Critical Reviews in Clinical Laboratory Sciences

ISSN: 1040-8363 (Print) 1549-781X (Online) Journal homepage: http://www.tandfonline.com/loi/ilab20

Thyroid in pregnancy: From physiology to

screening

Drahomira Springer, Jan Jiskra, Zdenka Limanova, Tomas Zima & Eliska
Potlukova

To cite this article: Drahomira Springer, Jan Jiskra, Zdenka Limanova, Tomas Zima & Eliska
Potlukova (2017): Thyroid in pregnancy: From physiology to screening, Critical Reviews in
Clinical Laboratory Sciences, DOI: 10.1080/10408363.2016.1269309

To link to this article: http://dx.doi.org/10.1080/10408363.2016.1269309

Published online: 19 Jan 2017.

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ISSN: 1040-8363 (print), 1549-781X (electronic)

Crit Rev Clin Lab Sci, Early Online: 1–15

! 2017 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.1080/10408363.2016.1269309

REVIEW ARTICLE

Thyroid in pregnancy: From physiology to screening

Drahomira Springer1, Jan Jiskra2, Zdenka Limanova2, Tomas Zima1, and Eliska Potlukova3
1
Institute of Medical Biochemistry and Laboratory Medicine, 1st Faculty of Medicine, Charles University and General University Hospital, Prague,
Czech Republic, 23rd Department of Medicine – Clinical Department of Endocrinology and Metabolism, 1st Faculty of Medicine, Charles University
and General University Hospital, Prague, Czech Republic, and 3Division of Internal Medicine, University Hospital Basel, Basel, Switzerland

Abstract Keywords
Thyroid hormones are crucial for the growth and maturation of many target tissues, especially Autoimmune thyroid disease, pregnancy,
the brain and skeleton. During critical periods in the first trimester of pregnancy, maternal screening, thyroid-stimulating hormone,
thyroxine is essential for fetal development as it supplies thyroid hormone-dependent tissues. anti-thyroperoxidase antibodies, preg-
The ontogeny of mature thyroid function involves organogenesis, and maturation of the nancy loss
hypothalamus, pituitary and the thyroid gland; and it is almost complete by the 12th–14th
gestational week. In case of maternal hypothyroidism, substitution with levothyroxine must be
History
started in early pregnancy. After the 14th gestational week, fetal brain development may
already be irreversibly affected by lack of thyroid hormones. The prevalence of manifest Received 10 June 2016
hypothyroidism in pregnancy is about 0.3–0.5%. The prevalence of subclinical hypothyroidism Revised 4 October 2016
varies between 4 and 17%, strongly depending on the definition of the upper TSH cutoff limit. Accepted 4 December 2016
Hyperthyroidism occurs in 0.1–1% of all pregnancies. Positivity for antibodies against thyroid Published online 13 January 2017
peroxidase (TPOAb) is common in women of childbearing age with an incidence rate of
5.1–12.4%. TPOAb-positivity may be regarded as a manifestation of a general autoimmune
state which may alter the fertilization and implantation processes or cause early missed
abortions. Women positive for TPOAb are at a significant risk of developing hypothyroidism
during pregnancy and postpartum. Laboratory diagnosis of thyroid dysfunction during
pregnancy is based upon serum TSH concentration. TSH in pregnancy is physiologically lower
than the non-pregnant population. Results of multiple international studies point toward
creation of trimester-specific reference intervals for TSH in pregnancy. Screening for
hypothyroidism in pregnancy is controversial and its implementation varies from country to
country. Currently, the case-finding approach of screening high-risk women is preferred in most
countries to universal screening. However, numerous studies have shown that one-third to one-
half of women with thyroid disorders escape the case-finding approach. Moreover, the
universal screening has been shown to be more cost-effective. Screening for thyroid disorders
in pregnancy should include assessment of both TSH and TPOAb, regardless of the screening
approach. This review summarizes the current knowledge on physiology of thyroid hormones
in pregnancy, causes of maternal thyroid dysfunction and its effects on pregnancy course and
fetal development. We discuss the question of case-finding versus universal screening
strategies and we display an overview of the analytical methods and their reference intervals in
the assessment of thyroid function and thyroid autoimmunity in pregnancy. Finally, we present
our results supporting the implementation of universal screening.

Abbreviations: TBG: thyroxin binding globulin; T3: triiodothyronine; T4: thyroxine; TSH:
thyroid-stimulating hormone; hCG: human chorionic gonadotropin; Tg: thyroglobulin; rT3:
reverse T3; D1-3: selenoenzyme type 1-3 iodothyronine deiodinase; TgAb: thyroid auto-
antibodies and/or thyroglobulin; TPOAb: thyroid autoantibodies against thyroid peroxidase;
TT4: determination of total T4; LC/MS/MS: liquid chromatography tandem mass spectrometry;
AITD: autoimmune thyroid diseases

Reviewers: Dr. Dennis Dietzen, Dennis, Washington University School

of Medicine, St. Louis, MO, USA; Dr. Zhongyan Shan, The First
Affiliated Hospital of China Medical University, Shenyang, Liaoning
Province, PR China.
Address for correspondence: D. Springer, Institute of Medical
Biochemistry and Laboratory Medicine, 1st Faculty of Medicine,
Charles University and General University Hospital, U Nemocnice 2,
Prague 13000, Czech Republic. Tel: +00 420224962883. Fax: +00
42224962848. E-mail: springer@vfn.cz
Thyroid physiology in pregnancy
Thyroid hormones have multiple fundamental physiological
roles and are essential for childhood development and normal
adult health. Many changes in the functioning of the thyroid
gland occur during pregnancy and some diseases of the
thyroid gland can affect both the pregnant woman and the
2 D. Springer et al.
fetus. Recent decades witnessed accumulating evidence that
maternal thyroid dysfunction, including subclinical forms, has
subtle yet clinically relevant adverse effects on the course of
pregnancy. Moreover, lack of thyroid hormones during
developmental periods influences the neurocognitive devel-
opment of the child and leads to number of serious adverse
effects later in life1. Adequate iodine supply is essential to
allow for thyroid hormone production, thus iodine levels are
important to observe during developmental periods1.
Thyroid hormones and embryo development
During pregnancy, demands on maternal thyroid hormone
production rise significantly. Total thyroxine concentrations
must increase by 20–50% in order to maintain a euthyroid
state2,3. This can be ensured only in a state of iodine
sufficiency which may require an increase in iodine supple-
mentation during pregnancy and the absence of destructive
autoimmune thyroid processes.
During pregnancy, several changes connected with thyroid
hormone production occur. Iodine clearance increases, as well
as serum levels of thyroxin binding globulin (TBG).
Moreover, the deiodination of the inner-ring of triiodothyr-
onine (T3) and thyroxine (T4) by the placenta is upregulated.
Secretion of thyroid-stimulating hormone (TSH) from the
anterior pituitary is regulated by the thyroid hormones via a
negative feedback loop. In pregnancy, however, other mech-
anisms participate in the regulation of TSH including
suppression by high human chorionic gonadotropin (hCG)
levels4. FT4 reflects the amount of the biologically active
hormone, which is available to the organism of both the mother
and the fetus. In contrast to total T4, FT4 is not affected by the
concentration of serum TBG. FT4 concentration in pregnancy
is influenced by iodine saturation and duration of pregnancy.
Total T4 concentration is increased in the first trimester, due to
the increased TBG levels, and relatively decreased during the
second and the third trimesters5.
Thyroid hormones are critical for early brain development,
somatic growth, and bone maturation. Their actions target
diverse cellular processes, such as progenitor turnover, cell
survival, and differentiation, cellular homeostasis and meta-
bolic regulation within multiple tissue types, and organs6,7.
They have a direct effect on tissue differentiation as well as a
permissive effect on actions of other growth factors8.
Extensive research has focused on the crucial role of thyroid
hormone on brain during neurodevelopment in the early as
well as adult life periods9,10. Abnormalities of thyroid
function in infancy and childhood result not only in the
metabolic consequences of thyroid dysfunction seen in adult
patients, but also in unique effects on the growth and/or
maturation of the thyroid hormone-dependent tissues. During
ontogenesis, there are critical time windows for development
of individual tissues depending on thyroid hormones. Thus,
specific clinical consequences of the lack of thyroid hormones
depend on the gestational age of the fetus affected11.
Two sources supply fetal tissues with thyroid hormones:
the developing fetal thyroid gland, and the maternal thyroid
gland. Both strongly depend on adequate iodine intake.
Maternal T4 is especially important in the first half of
pregnancy – the period before the fetal thyroid produces
Crit Rev Clin Lab Sci, Early Online: 1–15
sufficient amounts of hormones. The maternofetal transfer of
thyroid hormones occurs via placenta, where thyroid hormone
transporters are expressed8. Placental deiodinases regulate the
amount of T4 entering the fetal organism.
Maturation of thyroid function involves organogenesis and
development of the hypothalamus, pituitary and the thyroid
gland, as well as the maturation of thyroid hormone metab-
olism, and their actions. The thyroid gland is derived from
fusion of a medial outpouching from the floor of the primitive
pharynx, the precursor of the thyroxine producing follicular
cells and bilateral evaginations of the fourth pharyngeal pouch.
This process is largely completed by the 12th–14th gestational
week. At this stage, tiny follicle precursors can be seen, iodine
binding can be identified and thyroglobulin (Tg) detected in
follicular spaces. Thyroid hormones are detectable in fetal
serum by 11–12 weeks of gestation, with both T4 and T3 being
measurable. However, it is likely that a fraction of the
hormones detectable at this early stage is contributed by the
mother through transplacental transfer11.
Increased total T4/TSH and FT4/TSH ratios also indicate
an increased ability of the thyroid gland to respond to TSH
due to an upregulation of the TSH receptor6,11. Iodide
concentrating capacity can be detected in the thyroid of the
10–11-week-old fetus. TSH is detectable at 3–4 mIU/L at 12
weeks gestation with a moderate increase over the last two
trimesters to 6–8 mIU/L12. Maturation of the negative
feedback control of thyroid hormone synthesis is seen
approximately half way through the pregnancy. In hypothy-
roid infants, higher serum TSH levels can be detected by the
28th gestational week. Both the thyroid hormones and TBG
continue to increase gradually during the whole pregnancy13.
Thyroxin binding globulin and thyroglobulin in
pregnancy
TBG is a globulin binding thyroid hormone. Its production
can be modified by estrogen levels, corticosteroid levels, or
liver failure. The high levels of TBG in pregnancy cause an
overall higher binding of the thyroid hormones. Subsequently,
levels of the free hormones available in the blood fall. This
leads to stimulation of TSH production and an overall
increase in total thyroid hormone levels. TBG is present in the
fetal serum at levels of 100 nmol/L (5 mg/L) at 12 weeks
gestation and it increases up to 500 nmol/L (25 mg/L) at the
time of birth. Due to placental estrogen effects on fetal liver,
fetal serum TBG levels exceed those in adults. In addition to
the increase in total T4, there is also a progressive increase in
serum FT4 levels indicating a maturation of the hypothal-
amic-pituitary-thyroid axis11,14.
Tg is a thyroid storage protein and a precursor for synthesis
of T3 and T4. In iodine deficiency, an increased amount of Tg
is released into the blood, and its levels positively correlate
with thyroid volume. Tg levels increase in early pregnancy,
maintain stable levels throughout mid-pregnancy and increase
further at 36 weeks of gestation. After delivery, Tg decreases
to non-pregnant levels15. Recent studies report assessment of
serum Tg level as a marker for iodine deficiency16.
Usefulness and effectiveness of Tg in estimation of iodine
status seem to be promising, although there are several
DOI: 10.1080/10408363.2016.1269309
problems connected with this approach. The results are
method-dependent, they are influenced by age and pregnancy
and there is a high-inter-assay variability (up to 43%) due to
the heterogeneity of the Tg epitopes. Overcoming these issues
should be a priority in order to gain a reliable tool for
identification of iodine-deficient pregnant women17.
Iodothyronine deiodinases
The bioavailability of thyroid hormones in the fetus is
controlled not only by the output of the fetal thyroid gland and
placental transfer, but also by metabolism in peripheral
tissues. Iodothyronine deiodinases are crucial in maintaining
the appropriate tissue levels of thyroid hormones in the fetus.
By catalyzing removal of iodine from the thyroxine molecule
at different locations, they either produce the genomically
potent thyroid hormone T3 or they generate bio-inactive
reverse T3 (rT3). There are three iodothyronine deiodinases
involved in the activation and inactivation of thyroid
hormones. All three closely regulate the balance of T3
supply to the developing tissues and they prevent the negative
effects of excessive amounts of thyroid hormones.
Conversion of peripheral T4 to T3 accounts for 80% of all
T3 produced in healthy individuals18. The selenoenzyme type
1 iodothyronine deiodinase (D1) catalyzes the conversion of
T4 to T3 and inactivates the sulfated conjugates of T4. D1
activity decreases in pregnancy and, as a consequence,
circulating T3 concentrations in the fetus are quite low,
whereas serum levels of the biologically inactive isomer rT3
and T3 sulfate are increased. The physiological reason for the
maintenance of reduced circulating T3 concentrations
throughout fetal life is still unknown.
Unlike D1, both the type 2 deiodinase (D2, an activating
enzyme) and the type 3 deiodinase (D3, an inactivating
enzyme) are present in low concentrations in the fetal brain as
early as the 7th gestational week19. D2 converts T4 to T3, while
D3 converts T4 to rT3. D2 and D3 are the major isoforms
present in the fetus and play a crucial role in defining the T3
level in the brain and pituitary. D2 is most concentrated in the
brain, pituitary, placenta and the brown adipose tissue.
D3 is present in the brain as well as in the uteroplacental
unit20. As an enzymatic barrier, placental D3 limits the
exposure of the fetus to maternal thyroid hormones protecting
the fetus from overexposure to maternal T4. The released
iodide is further used for fetal thyroid hormone synthesis11.
Thus, D3 represents a key player in the homeostasis of thyroid
hormones in the fetus21.
Despite the low levels of circulating T3, fetal brain T3 levels
are at 60–80% of those of an adult by 20–26 weeks of
gestation22. Thus, whereas the physiological interrelationships
between the various deiodinases in the fetus and placenta seem
to be designed to maintain circulating T3 levels at a reduced
level, specific mechanisms have evolved for maintaining
sufficiently high brain T3 levels to ensure normal development.
Iodine intake in pregnancy
Globally, iodine deficiency is the most common cause of
hypothyroidism. In developed countries, mild-to-moderate
iodine insufficiency is linked to isolated hypothyroxinemia. In
countries with sufficient iodine supply, manifest
Thyroid in pregnancy: from physiology to screening 3
hypothyroidism is predominantly caused by thyroid auto-
immunity. Iodine is essential for thyroid hormone production
and thus for normal in-utero neurodevelopment. During
pregnancy, iodine intake must increase by 50% due to
physiological increases in maternal thyroid hormone produc-
tion, an increase in maternal renal iodine losses, and fetal
iodine needs for thyroid hormone production23.
Iodine deficiency affects 2 billion people worldwide and is
the main cause of preventable mental impairment, not only in its
severe form, but also with mild-moderate insufficiency like in
the UK24,25. Currently, pregnant women suffer from iodine
deficiency in at least 21 European countries26. We have previ-
ously shown that although the Czech Republic belongs to the
iodine-sufficient countries, more than half of the women after
spontaneous abortion suffer from mild iodine deficiency27.
According to the WHO, pregnant and lactating women
should be provided with 250-mg iodine daily. Adequate iodine
intake during pregnancy should be preferably achieved
already before conception28. This may be achieved by
administering iodine supplements containing 150–250 mg of
iodine in the form of potassium iodide, e.g. in the form of
vitamin supplements. This recommendation is supported by
the guidelines of the Endocrine Society, as well as the
guidelines of the European Thyroid Association29,30.
Thyroid dysfunction in pregnancy
According to large epidemiological studies, thyroid disorders
in pregnancy are associated with serious maternal, fetal and
newborn complications: spontaneous abortions31, preterm
birth32, preeclampsia, gestational diabetes, induction, cesar-
ean section, ICU admission, placental abruption and breech
presentation33.
Hypothyroidism
The most common thyroid gland dysfunction in pregnancy is
hypothyroidism with a prevalence of about 0.3–0.5% of
pregnant women. Manifest/overt hypothyroidism is defined as
a thyroid hormone deficiency reflected by TSH elevation and
concomitant hypothyroxinemia. According to the American
Thyroid Association, pregnant women with TSH levels of
10.0 mIU/L or above are also considered to have overt
hypothyroidism irrespective of their FT4 levels34. Subclinical
hypothyroidism is defined as TSH elevation and normal
thyroxine levels. It varies between 4 and 17% with the high
percentage reflecting the use of the recommended cutoff for
TSH in the first trimester at 2.5 mIU/L34–38. The causes of
both forms of hypothyroidism are most often nutritive (iodine
deficiency) and autoimmune, followed by causes like post-
operative and post-irradiational states and side effects of anti-
thyroid medication, amiodarone or lithium.
In pregnancy, hypothyroidism is linked to a number of
adverse effects both in the mother and in the offspring. In
women of childbearing age, it is associated with reduced
fertility and perinatal complications. In the offspring, numer-
ous pathological findings defining congenital hypothyroidism
have been well described including growth retardation, mental
retardation, deafness and failure of sexual development11. Lack
of thyroid hormones leads to irreversible damage to the fetus:
failure of differentiation of nervous cells, inadequate central
4 D. Springer et al.
nervous system development and psychomotor function and
increased risk of perinatal defects. Maternal hypothyroidism
may also adversely affect the psychomotor development of the
offspring including significant reduction in IQ scores39,40.
Women with hypothyroxinemia have been shown to give
birth to children with decreased IQ scores and expressive
language and nonverbal delays41,42. Also, women with TSH
above 6 mIU/L in the second trimester have been shown to
have a four times higher risk of fetal death than women with
TSH below this threshold32. Lazarus and colleagues, a well-
discussed randomized study, treated pregnant women with
hypothyroidism, including those with subclinical hypothy-
roidism, with high doses of levothyroxine starting at a median
gestational age of 13 weeks 3 d. IQ was assessed at three years
of age and no improvement of offspring’s IQ in treated versus
untreated mothers was found43. However, thyroid antibodies
were not assessed and this study had several limitations and
received critical comments.
Recently Korevaar and colleagues studied almost 4000
mother–child pairs and found that children of mothers with
hypo- and hyperthyroxinemia in pregnancy had significantly
lower IQ scores than children of mothers with FT4 in the
normal range44. This decrease in IQ was accompanied by a
reduction in gray matter and cortex volume as assessed by
MRI and it persisted after exclusion of overtly hyper- and
hypothyroid women. The psychological tests were done at the
age of six years. These data seem to corroborate the
hypothesis that both lack, and abundance, of thyroid hor-
mones disrupts the normal differentiation of the central
nervous tissue; the lack slowing it and the abundance
precociously accelerating it.
Hyperthyroidism
Hyperthyroidism (thyrotoxicosis) is defined as the clinical
syndrome of hypermetabolism and hyperactivity that results
when the serum concentrations of FT4 and/or FT3 are high.
At the same time, TSH is suppressed below the reference
interval (healthy range). Graves’ disease is the most common
cause of autoimmune hyperthyroidism in pregnancy, occur-
ring in 0.1–1% (0.4% clinical and 0.6% subclinical) of all
pregnancies34. Less common non-autoimmune causes of
thyrotoxicosis include toxic multinodular goiter, toxic aden-
oma and factitious thyrotoxicosis due to high exogenous
supply45. The most frequent cause of transient thyrotoxicosis
in pregnancy is the syndrome of gestational hyperthyroidism
which is defined as transient hyperthyroidism, limited to the
first half of pregnancy, characterized by normal or borderline
elevated FT4 or adjusted TT4 and suppressed or undetectable
serum TSH, in the absence of serum markers of thyroid
autoimmunity and normal thyroid ultrasound (US). It is
diagnosed in about 1–3% of pregnancies, it is caused by a
TSH-like effect of the hCG and it is a self-limiting disorder,
resolving spontaneously34.
Thyroid autoimmunity in pregnancy
Thyroid autoimmunity may be expressed as either an isolated
positivity for thyroid autoantibodies against thyroid peroxid-
ase (TPOAb) and/or thyroglobulin (TgAb), or positivity of the
antibodies connected with thyroid dysfunction. Isolated
Crit Rev Clin Lab Sci, Early Online: 1–15
positivity for TPOAb is common in pregnancy and it bears
a considerable risk for the development of postpartum
thyroiditis with an eventual long-term hypothyroidism in the
mother. Moreover, TPOAb-positivity has been associated
with a number of adverse effects in pregnancy. In this section,
we discuss the pathophysiology of thyroid autoimmunity in
pregnancy and its adverse effects on the mother and the
offspring (Table 1) .
A modulated-maternal immune response in the form of
partial immunosuppression ensures tolerance of fetal alloanti-
gens and maintenance of pregnancy (Overview in Table 2).
Pregnancy is accompanied by an increase in regulatory
T-cells and by changes in cytokine production46. The
immunopathology of reproductive failure may be partially
explained by an imbalance between Th1 and Th2 immunity,
Th17 cells and regulatory T-cells47. Lack of physiologically
occurring immunosuppression necessary to tolerate the fetal
semiallograft is regarded as one of the causes of the higher
miscarriage rate in women with thyroid autoimmunity. The
complexity of the immunological relationship between the
mother and the fetus still remains to be answered. However,
recent advances in molecular biology have enlightened some
of the molecular mechanisms participating in the fetomaternal
crosstalk during implantation48.
Positivity for TPOAb and/or TgAb is common in women of
reproductive age in countries with good iodine supply. The
prevalence of positive TPOAb among pregnant women has
been reported between 5.1 49,50 and 12.4%51. Although the
possible causative genes of thyroid autoimmunity remain
largely unknown, several novel genetic loci associated with
TPOAb and thyroid diseases have been identified and may
Table 1. Pregnancy-associated risks in euthyroid women with thyroid
autoimmunity.
 Thyroid dysfunction in pregnancy and postpartum (good evidence)
 Miscarriage (moderate/good evidence)
 Preterm birth (moderate evidence)
 Impaired child neurological development (insufficient evidence)
Table 2. Changes leading to immune tolerance to fetus in pregnancy.
Mechanical barrier
Different HLA expression Trophoblast cells do not express
MHC Ia and MHC II antigens,
but express MHC Ib antigens
(HLA-E, HLA-G).
Natural killers inhibition Due to HLA-G and HLA-E
expression by trophoblast.
CD8+ T cells inhibition Due to HLA-G expression by
trophoblast.
Treg production Due to HLA-G expression by
trophoblast.
Inhibition of complement activation
Apoptosis of activated T cells Due to FasL and TRAIL expression
by trophoblast
Shift toward Th2 immune Due to increased estrogen and
response progesterone secretion.
FasL: Fas ligand; TRAIL: TNF-alpha related apoptosis-inducing ligand;
Treg: regulatory T cells; HLA: human leucocyte antigen; MHC: major
histocompatibility complex.
Adapted from Weetman95.
DOI: 10.1080/10408363.2016.1269309
explain why some women are prone to certain types of
autoimmune thyroid disease52.
TPOAb positivity is associated with several risks both to
the mother and to the fetus (Table 1). Whereas the risk
of thyroid dysfunction in pregnancy and postpartum
in TPOAb-positive women is based on good evidence, the
association between positive TPOAb and miscarriages, pre-
term birth, and impaired child neurological development
remains much less understood and even controversial30.
Thyroid autoimmunity and pregnancy loss
Many studies report a link between thyroid autoimmunity and
miscarriages (usually defined as a pregnancy loss before 20
weeks of gestation) in euthyroid women. The miscarriage rate
varies between 0 and 36.3% in TPOAb-positive women53,54
and 1.3 and 20% in TPOAb-negative women55,56. In a
systematic review by Rasmussen and Bliddal, seven studies
reported a significantly higher risk of miscarriage in TPOAb-
positive women as compared to TPOAb-negative controls; six
studies did not find any association57. Toulis and colleagues
performed a meta-analysis and demonstrated that thyroid
autoimmunity in euthyroid women does not decrease the rate
of implantation, but it does increase the risk of miscarriage
in subfertile women undergoing IVF (RR 1.99)58. In a
meta-analysis by Thangarantinam and colleagues, TPOAb
and/or TgAb were shown to represent a significant risk factor
for miscarriage in 28 of 31 studies with an odds ratio of 3.9 in
the 19 cohort studies and 1.80 in the 12 case-control studies59.
Other studies have shown similar relative risks60–62. Thus, the
association between miscarriages and thyroid autoantibodies
seems to be well proven.
Thyroid autoimmunity and preterm birth
In contrast to pregnancy loss, the association between thyroid
autoimmunity and preterm birth is much more controversial.
Some studies reported a significant association56,63,64, but
others did not65–67. In an observational cohort study of almost
1500 pregnant American women (the FASTER trial), Cleary-
Goldman and colleagues found no association between posi-
tive TPOAb in the first and second trimester and preterm
delivery rates. Preterm premature rupture of membranes was
the only obstetric outcome associated with maternal thyroid
autoimmunity, and this was only the case in women with both
TPOAb- and TgAb-positivity68. Korevaar and colleagues
reported that TPOAb positivity was associated with a 1.7-
fold increased risk of premature delivery, a 2.1-fold increased
risk of spontaneous premature delivery and a 2.5-fold increased
risk of very premature delivery (534 weeks of gestation).
These effects remained similar after correction for TSH and
FT4 levels69. A similar association between TPOAb-positivity
in euthyroid women and very preterm deliveries was previ-
ously reported by Negro and colleagues70. In a further analysis
of the FASTER trial by Haddow and colleagues in 2010,
women with positive TPOAb and/or TgAb in the first trimester
had a higher rate of preterm delivery before 37 weeks of
gestation than the antibody-negative women (7.5% versus
6.4%). This was also the case for very preterm delivery before
32 weeks of gestation (1.2% versus 0.7); this effect was,
however, very weak71. Two recent studies published in 2015
Thyroid in pregnancy: from physiology to screening 5
did not confirm the association between TPOAb-positivity in
euthyroid women and preterm birth, finding only an associ-
ation with premature rupture of fetal membrane60,72. In
contrast, another study found a 2.5-fold increased risk of
preterm birth in isolated TPOAb-positivity which increased to
a 4.8-fold risk if concomitant subclinical hypothyroidism was
present73; and the meta-analysis of He and colleagues showed a
significantly increased risk of preterm delivery in women with
thyroid autoantibodies64. Given that the results of these
reviewed studies are very heterogeneous it is difficult to
make a concrete statement concerning the link of thyroid
autoimmunity and preterm birth.
Our research group has previously dealt with this topic in
2011, where we found an association between premature birth
and the positivity of thyroid autoantibodies connected to
pathological findings on thyroid US. We evaluated the
prognostic role of thyroid US on pregnancy outcome in
TPOAb-positive women. Only 64/131 (48.9%) of TPOAb-
positive pregnant women had US pattern typical for auto-
immune thyroiditis (US-positive). Pregnant women were
more likely to have TSH 410.0 mIU/L if they were
TPOAb-positive/US-positive as compared to TPOAb-posi-
tive/US-negative [8/64 (12.5%) versus 0/67 (0%), p ¼ 0.009].
The prevalence of preterm births among the TPOAb-positive
women was significantly higher in the TPOAb-positive/
US-positive women as compared to the TPOAb-positive/
US-negative women [(10/64 (15.6%) versus 2/67 (3.0%),
p ¼ 0.028]74. Thus, we can speculate that an autoimmune
pattern on US linked to positivity for thyroid autoantibodies
may represent a more severe form of an autoimmune process
with greater clinical importance than either entity alone.
The significance of the degree of TPOAb elevation
It is uncertain whether only slightly elevated levels of serum
TPOAb have a negative impact on pregnancy outcome.
Although early studies reported similar risks of miscarriages
with mild and markedly elevated TPOAb75,76, the clinical
significance of slightly elevated TPOAb remains controversial.
Major problems that must be rectified are the insufficient
standardization of the TPOAb tests and the varying cutoffs for
positivity. Moreover, cutoffs may be different in pregnancy
than the general population. Serum TPOAb levels are not
stable during pregnancy: they increase in the first and decrease
in the second and third trimesters77. Based on these reasons and
the lack of randomized interventional studies, some authorities
do not recommend the universal assessment of TPOAb in
pregnancy and in women with recurrent miscarriages30,78. In
our opinion, increased levels of TPOAb in pregnancy should
not be regarded as clinically relevant unless they exceed more
than twice the upper cutoff of the given analytical test.
Levothyroxine treatment in euthyroid TPOAb-positive
women
Although crucial, it is not known whether treatment of
euthyroid TPOAb-positive women improves pregnancy out-
come (i.e. decreases a risk of miscarriage and/or preterm
birth). There are only two small-randomized studies, includ-
ing a total of 187 women, evaluating the effect of
levothyroxine treatment on pregnancy outcomes. Both the
6 D. Springer et al.
study performed in unselected women79 and in women
scheduled to have IVF treatment80 showed relative miscar-
riage rate reductions of 36% and 75%, respectively. The study
performed in unselected women also reported a 69% decrease
in relative risk of preterm delivery rate in women treated with
levothyroxine. In the retrospective study of Vissenberg and
colleagues in 202 euthyroid women with recurrent miscar-
riage, TPOAb-positive women without levothyroxine treat-
ment (n ¼ 10) had a lower live birth rate (29%) than TPOAb-
positive women on levothyroxine (60%) and TPOAb-negative
women (51%)81. In our retrospective study in women after
miscarriages, we had comparable results and we proved the
cost-effectiveness of levothyroxine substitution. Of the 38
TPOAb-positive or subclinical hypothyroid women who were
not treated with levothyroxine, 8 (21%) reported secondary
infertility as compared to 16/147 (11%) healthy, and 3/73
(4%) TPOAb-positive or subclinical hypothyroid women
treated with levothyroxine (p ¼ 0.021). Treatment with
levothyroxine was associated with an increased rate of
successfully completed subsequent pregnancies (increment
of 6 newborns/100 women) and cost savings of E19 539/100
women. Total costs per successfully completed pregnancy
were E1189 in healthy controls, E1564 in the treated and
E2488 in the untreated women82.
Effect of levothyroxine on the live birth rate in TPOAb-
positive euthyroid women with recurrent miscarriages is
currently being studied in the ongoing T4-LIFE study. The
study is designed as a multicenter, placebo controlled,
randomized trial in euthyroid women with recurrent miscar-
riages (two or more miscarriages before the 20th gestational
week) and TPOAb-positivity. The primary outcome is live
birth, defined as the birth of a living fetus beyond 24 weeks of
gestation. The study needs to randomize 240 women (120 per
group) to demonstrate an improvement in live birth rate from
55% in the placebo group to 75% in the levothyroxine
treatment group83. In our opinion, the current evidence is
sufficient enough as to recommend treatment with levothyr-
oxine in pregnant women with positive thyroid autoantibodies
and coincident mild TSH-elevation and/or FT4 decrease, or in
cases with typical autoimmune pattern on thyroid US.
Maternal thyroid autoimmunity and child
neurological development
Studies investigating the relationship between positive TPOAb
in euthyroid pregnant women and cognitive skills of their
children have had conflicting results. In the pioneer study by
Pop and colleagues, preschool children born to TPOAb-
positive mothers had lower IQ as compared to TPOAb-
negative ones84. More than ten years later, both similar85,86 and
opposite87,88 findings have been reported. Wasserman and
colleagues reported in 2008 that 22.7% of the children born to
euthyroid TPOAb-positive (62.5 IU/mL) mothers had sen-
sorineural hearing loss as compared to 4.3% born to TPOAb-
negative mothers (OR adjusted for maternal race, age and
hypothyroidism 7.5, 95% CI 2.4–23.3). When a lower cut off of
TPOAb (31.25 IU/mL) was used, a smaller but still signifi-
cant association remained (OR 5.7, 95% CI 2.1–15.6). Four
years later, the same group reported a modest effect of TPOAb
on the cognitive performance of a child observed at four and
Crit Rev Clin Lab Sci, Early Online: 1–15
seven years of age. The authors suggested that association of
TPOAb with IQ may reflect a portion of children with
unexamined TPOAb-associated sensorineural hearing loss89.
More recently in 2014, Wilson and colleagues showed that
positive TPOAb was significantly associated with smaller head
circumference, reduced brain weight, and lower brain-to-body
ratio in children of white, non-Hispanic euthyroid TPOAb-
positive mothers90. In a cohort study by Ghassabian and
colleagues in 2012 in the Netherlands, children of TPOAb-
positive mothers were at a higher risk of attention deficit/
hyperactivity problems91. Conversely, Pakkila and colleagues
in 2014 in Finland did not find an association between TPOAb
and cognitive parameters and/or attention deficit/hyperactivity
problems92. Similarly, Williams and colleagues did not find an
association between maternal or cord levels of TPOAb or TgAb
with child neurodevelopment determined as McCarthy scale
scores at 5.5 years79.
Based on these conflicting results, it is difficult to draw a
conclusion. It seems that the isolated positivity of maternal
thyroid autoantibodies could be associated with adverse
neurodevelopment outcomes in the offspring. However, the
clinical impact of these findings remains unclear.
Possible mechanisms of adverse effects of TPOAb
positivity
There are three hypotheses as to how positive TPOAb in
euthyroid women could contribute to a negative pregnancy
outcome: i) subtle hypothyroxinemia with TSH still within
reference range (or slightly elevated) being unnoticed in the
first weeks of gestation; ii) failed mother’s immune tolerance
to fetus; and iii) increasing prevalence of both thyroid
autoantibodies and miscarriages/preterm births with advan-
cing age. The first theory is supported by the fact that among
initially euthyroid TPOAb- or TgAb-positive pregnant women
the risk of hypothyroidism varies between 16 and 19% during
the second and third trimesters of pregnancy, although the
levels of thyroid autoantibodies decrease70,93. Moreover, in a
meta-analysis in 2011 Thangaratinam and colleagues reported
that euthyroid TPOAb-positive women had serum TSH 0.5
mIU/L higher than TPOAb-negative women59. Finally, 65%
of euthyroid TPOAb-positive women with recurrent miscar-
riages showed increased TSH stimulation (415 mIU/L) after
TRH (thyroliberin), indicating subtle peripheral thyroid
dysfunction94,95.
Women with thyroid autoimmunity are considered to be at
high risk of failure of the immune tolerance to fetus. Some
authors believe that the association of thyroid autoimmunity
with miscarriages and preterm birth is not causal but it is just an
epiphenomenon underlying advanced age of pregnant women
(prevalence of both is linked with higher age). However,
several facts indicate that this hypothesis is rather unlikely: i)
treatment with levothyroxine decreases the incidence of
miscarriages and preterm births79,80, ii) there is no difference
in age between TPOAb-positive and TPOAb-negative women
with miscarriages59, and iii) advanced age is not a significant
predictor for TPOAb positivity in pregnant women36.
Therefore, we believe that thyroid autoimmunity is an
expression of a profound immunological dysbalance having
multiple adverse effects on pregnancy. These effects are
DOI: 10.1080/10408363.2016.1269309
mediated by both the immunopathological pathways as well
as by the subtle lack of thyroid hormones.
Reference intervals for thyroid markers in pregnancy
In pregnancy, a number of factors affect the determination of
reference intervals for thyroid parameters. The most import-
ant is the definition of euthyroidism. Moreover, iodine
saturation and analytical methodology play a role (differences
in recognition of antibody epitope by different reagents).
Clinical heterogeneity, test assay platform, thresholds used
and quality features of the studies are likely to have
contributed to the statistical heterogeneity observed.
Determining the reference range suitable for the first trimester
of pregnancy is possible by using the suggestion of the
National Academy of Clinical Biochemistry (NACB) on
selected samples from the population, or as 95th percentile
from a cohort of women with a sufficient iodine supply96. For
TSH and sometimes also for FT4, high-interindividual
variability exists and the inclined distribution of values may
be taken into account in a group of pregnant women. For the
definition of reference intervals for TSH and FT4, it is
necessary to select a group of pregnant women in whom
factors stimulating or inhibiting the thyroid function are
excluded. Preferably, this group should consist of TPOAb-
negative women without personal or family history for thyroid
disorders and without other influencing factors (Table 7) as
well as without multiple pregnancies. Any such determination
should include test for normality of data, which is important
in choice of parametric or non-parametric method for the
reference intervals calculation.
Serum concentrations of TSH, FT4 and TPOAb are usually
measured using immunoassays. Worldwide, there are sev-
eral immunoanalytical systems used. Given the significant
changes in the concentrations of thyroid hormones throughout
gestation30, the ATA has recommended that the reference
intervals be determined not only for each trimester of
pregnancy, but also for each specific geographical region34.
Moreover, potential variations between the analytical methods
should be taken into account.
Thyroid-stimulating hormone
The diagnosis of thyroid disease in pregnancy is based upon
serum TSH concentration, using trimester-specific TSH
reference intervals for pregnant women97,98. Due to the
high-hCG values and increased production of TBG99, the
reference interval for TSH is set lower in pregnancy than in a
non-pregnant population. Using the classical reference range
for serum TSH could lead to underdiagnosis of hypothyroid-
ism and overdiagnosis of hyperthyroidism. Therefore, the
implementation of pregnancy-specific reference intervals is
widely recommended29,100. The pregnancy-specific reference
intervals proposed by the American Thyroid Association and
the European Thyroid Association are shown in Table 330,34.
Various authors have published quite a wide range of
reference intervals for TSH. More than 90% of the published
reference intervals for TSH in the first trimester are higher
than the recommended upper limit of 2.5 mIU/L. Table 4
summarizes reference intervals determined in various coun-
tries, including the variations between different ethnic
Thyroid in pregnancy: from physiology to screening 7
Table 3. Recommended trimester specific
reference intervals for TSH.
TSH (mIU/L)
First trimester 0.1–2.5
Second trimester 0.2–3.0
Third trimester 0.3–3.0
According to the American Thyroid
Association 201134 and the Endocrine
Society 201230.
populations101–103. It is a matter of discussion whether these
reference intervals should be used worldwide. The use of
uniform reference intervals may lead to an unnecessary
initiation of treatment in women with high-normal TSH
levels104.
For practical purposes, the reference interval for TSH in
the first trimester of pregnancy can be set as the reference
interval published by the producer for the general population
decreased by about 0.15 mIU/L in the lower and 1.5 mIU/L in
the upper limit.
Very often, the TSH suppression in the first trimester of
pregnancy is caused by the syndrome of transitory gestational
hyperthyroidism. The beta subunit of hCG is specific for
hCG, while the alpha subunit of hCG is nearly identical to the
alpha subunit of TSH118. Thus, hCG is known to have a TSH-
like effect in pregnancy leading to transitory gestational
hyperthyroidism119. This inverse relationship between hCG
and TSH levels during early pregnancy has been well
documented1,107.
Free thyroxine
The measurement of maternal FT4 with the current immuno-
assay techniques may not be sufficiently accurate due the
interference of pregnancy-modified plasma proteins. Still,
some authors state that the reliability of the standard
immunoassay for FT4 is satisfactory120. Others point to its
unreliability and emphasize the measurement of FT4 in the
dialysate or ultrafiltrate using online solid phase extraction
liquid chromatography tandem mass spectrometry as gold
standard (LC/MS/MS)121,122. This method is ideal for deter-
mination of trimester specific reference ranges for FT4.
However, it is technically demanding and expensive, and at
present not available in most clinical laboratories123–125. For
most of the immunoanalytical systems used, there are
established and published reference intervals for FT4 in
pregnancy. These reference intervals are mostly similar to
those recommended by the manufacturers.
The determination of total T4 (TT4) has also been
proposed as an alternative method for evaluating thyroid
function during pregnancy, as TT4 measurements are per-
formed by a more robust methodology than those used for
FT4126. The increase in TT4 due to the increase in placental
hCG is more predictable than the increase in FT4. It appears
thus that the reference values established in different popu-
lations are better comparable and probably more reliable than
those obtained for FT4. Moreover, it has been proposed that
the reference values for TT4 in pregnancy may be confidently
obtained simply by multiplying the reference values of the
8 D. Springer et al. Crit Rev Clin Lab Sci, Early Online: 1–15

Table 4. Reference intervals for TSH (mIU/L) in the first trimester of pregnancy calculated according to international recommendations
for TPOAb negative women.

Method Reference n 2.5th–97.5th percentile

104
Advia Centaur Siemens Yan et al. (2011) , China 505 0.03–4.51
Bestwick et al. (2014)105, UK 16 334 0.06–3.50
Pearce et al. (2008)106, USA 585 0.04–3.60
Springer et al. (2009)107, Czech Rep. 4337 0.06–3.67
Architect Abbott Shen et al. (2014)108, China 1409 0.16–3.78
Bocos-Terraz et al. (2009)109, Spain 481 0.41–2.63
Gilbert et al. (2008)110, Australia 1817 0.02–2.15
La’ulu and Roberts (2011)101, USA 2172 0.02–2.69
Männisto et al. (2011)98, Finland 4333 0.08–3.54
Stricker et al. (2007)97, Switzerland 575 0.07–2.82
Immulite 2000. Siemens Xing et al. (2016)111, China 3314 0.07–3.96
Karakosta et al. (2011)112, Greece 425 0.05–2.53
Hadow et al. (2004)113, USA 1126 0.08–3.61
Lambert-Messerlian et al. (2008)114, USA 8351 0.12–3.37
Elecsys, Roche Li et al. (2014)115, China 640 0.10–4.34
Wang et al. (2011)116, China 406 0.19–3.54
Vaidya et al. (2007)36, UK 1089 0.14–3.19
Vitros ECI Ortho Medici et al. (2011)49, Netherlands 5186 0.03–4.04
AutoDELFIA Bestwick et al. (2014)105, Italy 5505 0.04–3.19
UniCel DxI 800 Beckman Coulter Zhang et al. (2015)117, China 3507 0.06–3.13

non-pregnant population by 1.5127. However, the potential
advantages of TT4 have been questioned due to its
close relationship to TBG, which serum levels are highly
variable128.
Thyroid autoantibodies
Autoantibodies against TPOAb and thyroglobulin (TgAb) are
markers of autoimmune process in the thyroid gland and their
determination is diagnostically and prognostically import-
ant129. Pregnant woman screened during the first trimester of
pregnancy have a high prevalence of thyroid autoantibodies
(up to 20%)49,107. In the second and third trimesters of
pregnancy, thyroid antibodies may decrease. This is caused by
the relative immune suppression allowing an immunotolerant
environment for the fetus46. The fall in both the TPO-Ab and
Tg-Ab in the second half of pregnancy is followed by an
increase postpartum49,130.
The measurement of TgAb is recommended in the case of
elevated TSH and negative TPOAb. In the presence of
elevated TSH and negative TPOAb and TgAb, thyroid
ultrasonography may be helpful in detecting abnormal thyroid
texture and establishing the diagnosis of autoimmune
thyroiditis77.
Studies dealing with specific pregnancy reference intervals
for TPOAb from USA, Europe, China and other countries
have been repeatedly published101,107,111. The differences in
TPOAb manufacturers’ reference ranges are incomparable:
the cutoff limits vary from 0.5 to 100 kU/L. In our study from
2009, we report a cutoff for TPOAb at 143 kU/L for the first
trimester of pregnancy (n ¼ 4337)107. For most of the tested
systems, the established cutoff limits in pregnancy are similar
to those recommended by the manufacturers. It is also
possible that the manufacturer modifies the immunoassay
method over time, changing the antibody used and thus also
changing the results achieved. Moreover, for clinical pur-
poses, it is often reasonable to consider the TPOAb-values in
a rather semiquantitative fashion (negative, borderline posi-
tive, moderately positive and highly positive).
Assessment of thyroid markers by different
analytical systems
The treating physician should be aware of which analytical
system for assessment of the thyroid markers their laboratory
uses and what the specific reference intervals are. In 2014, we
validated the reference intervals for thyroid markers in early
pregnancy on seven different analytical systems131. Table 5
provides an overview of reference intervals for TSH, FT4 and
TPOAb determined in a group of 216 healthy Czech pregnant
women in the 9th–13th gestational week without history of
thyroid dysfunction. An adequate iodine supply can be
expected, as iodized salt has been in regular use in the
Czech Republic since the 1950s132. No participants had any
history of family or personal thyroid dysfunction. We
measured TSH, FT4 and TPOAb serum levels simultaneously
using seven different immunoassay systems representing the
methods most often used globally. As the TSH and FT4 levels
did not follow a normal distribution, we used a power-
transformation of the original data in order to gain better
results for normality testing. We established the 95% refer-
ence intervals (range from 2.5th to 97.5th percentiles) by
employing the parametric approach and we retransfomed all
parameters afterwards. Moreover, we established the positiv-
ity cutoff limits for TPOAb by a simple nonparametric
method – as the 95th percentile of all values. We applied this
approach for each of the different analytical systems analyzed.
Since, it is very difficult to standardize the determination
of TPOAb; it is preferable to indicate the result as TPOAb-
positive or TPOAb-negative. Single numerical cutoff for all
methods is difficult or even impossible to establish.
Screening of thyroid disorders in pregnancy
Discussions on the screening for hypothyroidism in pregnancy
are ongoing and the opinions are different from country to
DOI: 10.1080/10408363.2016.1269309 Thyroid in pregnancy: from physiology to screening 9
Table 5. Reference intervals for thyroid function tests established simultaneously with seven different analytical systems in the same
serum pool from 216 healthy pregnant women in 9th–13th gestational weeks131.

Analytical system FT4 (pmol/L) TSH (mIU/L)

TPOAb (IU/mL)
Producer Median Reference interval Median Reference interval Median Cutoff
Architect i2000SR, 14.41 11.76–17.7 1.37 0.22–3.27 9 11.2
Abbott
UniCel DxI 800 10.43 8.13–13.2 1.33 0.20–3.23 0.7 7.6
Beckman Coulter
Immulite 2500 12.95 10.44–16.39 1.16 0.17–2.83 5 16.7
Siemens
Advia Centaur 14.59 11.83–18.37 1.39 0.22–3.34 7 54
Siemens
Modular E170 14.66 11.49–18.62 1.56 0.25–3.81 33 20.1
Roche
AIA 2000 13.4 9.97–17.25 1.09 0.18–2.78 5.7 7
Tosoh Bioscience
RIA/IRMA Immunotech 15.18 12.31–18.67 1.53 0.25–3.91 0.26 14
Beckman Coulter

country. Results of the population screenings for thyroid
disorders vary, depending on level of medical care and
approach to prevention, geographical conditions, iodine
supplementation and other circumstances (including diagnos-
tic criteria used)126,133,134. Evaluation of thyroid function in
pregnancy is difficult, considering the number of interfering
influences in pregnancy.
However, implementation of universal screening for con-
genital hypothyroidism and early administration of levothyr-
oxine successfully prevent the worst detrimental effects of
hypothyroidism – severe mental and growth retardation of the
child.
In recent years, a fierce debate on whether at all, and if yes,
how to screen pregnant women for thyroid disorders has
emerged126. Although the clinical efficacy of treatment of
overt hypothyroidism in pregnancy has been accepted as
adequately proven, data on effectiveness of treatment of
subclinical hypothyroidism in pregnancy are regarded as
insufficient due to lack of randomized studies135. This is the
main argument against implementation of general screening
for autoimmune thyroid diseases (AITD) in pregnancy.
Therefore, the majority of endocrine societies still prefer the
case-finding approach of screening of the high-risk women.
The Endocrine Society Guidelines from 2012 resulted in a
majority opinion advocating selective screening and a
minority opinion recommending universal screening30. The
selective screening involves evaluation of 15 risk factors in
the pregnant women and if any of them is present, a TSH
measurement should be performed (Table 6)34. The European
Thyroid Association has not recommended universal screen-
ing in their Guidelines from 2014. However, the authors state
that in the opinion of the majority of experts this screening
should be implemented29.
The arguments for implementation of universal screening
are compelling. Thyroid dysfunction is common in preg-
nancy, is easy to detect and can be treated efficiently, safely
and inexpensively. Moreover, statistical models have shown
its cost-effectiveness136,137. Also, about one-third to one-half
of the women with thyroid disorders will escape the case-
finding approach38,138.Therefore, more and more specialists
have started to favor the universal screening recently, and
Table 6. Risk factors necessitating a screening for thyroid disorders in
pregnancy according to the guidelines of the American thyroid
association34.
 Women with a history of thyroid dysfunction and/or thyroid
surgery.
 Women with a family history of thyroid disease.
 Women with goiter.
 Women with thyroid antibodies.
 Women with symptoms or clinical signs suggestive of
hypothyroidism.
 Women with type I diabetes.
 Women with a history of either miscarriage or preterm delivery.
 Women with other autoimmune disorders that are frequently
associated with autoimmune thyroid dysfunction, including viti-
ligo, adrenal insufficiency, hypoparathyroidism, atrophic gastritis,
pernicious anemia, systemic sclerosis, systemic lupus erythemato-
sus, and Sjögren’s syndrome
 Women with infertility should have screening with TSH as part of
their infertility work-up.
 Women with prior therapeutic head or neck irradiation.
 Women with a body mass index 40 kg/m2
 Women age 30 or older. The prevalence of hypothyroidism
increases with age.
 Women treated with amiodarone.
 Women treated with lithium.
 Women with a recent (in the past 6 weeks) exposure to iodinated
radiological contrast agents.
voices emerge calling for universal screening from the USA,
United Kingdom, Belgium, the Netherlands, Italy, Spain, the
Czech and Slovak Republics, as well as China135,139–145. In
fact, thyroid disorders in pregnancy fulfill all the demands for
implementation of a universal screening as proposed by
Wilson and Jungner (Table 7).
However, there are several issues of concern. Most
importantly: what value of TSH should be taken as a cutoff
for pathology and indication for treatment? General consensus
states that every woman with manifest hypothyroidism should
be treated34. According to international guidelines, TSH in
the first trimester of pregnancy should be below 2.5 mIU/L
10 D. Springer et al.
Table 7. Thyroid disorders in pregnancy in the view of criteria for
universal screening.
1. Is the condition an important health problem? Yes
Deficiency of thyroid hormones may have serious consequences
for both the pregnant woman and the fetus1,4,5,21,31.
2. Is there an accepted treatment for patients with Yes
recognized disease?
Treatment of thyroid disorders is undemanding in terms of
oral medication23,30,34.
3. Are facilities for diagnosis and treatment Yes
available?
Diagnostics is based on available laboratory and ultrasonographic
examination. The treatment is well established and undemanding29,100.
4. Is there a recognizable latent or early symptomatic Yes
stage?
Investigations at very early pregnancy may reveal a hidden and
yet asymptomatic, but easily treatable disease49,114.
5. Is there a suitable test or examination? Yes
Laboratory tests are widely available and inexpensive96,97,113.
6. Is the test acceptable to the population? Yes
The acceptability of the thyroid tests is not problematic140.
7. Is the natural history of the condition, including Yes
development from latent to declared disease
adequately understood?
The studies in physiology of the thyroid gland and its disorders
are available1,5,40.
8. Is there an agreed policy on whom to treat as Yes
patients?
Expert guidelines are available for the treatment and management
of pregnant women with thyroid disorders30,40.
9. Is the cost of case finding (including diagnosis Yes
and treatment) economically balanced in relation
to possible expenditure on medical care as a
whole?
Diagnosis and treatment of thyroid disorders is relatively
inexpensive. The cost-effectiveness has been confirmed by
several studies82,136,137.
10. Case finding should be a continuing process and Yes
not a ‘‘once and for all’’ project.
More than half of the women with TPOAb positivity during
pregnancy undergo postpartum thyroiditis and the other half of them
will have permanent damage of the thyroid gland39,100,145.
Adopted from Wilson and Jungner: Principles and practice of screening
for disease146.
and in the second and third trimester below 3 mIU/L34.
However, should all women with a TSH above 2.5 mIU/L and
normal FT4 be treated? As was shown previously, this could
involve almost 17% of all pregnant women35,36. Addition of
TPOAb-positivity to this threshold seems to be a reasonable
way to select women who could benefit from treatment. This
approach was used by Negro and colleagues147. In his study,
more than 4500 women were randomized to universal or
selective screening, and treatment was initiated in the first
trimester when TSH was above 2.5 mIU/L and TPOAb were
positive. Although universal screening compared with case
finding did not result in a decrease in adverse outcomes in
general, women identified as having AITD and treated during
pregnancy had significantly fewer adverse outcomes than
women with AITD who were not identified until after
delivery and, therefore, not treated. Due to the current
knowledge on adverse effects of thyroid dysfunction in
pregnancy, it is difficult to perform a randomized study with a
control group of untreated high-risk women (e.g. women
Crit Rev Clin Lab Sci, Early Online: 1–15
above 30 years of age, women with TPOAb-positivity).
Reliable studies in children born to women with high risk for
thyroid dysfunction are needed.
Another concern about the levothyroxine-substitution
therapy has emerged. There is full agreement that substitution
in hypothyroid pregnant women is necessary, but it should
be done cautiously and overdose should be avoided.
Hyperthyroxinemia might be associated with decreased
cognitive functions in the offspring44.
Results from the Czech Republic
In the Czech Republic, efforts to screen for thyroid diseases in
pregnancy emerged in 2006. Since then, a number of studies
have been performed, all concluding that AITD are frequent
among the pregnant women35,74,83,107,138,141.
In 2009, we performed a pilot screening project in 13
Czech regions with good laboratory and endocrinological
backup. The aim of the project was to assess the prevalence of
thyroid dysfunction and thyroid autoimmunity in pregnant
women under optimal combination and economic feasibility
of the diagnostic tests. The timing of the venipuncture was
connected to the test for chromosomal abnormalities in the
first trimester of pregnancy (9th–11th gestational week).
Three tests were measured in 2937 pregnant women without
risk factors for thyroid disorders: FT4, TSH and TPOAb. The
results have shown a surprisingly high proportion of pregnant
women with any pathology in the screening. Overall, 18% of
asymptomatic pregnant women had a pathological value in at
least one parameter screened. Hyperthyroidism was rather
infrequent, and was manifest only in 0.5% of women in the
whole group; in the remaining women TSH suppression was
most likely due to hCG influence. Hypothyroidism mani-
fested as an increased TSH and/or decreased FT4 was found
in 7.8% of women. Importantly, hypothyroxinemia was found
in 3.7% of all women. TPOAb positivity was found in 8.9% of
all women: 5.4% had isolated TPOAb-positivity thyroid
dysfunction and 3.4% were TPOAb-positive with concomitant
pathological finding in FT4 and/or TSH. In 2012, we
confirmed these results in a larger study including 5223
pregnant women35. Moreover, in this study, we have shown
that pregnant women over 30 years of age did not have a
higher risk of thyroid dysfunction than younger women.
However, thanks to the increasing age of pregnant women, the
inclusion of this criterion among the high-risk criteria for
thyroid dysfunction increased the proportion of hypothyroid
women identified in a case-finding screening strategy from
55.3 to 85.6%.
Based on these findings, multiple educational activities
for the public have been implemented; lectures and
seminars for the professional community (most notably
for general practitioners, gynecologists and internists) have
been organized by the Czech Endocrine Society. The pilot
project has led to the conclusion that universal screening
for thyroid disorders in pregnancy should strongly be
recommended. Moreover, the pilot project has proven that a
suitable organization of the screening is possible, including
the continuity in treatment ascertained by the network of
endocrinologists.
DOI: 10.1080/10408363.2016.1269309 Thyroid in pregnancy: from physiology to screening 11

Conclusions pregnant women not only for TSH, but also for TPOAb,
regardless of whether the screening is targeted or universal.
Thyroid disorders in pregnancy are common and they
The risk of thyroid dysfunction in pregnancy and postpartum
constitute a major epidemiological risk concerning current
in TPOAb-positive women is based on good evidence.
and future pregnancies, as well as development of the
However, the relevance of other potential negative outcomes
offspring. Pregnant women with a diminished functional
associated with thyroid antibodies (pregnancy loss, preterm
reserve due to iodine insufficiency or thyroid autoimmunity
birth and impaired child neurological development) seems to
fail to increase the thyroid hormone production and develop
depend on other circumstances. Most notably on the serum
subclinical or overt hypothyroidism.
level of autoantibodies, duration of positivity, presence of US
In the scientific community, there is a continuous debate
thyroid texture typical of autoimmune thyroiditis and serum
on the definitions and the clinical relevance of hypothyroid-
TSH. In our opinion, measurement of both TSH and thyroid
ism, subclinical hypothyroidism, hypothyroxinemia, and the
antibodies in the systematic screening for thyroid disorders in
importance of thyroid antibodies in the course of pregnancy
pregnancy is beneficial and it can help decide whether women
and postpartum.
positive in the screening should be treated with levothyroxine
The link between overt hypothyroidism, obstetric compli-
or not. We consider the elevation of serum levels of thyroid
cations and disturbances in neuropsychological development
autoantibodies greater than double the upper cutoff limit for
of the offspring has been well established; and treatment with
the non-pregnant population for the given analytical test to be
levothyroxine has been uniformly recommended. Manifest
clinically relevant. In euthyroid pregnant women with positive
hypothyroidism affects at least 0.4% of pregnant women.
thyroid antibodies, we recommend levothyroxine treatment in
Extrapolated to a population of 10 million inhabitants with
cases with coincident mild TSH elevation and/or hypothyr-
100 000 deliveries per year, 400 neonates per year are in
oxinemia or when there is a typical pattern of autoimmune
danger of serious neuropsychological complications.
thyroiditis on thyroid US. Otherwise, frequent TSH monitor-
Screening for thyroid dysfunction should be applied in all
ing during pregnancy and postpartum is required.
high-risk women – and, according to some authorities – in all
In the Czech Republic, we have verified the practicability
women in early pregnancy. The screening is simple by
of universal screening of pregnant women with a subsequent
measuring TSH, and pregnancy-specific TSH reference
endocrinological care. The universal screening for AITD in
intervals should be used. Substitution with levothyroxine is
pregnancy has been recommended by the Czech Endocrine
inexpensive and widely available. It should be aimed at
Society and it has been implemented in several large obstetric
achieving normal TSH and according to some authors also
centers. The global future of screening for maternal thyroid
normal FT4 levels according to the trimester-specific refer-
disorders depends on the ongoing clinical trials.
ence ranges and the local laboratory. Moreover, inadequately
low or high doses should be avoided, and adequate iodine
supply should be ensured for all pregnant women. As the Acknowledgments
system of care of pregnant women differs across continents
This work was supported by a Research Project of the General
and countries, it remains yet to be defined who should be the
University Hospital Prague RVO-VFN 64165 and Research
primary provider of the screening (general practitioner,
Project of the Grant Agency of Ministry of Health of the
gynecologist and other treating physician).
Czech Republic MZ0/NT 11277.
Expert opinions differ in terms of clinical relevance of
subclinical forms of thyroid dysfunction. The problems begin
with the diagnostics. Several immunoanalytical systems for the Declaration of interest
measurement for thyroid parameters are used worldwide, with
The authors report no declarations of interest.
substantially different reference intervals recommended by the This work was supported by a Research Project of the
manufacturers. Moreover, the determination of the upper TSH General University Hospital Prague RVO-VFN 64165 and
cutoff value is crucial for the definition of thyroid dysfunction. Research Project of the Grant Agency of Ministry of Health of
According to the world’s authorities, the upper cutoff for TSH the Czech Republic MZ0/NT 11277.
in the first trimester has been set at 2.5 mIU/L. Using this
cutoff, up to 17% of all pregnant women could be classified as
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