FDA
had approved this medication for the treatment of hyperthyroidism.
This patient was successfully managed with supportive
care after discontinuation of the drug. Six years later,
Eisen [2] reported the first case of fulminant hepatic failure
attributed to PTU, an ominous adverse reaction that since
then has been observed in an extremely small number of
patients receiving this medication. Based on published data
about the annual incidence of hypothyroidism, the reported
frequency of PTU therapy (15,000 adults per year), and the
incidence of PTU-induced severe liver injury (approximately
0.1% in the adult population), approximately 15 adults will
develop this complication annually in USA and 10% of
them (1 : 10,000 adults) will progress to ALF. Asymptomatic
elevations of alanine aminotransferase (ALT) are observed
in 14–28% of patients started on PTU during the first 2
months of therapy and usually resolve with no intervention
[3]. Acute hepatitis associated with this medication has been
reported to occur in 0.1–1.2% of patients [4]. The mortality
associated with PTU-induced acute hepatitis can be as high
as 25% [5]. Data suggest that the risk of severe hepatotoxicity
is greater in children treated with PTU (1 : 1,000 children),
but the overall incidence is significantly lower because fewer
children are treated with this drug (1,500–4,000 children per
year) [6]. For example, a significant reduction in PTU use by
pediatric endocrinologists has been observed over the past
several years, and some authors advocate that PTU should
never be used as a first-line therapy in children due to the
potential risk severe hepatotoxicity [7].
Liver biopsy remains the gold standard for diagnosis
of PTU-induced hepatic injury, but the diagnosis is often
inferred from the time course after initiation of PTU
therapy [5, 8]. PTU hepatotoxicity has been reported to
cause a variety of histological changes including portal and
periportal inflammation with eosinophilic, lymphocytic, and
plasmacytic infiltration in varying combinations, chronic
active hepatitis, and submassive or massive hepatic necrosis
[9]. These histological features resemble autoimmune
hepatitis type 1 (AIH-1) and are referred to as druginduced
AIH-1. A multifactorial hypothesis has been proposed
as an explanation for PTU-induced hepatopathy in
International Journal of Endocrinology 3
(a) (b)
(c) (d)
Figure 1: (a) Submassive confluent necrosis with hemorrhage (H & E, 40x). (b) Periportal bile duct proliferation and mixed inflammatory
infiltrate (H&E, 100x). (c) Residual hepatocytes with cholestasis, acidophilic bodies, and mononuclear inflammation (H&E, 400x). (d)
Eosinophilic and lymphoplasmacytic infiltrate (H&E, 400x).
which inhibition of glucuronyl transferase, reduced bile
acid synthesis, and increased oxygen consumption by the
hepatocytes could be implicated in more or less extent
[10, 11]. Severe PTU-induced hepatotoxicity is postulated
to be a dose independent, idiosyncratic hypersensitivity
reaction. This theory is supported by positive lymphocyte
sensitization studies [3, 4, 12]. Some authors have noted an
association between this pathologic condition and positive
antineutrophil cytoplasmic antibodies (ANCA); however,
ANCA positivity has been reported in up to 50% of
asymptomatic patients receiving PTU, and this finding has
been considered to be incidental in the majority of cases and
not directly related to DILI or ANCA-associated vasculitis
[13, 14].
Treatment options for PTU-induced liver failure are limited.
Immediate discontinuation of the drug is imperative,
but progression of liver injury may occur, particularly in
cases with severe forms of DILI, and aggressive supportive
care is usually required. The milder form of PTU-induced
hepatotoxicity, characterized by symptomatic hepatitis, has
been associated with complete recovery after discontinuation
of the drug [15]. This outcome has also been reported in
cases with cholestatic liver injury, although the time required
for normalization of biochemical markers was longer in
the latter group [4]. Some authors have suggested that
the coincidental clinical improvement in patients receiving
systemic corticosteroids for the treatment of thyrotoxicosis
might reflect a therapeutic response [16]. Plasmapheresis was
apparently successfully used, in one case report of fulminant
hepatic failure; nonetheless, concomitant use of prednisone
confounded evaluation [8]. Liver transplantation has been
reported in severe, life-threatening cases of PTU-induced
hepatotoxicity with good outcomes [5, 15]. Between 1990
and 2007, the United Network for Organ Sharing (UNOS)
reported 23 liver transplants (16 in adults and 7 in children)
for PTU-induced ALF. Population-based estimates of liver
transplantations for ALF using the UNOS database indicate
that drug-induced ALF accounts for approximately 12–15%
of liver transplants for ALF in USA [17, 18]. PTU is the third
most common single drug responsible for DILI requiring
liver transplantation in the general population, preceded by
acetaminophen and isoniazid in the adult population and by
acetaminophen and valproic acid in pediatric patients [17].
The mean age of patients with PTU-induced ALF is 28 years;
over two thirds of these patients are females and almost half
of them are African Americans. Therefore, African American
ethnicitymay be a risk factor for severe formof PTU-induced
hepatotoxicity; nonetheless, there are no data supporting
ethnicity-specific or genetic variations responsible for these
observations, and specific recommendations about the use of
4 International Journal of Endocrinology
PTU in African Americans cannot be made. ALF secondary
to PTU and herbal substances is associated with higher
bilirubin levels (23.2mg/dL and 23.6mg/dL on average,
resp.) compared to other drugs, including acetaminophen
(9.8 mg/dL on average). The one-year graft survival rate after
liver transplantation for PTU-induced ALF is 84%; however,
no significant difference has been found in graft survival
rates after ALF caused by PTU, acetaminophen, isoniazid ,
or phenytoin [17].
We add to the body of literature two more cases of
severe PTU-induced liver failure successfully treated with
OLT. The first patient had an uneventful posttransplant
recovery, but the second case had a complicated clinical
course requiring retransplantation and multiple interventions
to prevent loss of the second allograft. Extended
criteria for donor organs, including advanced-age donors,
may be used due to the emergency need for OLT in patients
with fulminant hepatic failure; nonetheless, higher rates of
severe complications requiring specialized care underscore
the importance of treating these patients in experienced,
high-volume transplant centers. There are no official recommendations
regarding monitoring for serologic markers of
liver injury during PTU therapy; however, some authors have
recommended monthly monitoring of serum transaminases
for the first six months of therapy, which is the period
where most cases of PTU-induced DILI occur [19, 20].
Although there are no evidence-based data to support this
recommendation, we agree with the suggested time intervals
and duration of monitoring and emphasize the importance
of early discontinuation of therapy when early signs of liver
injury are detected.
4. Conclusions
Clinicians taking care of patients being treated with PTU
should have a low threshold for suspecting medicationrelated
adverse reactions, particularly for PTU-induced DILI.
Routine monitoring of serum transaminases and close
followup is recommended; nonetheless, the appropriate
intervals and duration of followup have not been established.
Early identification of clinical signs and abnormalities in
biochemical markers of hepatic injury followed by immediate
discontinuation of PTU, aggressive supportive care,
and transfer of patients to centers capable of performing
emergent liver transplantation is strongly advised due to
the high mortality associated with severe forms of this
complication.
Conflict of Interest Disclosure
None; Dr. Martin is a consultant and speaker for Roche,
Gilead, and Bristol-Myers Squibb Pharmaceuticals.
Declaration of Funding Source
There are no sources of pharmaceutical or industry support
related to this report.
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International Journal of Endocrinology 5
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2. Ami az irányeleveket illelti:
Guidelines of the American Thyroid Association
for the Diagnosis and Management of Thyroid Disease
During Pregnancy and Postpartum
The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum
Alex Stagnaro-Green (Chair),1 Marcos Abalovich,2 Erik Alexander,3 Fereidoun Azizi,4 Jorge Mestman,5
Roberto Negro,6 Angelita Nixon,7 Elizabeth N. Pearce,8 Offie P. Soldin,9
Scott Sullivan,10 and Wilmar Wiersinga11
INTRODUCTION
Pregnancy has a profound impact on the thyroid gland
and thyroid function. The gland increases 10% in size
during pregnancy in iodine-replete countries and by 20%–
40% in areas of iodine deficiency. Production of thyroxine
(T4) and triiodothyronine (T3) increases by 50%, along with a
50% increase in the daily iodine requirement. These physiological
changes may result in hypothyroidism in the later
stages of pregnancy in iodine-deficient women who were
euthyroid in the first trimester. The range of thyrotropin
(TSH), under the impact of placental human chorionic gonadotropin
(hCG), is decreased throughout pregnancy with
the lower normal TSH level in the first trimester being
poorly defined and an upper limit of 2.5 mIU/L. Ten percent
to 20% of all pregnant women in the first trimester of
pregnancy are thyroid peroxidase (TPO) or thyroglobulin
(Tg) antibody positive and euthyroid. Sixteen percent of the
women who are euthyroid and positive for TPO or Tg antibody
in the first trimester will develop a TSH that exceeds
4.0 mIU/L by the third trimester, and 33%–50% of women
who are positive for TPO or Tg antibody in the first trimester
will develop postpartum thyroiditis. In essence,
pregnancy is a stress test for the thyroid, resulting in hypothyroidism
in women with limited thyroidal reserve or
iodine deficiency, and postpartum thyroiditis in women
with underlying Hashimoto’s disease who were euthyroid
prior to conception.
Knowledge regarding the interaction between the thyroid
and pregnancy/the postpartum period is advancing at a
rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted
as the upper limit of normal for TSH in the first trimester.
This has important implications in regards to
interpretation of the literature as well as a critical impact for
the clinical diagnosis of hypothyroidism. Although it is well
accepted that overt hypothyroidism and overt hyperthyroidism
have a deleterious impact on pregnancy, studies are
now focusing on the potential impact of subclinical hypothyroidism
and subclinical hyperthyroidism on maternal and
fetal health, the association between miscarriage and preterm
delivery in euthyroid women positive for TPO and/or Tg
antibody, and the prevalence and long-term impact of postpartum
thyroiditis. Recently completed prospective randomized
studies have begun to produce critically needed data
on the impact of treating thyroid disease on the mother, fetus,
and the future intellect of the unborn child.
It is in this context that the American Thyroid Association
(ATA) charged a task force with developing clinical guidelines
on the diagnosis and treatment of thyroid disease during
pregnancy and the postpartum. The task force consisted of
international experts in the field of thyroid disease and
pregnancy, and included representatives from the ATA, Asia
and Oceania Thyroid Association, Latin American Thyroid
Society, American College of Obstetricians and Gynecologists,
and the Midwives Alliance of North America. Inclusion
of thyroidologists, obstetricians, and midwives on the task
1Departments of Medicine and Obstetrics/Gynecology, George Washington University School of Medicine and Health Sciences, Washington,
District of Columbia.
2Endocrinology Division, Durand Hospital, Favaloro University, Buenos Aires, Argentina.
3Division of Endocrinology, Diabetes, and Hypertension, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
4Internal Medicine and Endocrinology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medicine Sciences, Tehran,
Iran.
5Department of Medicine and Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles,
California.
6Division of Endocrinology, V. Fazzi Hospital, Lecce, Italy.
7Angelita Nixon, CNM, LLC, Scott Depot, West Virginia.
8Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts.
9Departments of Medicine, Oncology, Obstetrics and Gynecology, Georgetown University Medical Center, Washington, District of Columbia.
10Department of Obstetrics/Gynecology, Medical University of South Carolina, Charleston, South Carolina.
11Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
THYROID
Volume 21, Number 10, 2011
ª Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2011.0087
1
force was essential to ensuring widespread acceptance and
adoption of the developed guidelines.
The clinical guidelines task force commenced its activities
in late 2009. The guidelines are divided into the following
nine areas: 1) thyroid function tests, 2) hypothyroidism, 3)
thyrotoxicosis, 4) iodine, 5) anti-thyroid antibodies and
miscarriage/preterm delivery, 6) thyroid nodules and cancer,
7) postpartum thyroiditis, 8) recommendations on screening
for thyroid disease during pregnancy, and 9) areas for future
research. Each section consists of a series of questions germane
to the clinician, followed by a discussion of the questions
and concluding with recommendations.
Literature review for each section included an analysis of
all primary papers in the area published since 1990 and selective
review of the primary literature published prior to
1990 that was seminal in the field. In the past 15 years there
have been a number of recommendations and guideline
statements relating to aspects of thyroid and pregnancy (1,2).
In deriving the present guidelines the task force conducted a
new and comprehensive analysis of the primary literature as
the basis for all of the recommendations. The strength of each
recommendation was graded according to the United States
Preventive Services Task Force (USPSTF) Guidelines outlined
below (3).
Level A. The USPSTF strongly recommends that clinicians
provide (the service) to eligible patients. The USPSTF found
good evidence that (the service) improves important health outcomes
and concludes that benefits substantially outweigh harms.
Level B. The USPSTF recommends that clinicians provide
(this service) to eligible patients. The USPSTF found at least fair
evidence that (the service) improves important health outcomes and
concludes that benefits outweigh harms.
Level C. The USPSTF makes no recommendation for or
against routine provision of (the service). The USPSTF found at
least fair evidence that (the service) can improve health outcomes but
concludes that the balance of benefits and harms is too close to justify
a general recommendation.
Level D. The USPSTF recommends against routinely providing
(the service) to asymptomatic patients. The USPSTF
found at least fair evidence that (the service) is ineffective or that
harms outweigh benefits.
Level I. The USPSTF concludes that evidence is insufficient to
recommend for or against routinely providing (the service).
Evidence that (the service) is effective is lacking, or poor quality, or
conflicting, and the balance of benefits and harms cannot be determined.
The organization of these guidelines is presented in Table 1.
A complete list of the Recommendations is included in the
Appendix. It should be noted that although there was unanimity
in the vast majority of recommendations there
were two recommendations for which one of the committee
members did not agree with the final recommendation. The
two recommendations for which there were dissenting opinions
are Recommendations 9 and 76. The alternative view
points are included in the body of the report.
The final document was approved by the ATA Board of
Directors and officially endorsed by the British Thyroid Association
(BTA), European Association of Nuclear Medicine
(EANM), European Thyroid Association (ETA), Italian Association
of Clinical Endocrinologists (AME), Korean Thyroid
Association (KTA), andLatinAmericanThyroidSociety (LATS).
Finally, the committee recognizes that knowledge on
the interplay between the thyroid gland and pregnancy/
postpartum is dynamic, and new data will continue to come
forth at a rapid rate. It is understood that the present guidelines
are applicable only until future data refine our understanding,
define new areas of importance, and perhaps even refute some
of our recommendations. In the interim, it is our hope that the
present guidelines provide useful information to clinicians and
help achieve our ultimate goal of the highest quality clinical
care for pregnant women and their unborn children.
Table 1. Organization of Pregnancy Management Guidelines—Sections, Questions, and Recommendations
Page
number
INTRODUCTION
THYROID FUNCTION TESTS IN PREGNANCY
Q 1 How do thyroid function tests change during pregnancy? 6
Q 2 What is the normal range for TSH in each trimester? 6
R 1 Trimester-Specific Reference Ranges for TSH, # 1 7
R 2 Trimester-Specific Reference Ranges for TSH, # 2 7
Q 3 What is the optimal method to assess FT4 during pregnancy? 7
R 3 FT4 Assay Methods, # 1 8
R 4 FT4 Assay Methods, # 2 8
R 5 FT4 Assay Methods, # 3 8
HYPOTHYROIDISM IN PREGNANCY
Q 4 What are the definitions of OH and SCH in pregnancy? 8
Q 5 How is isolated hypothyroxinemia defined in pregnancy ? 8
Q 6 What adverse outcomes are associated with OH in pregnancy? 8
Q 7 What adverse outcomes are associated with SCH in pregnancy? 9
Q 8 What adverse outcomes are associated with isolated hypothyroxinemia in pregnancy? 9
Q 9 Should OH be treated in pregnancy? 10
(continued)
2 STAGNARO-GREEN ET AL.
Table 1. (Continued)
Page
number
R 6 Treatment of OH in Pregnancy 10
Q 10 Should isolated hypothyroxinemia be treated in pregnancy? 10
R 7 Isolated Hypothyroxinemia in Pregnancy 10
Q 11 Should SCH be treated in pregnancy? 10
R 8 Treatment of SCH in Pregnancy, # 1 10
R 9 Treatment of SCH in Pregnancy, # 2 10
Q 12 When provided, what is the optimal treatment of OH and SCH? 10
R 10 The Optimal Form of Thyroid Hormone to Treat OH and SCH 10
Q 13 When provided, what is the goal of OH and SCH treatment? 10
R 11 Goal of LT4 Treatment for OH and SCH 10
Q 14 If pregnant women with SCH are not initially treated, how should they be monitored
through gestation?
10
R 12 Monitoring Women With SCH Who Are Not Initially Treated During Their
Pregnancy
10
Q 15 How do hypothyroid women (receiving LT4) differ from other patients during
pregnancy?
What changes can be anticipated in such patients during gestation?
11
Q 16 What proportion of treated hypothyroid women (receiving LT4) require changes in their
LT4 dose during pregnancy?
11
Q 17 In treated hypothyroid women (receiving LT4) who are planning pregnancy, how should
the LT4 dose be adjusted?
11
R 13 LT4 Dose Adjustment for Hypothyroid Women Who Miss a Menstrual Period or
Have a Positive Home Pregnancy Test
11
Q 18 In hypothyroid women (receiving LT4) who are newly pregnant, what factors influence
thyroid status and LT4 requirements during gestation?
11
R 14 Factors Influencing Changes in LT4 Requirements During Pregnancy 11
R 15 Adjustment of LT4 Dose in Hypothyroid Women Planning Pregnancy 11
Q 19 In hypothyroid women (receiving LT4) who are newly pregnant, how often should
maternal thyroid function be monitored during gestation?
11
R 16 Frequency that Maternal Serum TSH Should be Monitored During Pregnancy in
Hypothyroid Women Taking LT4. # 1
12
R 17 Frequency that Maternal Serum TSH Should be Monitored During Pregnancy in
Hypothyroid Women Taking LT4. # 2
12
Q 20 How should the LT4 dose be adjusted postpartum? 12
R 18 Dose Adjustment and Serum TSH Testing Postpartum 12
Q 21 What is the outcome and long-term prognosis when SCH and OH are effectively treated
through gestation?
12
Q 22 Except for measurement of maternal thyroid function, should additional maternal or
fetal testing occur in treated, hypothyroid women during pregnancy?
12
R 19 Tests Other Than Serum TSH in Hypothyroid Women Receiving LT4 Who Have an
Uncomplicated Pregnancy
12
Q 23 In euthyroid women who are TAbþ prior to conception, what is the risk of
hypothyroidism once they become pregnant?
12
Q 24 How should TAbþ euthyroid women be monitored and treated during pregnancy? 12
R 20 Monitoring Women Without a History of Hypothyroidism, But Who are TAbþ During Pregnancy
12
Q 25 Should TAbþ euthyroid women be monitored or treated for complications other than
the risk of hypothyroidism during pregnancy?
12
R 21 Selenium Supplementation During Pregnancy for Women Who Are TPOAbþ 13
THYROTOXICOSIS IN PREGNANCY
Q 26 What are the causes of thyrotoxicosis in pregnancy? 13
Q 27 What is the appropriate initial evaluation of a suppressed serum TSH concentration
during the first trimester of pregnancy?
13
Q 28 How can gestational hyperthyroidism be differentiated from Graves’ hyperthyroidism in
pregnancy?
13
R 22 Workup of Suppressed Serum TSH in First Trimester of Pregnancy 13
R 23 Ultrasound to Work-up Differential Diagnosis of Thyrotoxicosis in Pregnancy 13
R 24 Prohibition of Radioactive Iodine Scans and Uptake Studies During Pregnancy 13
Q 29 What is the appropriate management of gestational hyperthyroidism? 13
R 25 Management of Women with Gestational Hyperthyroidism and Hyperemesis
Gravidarum
14
(continued)
PREGNANCY AND POSTPARTUM THYROID MANAGEMENT GUIDELINES 3
Table 1. (Continued)
Page
number
R 26 Antithyroid Drugs in the Management of Gestational Hyperthyroidism 14
Q 30 How should women with Graves’ disease be counseled before pregnancy? 14
R 27 Need to Render Hyperthyroid Women Euthyroid Before Pregnancy 14
Q 31 What is the management of patients with Graves’ hyperthyroidism in pregnancy? 14
R 28 Timing of PTU and MMI Use in Pregnancy 14
R 29 Combining ATDs and LT4 During Pregnancy 14
Q 32 What tests should be performed in women treated during pregnancy with ATDs? What
is the target value of FT4?
15
R 30 Monitoring Frequency of FT4 and Target FT4 in Women on Antithyroid Drugs During
Pregnancy
15
Q 33 What are the indications and timing for thyroidectomy in the management of Graves’
disease during pregnancy
15
R 31 Relative Role of Thyroidectomy and Its Timing for Managing Thyrotoxicosis in
Pregnancy
15
Q 34 What is the value of TRAb measurement in the evaluation of a pregnant women with
Graves’ hyperthyroidism?
15
R 32 History of Graves’ Disease as a Determinant of TRAb Measurement, and Timing of
TRAb Measurement, in Pregnancy
15
Q 35 Under what circumstances should additional fetal ultrasound monitoring for growth,
heart rate, and goiter be performed in women with Graves’ hyperthyroidism
in pregnancy?
15
R 33 Recommendations for Pregnant Women with High Risk of Fetal Thyroid Dysfunction 16
Q 36 When should umbilical blood sampling be considered in women with Graves’ disease in
pregnancy?
16
R 34 Cordocentesis in Pregnancy 16
Q 37 What are the etiologies of thyrotoxicosis in the postpartum period? 16
Q 38 How should the etiology of new thyrotoxicosis be determined in the postpartum period? 16
Q 39 How should Graves’ hyperthyroidism be treated in lactating women? 16
R 35 Safe Doses of Antithyroid Drugs for Infants of Breastfeeding Mothers 16
CLINICAL GUIDELINES FOR IODINE NUTRITION
Q 40 Why is increased iodine intake required in pregnancy and lactation, and how is iodine
intake assessed?
16
Q 41 What is the impact of severe iodine deficiency on the mother, fetus, and child? 16
Q 42 What is the impact of mild to moderate iodine deficiency on the mother, fetus, and child? 17
Q 43 What is the iodine status of pregnant and breastfeeding women in the United States? 17
Q 44 What is the iodine status of pregnant and breastfeeding women worldwide? 17
Q 45 Does iodine supplementation in pregnancy and lactation improve outcomes in severe
iodine deficiency?
17
Q 46 Does iodine supplementation in pregnancy and lactation improve outcomes in mildly to
moderately iodine-deficient women?
17
Q 47 What is the recommended daily iodine intake in women planning pregnancy, women
who are pregnant, and women who are breastfeeding?
17
R 36 Minimum Iodine Intake Requirements in Pregnant Women, # 1 18
R 37 Minimum Iodine Intake Requirements in Pregnant Women, # 2 18
R 38 Minimum Iodine Intake Requirements in Pregnant Women, # 3 18
Q 48 What is the safe upper limit for iodine consumption in pregnant and breastfeeding
women?
18
R 39 Recommendation Against High Amounts of Iodine in Pregnancy, # 1 18
R 40 Recommendation Against High Amounts of Iodine in Pregnancy, # 2 18
SPONTANEOUS PREGNANCY LOSS, PRETERM DELIVERY, AND THYROID ANTIBODIES
Q 49 Is there an association between thyroid antibody positivity and sporadic spontaneous
abortion in euthyroid women?
19
Q 50 Should women be screened for TPO antibodies before or during pregnancy with the
goal of treating TPOAbþ euthyroid women with LT4 to decrease the rate of spontaneous
miscarriage?
19
R 41 Screening for Anti-Thyroid Antibodies in the First Trimester 19
Q 51 Is there an association between anti-thyroid antibodies and recurrent spontaneous
abortion in euthyroid women?
19
Q 52 Should women with recurrent abortion be screened for TAb before or during
pregnancy with the goal of treating euthyroid Abþ women with LT4 or IVIG
therapy to decrease the rate of recurrent spontaneous abortion?
19
(continued)
4 STAGNARO-GREEN ET AL.
Table 1. (Continued)
Page
number
R 42 Screening for Abþ and Treating Abþ Women with LT4 in the First Trimester 19
Q 53 Should euthyroid women who are known to be TAbþ either before or during pregnancy
be treated with LT4 in order to decrease the chance of sporadic or recurrent miscarriage?
20
R 43 Treating Euthyroid, TAbþ Women with LT4 in Pregnancy 20
Q 54 Is there an association between thyroid antibody positivity and pregnancy loss in
euthyroid women undergoing IVF?
20
Q 55 Should women undergoing in vitro fertilization be screened for TPOAbþ before or
during pregnancy with the goal of treating euthyroid TPOAbþ women with LT4 to
decrease the rate of spontaneous miscarriage?
20
R 44 Treating Euthyroid TAbþ Women Undergoing Assisted Reproduction Technologies
with LT4
20
Q 56 Is there an association between anti-thyroid antibodies and preterm delivery in
euthyroid women?
20
Q 57 Should women be screened for anti-thyroid antibodies before or during pregnancy with
the goal of treating TAbþ euthyroid women with LT4 to decrease the rate of preterm
delivery?
20
R 45 First Trimester Screening for Anti-Thyroid Antibodies with Consideration of LT4
Therapy to Decrease the Risk of Preterm Delivery
20
THYROID NODULES AND THYROID CANCER
Q 58 What is the frequency of thyroid nodules during pregnancy? 20
Q 59 What is the frequency of thyroid cancer in women with thyroid nodules discovered
during pregnancy?
21
Q 60 What is the optimal diagnostic strategy for thyroid nodules detected during pregnancy? 21
R 46 Workup of Thyroid Nodules During Pregnancy 21
R 47 Measurement of Serum Calcitonin in Pregnant Women With Thyroid Nodules 21
R 48 Risk of FNA of Thyroid Nodules in Pregnancy 22
R 49 FNA of Thyroid Nodules in Pregnancy 22
R 50 Recommendation Against Use of Radioiodine in Pregnancy 22
Q 61 Does pregnancy impact the prognosis of thyroid carcinoma? 22
R 51 Time of Surgery for Pregnant Women With Well-Differentiated Thyroid Carcinoma 22
R 52 Time of Surgery for Pregnant Women with Medullary Thyroid Carcinoma 22
Q 62 What are the perioperative risks to mother and fetus of surgery for thyroid cancer
during pregnancy?
22
R 53 Risk of Surgery for Thyroid Carcinoma in the Second Trimester 22
Q 63 How should benign thyroid nodules be managed during pregnancy? 23
R 54 Surgery During Pregnancy for Benign Thyroid Nodules 23
Q 64 How should DTC be managed during pregnancy? 23
R 55 Role of Thyroid Ultrasound in Pregnant Women With Suspected Thyroid Carcinoma 23
R 56 Time of Surgery for Pregnant Women With Differentiated Thyroid Carcinoma 23
R 57 LT4 Treatment in Pregnant Women With Differentiated Thyroid Carcinoma 23
Q 65 How should suspicious thyroid nodules be managed during pregnancy? 23
R 58 Time of Surgery for Pregnant Women With FNA Suspicious for Thyroid Cancer 23
Q 66 What are the TSH goals during pregnancy for women with previously treated thyroid
cancer and who are on LT4 therapy?
23
R 59 Goal for TSH Level in Pregnant Women With History of Thyroid Cancer 24
Q 67 What is the effect of RAI treatment for DTC on subsequent pregnancies? 24
R 60 Timing of Pregnancy in Women With a History of Radioactive Iodine Treatment 25
Q 68 Does pregnancy increase the risk of DTC recurrence? 25
Q 69 What type of monitoring should be performed during pregnancy in a patient who has
already been treated for DTC prior to pregnancy?
25
R 61 Role of Ultrasound and Tg Monitoring During Pregnancy in Women With a History
of Low-Risk DTC
25
R 62 Role of Ultrasound Monitoring in Women With DTC and High Thyroglobulin Levels
or Persistent Structural Disease
25
POSTPARTUM THYROIDITIS
Q 70 What is the definition of PPT and what are its clinical implications? 25
Q 71 What is the etiology of PPT? 25
Q 72 Are there predictors of PPT? 25
Q 73 What is the prevalence of PPT? 26
Q 74 What symptoms are associated with PPT? 26
(continued)
PREGNANCY AND POSTPARTUM THYROID MANAGEMENT GUIDELINES 5
RESULTS
Thyroid Function Tests in Pregnancy
Question 1: How do thyroid function tests change
during pregnancy?
To meet the challenge of increased metabolic needs during
pregnancy, the thyroid adapts through changes in thyroid
hormone economy and in the regulation of the hypothalamicpituitary-
thyroid axis (4,5). Consequently, thyroid function
test results of healthy pregnant women differ from those of
healthy nonpregnant women. This calls for pregnancyspecific
and ideally trimester-specific reference intervals for
all thyroid function tests but in particular for the most widely
applied tests, TSH and free T4 (FT4).
Following conception, circulating total T4 (TT4) and T4
binding globulin (TBG) concentrations increase by 6–8 weeks
and remain high until delivery. Thyrotropic activity of hCG
results in a decrease in serum TSH in the first trimester (5,6).
Therefore, during pregnancy, women have lower serum TSH
concentrations than before pregnancy, and frequently TSH is
below the classical lower limit of 0.4 mIU/L (7,8).
Most studies also report a substantial decrease in serum FT4
concentrations with progression of gestation (7,9,10). Serum
FT4 measurements in pregnant women are complicated by
increased TBG and decreased albumin concentrations that can
cause immunoassays to be unreliable (11,12). Therefore the
analytical method used for serum FT4 analysis should be
taken into consideration.
Question 2: What is the normal range for TSH
in each trimester?
There is strong evidence in the literature that the reference
range for TSH is lower throughout pregnancy; i.e., both the
lower normal limit and the upper normal limit of serum TSH
are decreased by about 0.1–0.2 mIU/L and 1.0 mIU/L, respectively,
compared with the customary TSH reference interval
of 0.4–4.0 mIU/L of nonpregnant women. The largest
decrease in serum TSH is observed during the first trimester
Table 1. (Continued)
Page
number
Q 75 Is PPT associated with depression? 26
R 63 Postpartum Depression as an Indication for Thyroid Function Testing 26
Q 76 What is the treatment for the thyrotoxic phase of PPT? 26
R 64 Propranolol Treatment of PPT 26
R 65 Recommendation Against Use of ATDs to Treat PPT 26
Q 77 Once the thyrotoxic phase of PPT resolves, how often should serum TSH be measured to
screen for the hypothyroid phase
26
R 66 Timing of Serum TSH After Resolution of the Thyrotoxic Phase of PPT, # 1 of 3 26
Q 78 What is the treatment for the hypothyroid phase of PPT? 26
R 67 Timing of Serum TSH After PPT, # 2 of 3 26
R 68 Indication for Treatment with LT4 in Women with PPT 26
Q 79 How long should LT4 be continued in women with postpartum thyroiditis? 26
R 69 Indication and Method for Stopping LT4 in Women with a History of PPT 27
Q 80 How often should screening be performed after the hypothyroid phase of PPT resolves? 27
R 70 Timing of Serum TSH after PPT, # 3 of 3 27
Q 81 Does treatment of TAbþ euthyroid women with LT4 or iodine during pregnancy
prevent PPT?
27
R 71 Recommendation Against Use of LT4 or Iodine for Prevention of PPT
in Euthyroid TAbþ Women
27
Q 82 Does treatment of TAbþ euthyroid women with selenium during pregnancy
prevent PPT?
27
THYROID FUNCTION SCREENING IN PREGNANCY
Q 83 Should all pregnant women be screened for serum TSH level in the first trimester
of pregnancy?
27
R 72 Recommendation Regarding Universal Screening with Serum TSH Determination at
the First Trimester Visit
30
R 73 Recommendation Regarding Universal Screening with Serum Free T4 Determination
in Pregnant Women
30
Q 84 Should serum TSH testing be carried out in a targeted population of pregnant women? 30
R 74 Determination of Serum TSH Before Pregnancy in Women at High Risk for
Hypothyroidism
30
R 75 History Taking in Pregnant Women at Their Initial Prenatal Visit 30
R 76 Determination of Serum TSH in Early Pregnancy in Women at High Risk for OH 30
FUTURE RESEARCH DIRECTIONS
ATD, antithyroid drug; DTC, differentiated thyroid carcinoma; FNA, fine-needle aspiration; FT4, free thyroxine; IVF, in vitro fertilization;
IVIG, intravenous immunoglobin; LT4, levothyroxine; MMI, methimazole; OH, overt hypothyroidism; PPT, postpartum thyroiditis; PTU,
propylthiouracil; RAI, radioactive iodine; SCH, subclinical hypothyroidism; TAbþ, positive for thyroid peroxidase antibody and/or
thyroglobulin antibody; Tg, thyroglobulin; TPOAbþ, positive for thyroid peroxidase antibody; TRAb, TSH receptor antibodies; TSH,
thyrotropin.
6 STAGNARO-GREEN ET AL.
and is transient, apparently related to hCG levels, which are
highest early in gestation (Table 2). The median TSH values in
the three trimesters in Table 2 are quite consistent, except for
the study by Marwaha et al. (18) which, for unexplained reasons,
reports higher TSH values throughout pregnancy.
Serum TSH and its reference range gradually rise in the second
and third trimesters, but it is noteworthy that the TSH
reference interval remains lower than in nonpregnant women
(13,15). Since hCG concentrations are higher in multiple
pregnancies than in singleton pregnancies, the downward
shift in the TSH reference interval is greater in twin pregnancies
than in singleton pregnancies (19). In a study of 63
women with hCG concentrations >200,000 IU/L, TSH was
suppressed (0.2 mIU/L) in 67% of women, and in 100% of
women if hCG concentrations were >400,000 IU/L (20).
In a small percentage ofwomen, TSHcan be very suppressed
(<0.01 mIU/L) and yet still represent a normal pregnancy.
There are slight but significant ethnic differences in serum TSH
concentrations. Black and Asian women have TSH values that
are on average 0.4 mIU/L lower than in white women; these
differences persist during pregnancy (21,22). Pregnant women
of Moroccan, Turkish, or Surinamese descent residing in The
Netherlands, have TSH values 0.2–0.3 mIU/L lower than
Dutch women throughout pregnancy (23). TSH ranges vary
slightly depending on differences betweenmethods of analysis
(24). Subclinical hyperthyroidismis not associated with adverse
pregnancy outcomes; therefore, a TSH value that is within
detection is unlikely to be clinically significant (25).
& RECOMMENDATION 1
Trimester-specific reference ranges for TSH, as defined in
populations with optimal iodine intake, should be applied.
Level B-USPSTF
& RECOMMENDATION 2
If trimester-specific reference ranges for TSH are not
available in the laboratory, the following reference ranges
are recommended: first trimester, 0.1–2.5 mIU/L; second
trimester, 0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L.
Level I-USPSTF
Question 3: What is the optimal method to assess FT4
during pregnancy?
The normal ranges for FT4 index are calculated by TT4T3
uptake or a ratio of TT4 and TBG, but trimester-specific reference
intervals for FT4 index have not been established in a
reference population. Only 0.03% of serum TT4 content is
unbound to serum proteins and is the FT4 available for tissue
uptake. Sera TT4 concentrations are in the nanomolar range,
but FT4 concentrations are in the picomolar range. Measuring
FT4 in the presence of high concentrations of bound T4 has
proved challenging especially in abnormal binding-protein
states such as pregnancy.
Equilibrium dialysis and ultrafiltration are used for physical
separation of serum FT4 from bound T4 prior to analysis of
the dialysate or ultrafiltrate. Assays based on classical equilibrium
dialysis or ultrafiltration are laborious, timeconsuming,
expensive, and not widely available.
FT4 immunoassay approaches are liable to error by disrupting
the original equilibrium, which is dependent on dilution,
temperature, buffer composition, affinity, and concentration of
the T4 antibody reagent and T4-binding capacity of the serum
sample (26). High TBG concentrations in serum samples tend to
result in higher FT4 values,whereas lowalbumin in serum likely
will yield lower FT4 values. In order to decrease nonspecific
binding and neutralize the effect of nonesterified fatty acids on
serum FT4, some assays add albumin; however, albumin binds
T4 andwhen it is added in sufficient amounts, itmay disrupt the
equilibrium. Nevertheless, the currently used FT4 immunoassays
perform reasonably well under most circumstances, accurately
reporting low FT4 levels in thyroid hormone deficiency
and high FT4 levels in thyroid hormone excess (27).
The serum of pregnant women is characterized by higher
concentrations of TBG and nonesterified fatty acids and by
lower concentrations of albumin relative to the serum of nonpregnant
women. Many current FT4 immunoassays fail to account
for the effect of dilution (26,28). Because FT4 reference
intervals in pregnancy varied widely between methods, interpretation
of FT4 values requires method-specific ranges
(11,12,29). Moreover, such ranges are also influenced by the
iodine status of the population studied. Whereas it is customary
for manufacturers to suggest that laboratories establish
their own reference range for a test, this is impractical in clinical
practice. It is especially difficult to recruit subjects with specific
conditions such as pregnancy in order to independently establish
method- and trimester-specific ranges. It follows that it
is customary for laboratories to adopt the ranges provided by
the manufacturer of the test. Typically, the characteristics of
these reference pregnant cohorts are not disclosed and may
differ in iodine intake and ethnicity to an extent that compromises
the value of adopting the manufacturer ranges across
different populations.
Current uncertainty around FT4 estimates in pregnancy has
led some to question the wisdom of relying on FT4 immunoassays
during pregnancy (30,31). In contrast to FT4 as measured
Table 2. Sample Trimester-Specific Reference Intervals for Serum TSH
Trimestera
Reference First Second Third
Haddow et al. (13) 0.94 (0.08–2.73) 1.29 (0.39–2.70) —
Stricker et al. (14) 1.04 (0.09–2.83) 1.02 (0.20–2.79) 1.14 (0.31–2.90)
Panesar et al. (15) 0.80 (0.03–2.30) 1.10 (0.03–3.10) 1.30 (0.13–3.50)
Soldin et al. (16) 0.98 (0.24–2.99) 1.09 (0.46–2.95) 1.20 (0.43–2.78)
Bocos-Terraz et al. (17) 0.92 (0.03–2.65) 1.12 (0.12–2.64) 1.29 (0.23–3.56)
Marwaha et al. (18) 2.10 (0.60–5.00) 2.40 (0.43–5.78) 2.10 (0.74–5.70)
aMedian TSH with mIU/L with 5th and 95th percentiles (13,15,18) or 2.5th and 97.5th percentiles (14,16,17).
PREGNANCY AND POSTPARTUM THYROID MANAGEMENT GUIDELINES 7
by two commercial immunoassays, TT4 and the FT4 index
showed the expected inverse relationship with TSH (30). The
authors argue that TT4 measurements may be superior to FT4
measurements by immunoassay in sera of pregnant women,
provided the reference values take into account the 50% increase
of TBG in pregnancy by calculating the FT4 index with
the help of a serum thyroid hormone uptake test.
The latest development in the field of FT4 analysis is to
measure free thyroid hormones in the dialysate or ultrafiltrate
using online solid phase extraction–liquid chromatography/
tandem mass spectrometry (LC/MS/MS). The method is regarded
as a major advance, with higher specificity in comparison
to immunoassays and great potential to be applied in
the routine assessment of FT4 and FT3. Using direct equilibrium
dialysis and LC/MS/MS, the 95% FT4 reference intervals
decreased gradually with advancing gestational age:
from 1.08–1.82 ng/dL in week 14 to 0.86–1.53 ng/dL in week
20 (32). Using ultrafiltration followed by isotope dilution LC/
MS/MS, serum FT4 concentrations (given as meanSE) were
0.930.25 ng/dL in nonpregnant women, 1.130.23 ng/dL
in the first trimester, 0.920.30 ng/dL in the second trimester,
and 0.860.21 ng/dL in the third trimester (9). Serum FT4
measured by a direct analog immunoassay in the same samples
also demonstrated decreasing values during pregnancy:
1.050.22 ng/dL, 0.880.17 ng/dL, and 0.890.17 ng/dL
in the first, second, and third trimesters, respectively. Serum
FT4 by LC/MS/MS correlated very well with serum FT4
measured by classical equilibriumdialysis, but correlationwith
results from the FT4 immunoassay were less satisfactory (9).
Free thyroid hormone concentrations measured by LC/
MS/MS correlate generally to a greater degree with log TSH
values compared with concentrations measured by immunoassay
(31). In pregnancy, however, there is little relationship
between log TSH and FT4 (r¼0.11 for FT4 LC/MS/MS,
and r¼0.06 for FT4 immunoassay) (33), suggesting changes
in the set point of the hypothalamic-pituitary-thyroid axis
during pregnancy. Application of LC/MS/MS for measurement
of free thyroid hormones is currently in routine clinical
use in a few centers. The method is ideally suited for generating
reliable, reproducible trimester-specific reference ranges
for FT4 (9).Aworking group of the International Federation of
Clinical Chemistry and Laboratory Medicine recommends the
use of isotope dilution-LC/MS/MS for measuring T4 in the
dialysate from equilibrium dialysis of serum in order to obtain
a trueness-based reference measurement procedure for serum
FT4 (34). This assay technology, unfortunately, is currently not
widely available due to high instrument and operating costs.
& RECOMMENDATION 3
The optimal method to assess serum FT4 during pregnancy
is measurement of T4 in the dialysate or ultrafiltrate of
serum samples employing on-line extraction/liquid
chromatography/tandem mass spectrometry (LC/MS/
MS). Level A-USPSTF
& RECOMMENDATION 4
If FT4 measurement by LC/MS/MS is not available, clinicians
should use whichever measure or estimate of FT4 is
available in their laboratory, being aware of the limitations
of each method. Serum TSH is a more accurate indication of
thyroid status in pregnancy than any of these alternative
methods. Level A-USPSTF
& RECOMMENDATION 5
In view of the wide variation in the results of FT4 assays,
method-specific and trimester-specific reference ranges of
serum FT4 are required. Level B-USPSTF
Hypothyroidism in Pregnancy
In the absence of rare exceptions (TSH-secreting pituitary
tumor, thyroid hormone resistance, a few cases of central
hypothyroidism with biologically inactive TSH) primary
maternal hypothyroidism is defined as the presence of an elevated
TSH concentration during gestation. Historically, the
reference range for serum TSH was derived from the serum of
healthy, nonpregnant individuals. Using these data, values
greater than *4.0 mIU/L were considered abnormal. More
recently, normative data from healthy pregnant women
suggest the upper reference range may approximate 2.5–3.0
mIU/L (15,19). When maternal TSH is elevated, measurement
of serum FT4 concentration is necessary to classify the patient’s
status as either subclinical (SCH) or overt hypothyroidism
(OH). This is dependent upon whether FT4 is within
or below the trimester-specific FT4 reference range. The distinction
of OH from SCH is important because published data
relating to the maternal and fetal effects attributable toOHare
more consistent and easier to translate into clinical recommendations
in comparison to those regarding SCH.
Several investigations report that at least 2%–3% of apparently
healthy, nonpregnant women of childbearing age
have an elevated serum TSH (35,36). Among these healthy
nonpregnant women of childbearing age it is estimated that
0.3%–0.5% of them would, after having thyroid function tests,
be classified as having OH, while 2%–2.5% of them would be
classified as having SCH. These data derive from a population
in the United States, which is considered a relatively iodinesufficient
country. It would be anticipated that such percentages
would be higher in areas of iodine insufficiency. When
iodine nutrition is adequate, the most frequent cause of hypothyroidism
is autoimmune thyroid disease (also called
Hashimoto’s thyroiditis). Thyroid auto-antibodies were detected
in *50% of pregnant women with SCH and in more
than 80% with OH (36).
Question 4: What are the definitions of OH
and SCH in pregnancy?
Elevations in serum TSH during pregnancy should be defined
using pregnancy-specific reference ranges. OH is defined
as an elevated TSH (>2.5 mIU/L) in conjunction with a
decreased FT4 concentration. Women with TSH levels of 10.0
mIU/L or above, irrespective of their FT4 levels, are also
considered to have OH. SCH is defined as a serum TSH between
2.5 and 10 mIU/L with a normal FT4 concentration.
Question 5: How is isolated hypothyroxinemia defined
in pregnancy?
Isolated hypothyroxinemia is defined as a normal maternal
TSH concentration in conjunction with FT4 concentrations in
the lower 5th or 10th percentile of the reference range.
Question 6: What adverse outcomes are associated
with OH in pregnancy?
OH in pregnancy has consistently been shown to be
associated with an increased risk of adverse pregnancy com-
8 STAGNARO-GREEN ET AL.
plications, as well as detrimental effects upon fetal neurocognitive
development (37). Specific adverse outcomes associated
with maternal OH include an increased risk of
premature birth, low birth weight, and miscarriage. Abalovich
et al. (38) demonstrated such patients carry an estimated
60% risk of fetal loss when OH was not adequately detected
and treated. Leung et al. (39) demonstrated a 22% risk of
gestational hypertension in pregnant women with OH, higher