Review

Autoimmune thyroid disease during pregnancy

Simone De Leo, Elizabeth N Pearce

Understanding of changes in thyroid function and the consequences of thyroid disease during pregnancy has rapidly Lancet Diabetes Endocrinol
grown in the past two decades, and revised American Thyroid Association guidelines on this topic were published in 2018; 6: 575–86

2017. This Review explores the association between thyroid autoimmunity and complications during and after Published Online
December 12, 2017
pregnancy. Thyroid autoimmunity refers to the presence of antibodies to thyroperoxidase or thyroglobulin, or
http://dx.doi.org/10.1016/
thyroid-stimulating hormone receptor antibodies (TRAbs), or a combination of these, and is present in up to 18% of S2213-8587(17)30402-3
pregnant women. Thyroid antibodies in pregnant women with normal functioning thyroids (ie, euthyroid) have been Division of Endocrine and
associated with several complications, including miscarriage and premature delivery. Treatments to improve pregnancy Metabolic Diseases, Istituto
outcomes are being studied. Whether thyroid antibodies are associated with infertility and assisted reproductive Auxologico Italiano, Milan,
Italy (S De Leo MD);
technology outcomes is unclear; although, treatment with low doses of levothyroxine, which is usually used to treat
Department of Clinical Sciences
hypothyroidism, can be considered in such situations. Additionally, thyroid antibodies have been associated with other and Community Health,
neonatal and maternal complications. All these associations require confirmation in larger prospective studies, and University of Milan, Milan, Italy
their pathogenic mechanisms need to be better understood. Post-partum thyroiditis is substantially more frequent in (S De Leo); and Section of
Endocrinology, Diabetes and
women who have thyroid antibodies during pregnancy than in those who do not have thyroid antibodies; however,
Nutrition, Boston University
whether treatment can prevent post-partum thyroiditis in women who are or have been antibody positive is unknown. School of Medicine, Boston
Finally, TRAbs cross the placenta from the mother to the fetus and can cause fetal or neonatal hyperthyroidism. MA, USA (S De Leo,
Therefore, women who are positive for TRAbs during pregnancy should be monitored. E N Pearce MD)
Correspondence to:
Introduction However, only 15–65% of pregnant women with a TSH Dr Elizabeth N Pearce, Section of
Endocrinology, Diabetes, and
Many studies of thyroid disease during pregnancy have concentration above the trimester-specific reference Nutrition, Boston University
been published in the past two decades, and the ranges are positive for thyroid anti­bodies,13–15 suggesting School of Medicine, Boston,
understanding of thyroid physiology and the consequences a role for other causes (eg, iodine deficiency) in the MA 02118, USA
elizabeth.pearce@bmc.org
of thyroid disease during pregnancy has expanded development of hypo­ thyroidism during pregnancy.
substantially. In 2017, the American Thyroid Association Because of the increased risk of hypothyroidism in
(ATA) published new guidelines1 on the diagnosis and pregnant women who have thyroid autoimmunity, ATA
management of thyroid disease in women during preg­ guidelines recommend that women with known thyroid
nancy and post partum. This Review will explore the auto­
immunity have their TSH con­ centrations assessed
associations between thyroid autoimmunity and com­ every 4 weeks through to mid-pregnancy. Thyroperoxidase
plications during pregnancy and post partum. antibody status should be assessed in pregnant women
Thyroid autoimmunity refers to the presence of with a TSH concentration of 2·5–10·0 mU/L, since this
antibodies to thyroperoxidase and thyro­ globulin, or information could be helpful in deciding which patients
thyroid-stimulating hormone (TSH) receptor antibodies should be treated.1
(TRAbs). The term TRAbs refers to any type of TSH
receptor antibodies. Although TRAbs have a direct role in Epidemiology and natural history of thyroid
the pathogenesis of Graves’ disease, the roles of the anti­ antibodies during pregnancy
bodies to thyroperoxidase and thyroglobulin are not clear. Thyroid autoimmunity is one of the most common
Antibodies to thyroperoxidase and thyroglobulin are autoimmune disorders. In the general population of the
markers of thyroid autoimmunity and their production is USA, the prevalence of thyroid antibody positivity is
probably a response to, rather than a cause of, thyroid highest in non-Hispanic white people, and increases with
injury (figure 1) age.16 The prevalences of thyroglobulin and thyroperoxidase
Graves’ disease is the most frequent cause of hyper­ antibody positivity in women who are aged 20–29 years are
thyroidism in women of childbearing age. However, 9·2% and 11·3%; in those aged 30–39 years they are
during early pregnancy, high concentrations of human 14·5% and 14·2%; and in those aged 40–49 years old, they
chorionic gonadotropin (hCG) are the most important are 16·4% and 18·0%, respectively.16 In the general popu­
risk factor for hyperthyroidism, and women with high lation of pregnant women, the prevalence of thyro­
hCG concentrations often present with transient peroxidase antibody positivity ranges from 5% to 14%, and
gestational thyrotoxicosis.2–4 TRAbs might be responsible that of thyroglobulin antibodies from 3% to 18%.11,13,14,17–24
for fetal and neonatal hyperthyroidism; therefore, However, the differences between assays and cutoffs used
monitoring of TRAb concentrations is recommended in in various studies could contribute to the differences in the
women who are at risk (panel).5–9 reported prevalence of thyroid antibodies, and differences
Pregnant women who are positive for thyroperoxidase or in antibody associations with pregnancy outcomes. Several
thyroglobulin antibodies are at higher risk of developing risk factors for thyroid autoimmunity have been reported—
both subclinical and overt hypothyroidism during ges­ eg, a family history of autoimmune thyroid disease, older
tation than women who are negative for anti­bodies.10–12 age, iodine deficiency or excess, and European ancestry.18,19

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 Review

Thyroid gland Lymphoid Thyroid gland

tissue CD4
APC
positive
T cell
Environmental APC
factors Thyrocyte B cell
Thyrocyte

Apoptosis
APC
APC
Thyroid
antibody Thyroid antibodies
Infiltration Antigens production Cytokines
Macrophages
TAPC
cell
Cytotoxic T cells
B cells

Figure 1: Mechanisms involved in thyroid autoimmune disease

Thyroid autoimmune disease, similar to other autoimmune diseases, occurs because of an absence of adequate T-cell tolerance. Although the cause of thyroid
autoimmunity is unknown, genetic, and non-genetic factors, such as environmental factors, could be involved. In the initial stage of thyroid autoimmunity, these
factors cause thyrocyte damage and exposure of thyroid antigens, such as thyroperoxidase, thyroglobulin, thyroid-stimulating hormone receptor, sodium iodine
symporter, and pendrin. Antigen-presenting cells (APCs), particularly dendritic cells, recognise these peptides and infiltrate the thyroid gland. After processing the
protein antigen, the thyroid APCs migrate to lymphoid tissue where they activate T cells. CD4+ T cells mediate B-cell activation and thyroid antibody induction. The
T cells also release cytokines and have a direct cytotoxic effect on the thyroid gland. Cytotoxic T cells, B cells, macrophages, cytokines, and thyroid antibodies infiltrate
the thyroid gland and induce apoptosis and destruction of the thyrocyte.

Panel: Thyroid-stimulating hormone receptor antibodies in pregnancy

General information and assay reliability
• Thyroid-stimulating hormone (TSH) receptor antibodies
(TRAb) refers to any type of antibody interacting with the
TSH receptor
• Receptor assays measure TSH inhibitory immunoglobulins,
and are based on the ability of autoantibodies to bind to the
TSH receptor; however, they do not distinguish between
stimulating and blocking immunoglobulins
• Bioassays detect the production of cyclic adenosine
monophosphate, and measure TSH-receptor stimulatory
antibodies, TSH-receptor blocking antibodies, and
antibodies with a neutral effect5
• TRAb assays have become highly reliable, with third-generation
immunoassays having a sensitivity and specificity of 97–99%6
Natural history
• TRAb concentrations tend to decrease throughout
pregnancy, with a subsequent increase after delivery;
however, occasionally women can have stable or
unexpectedly increasing titres during pregnancy7
• A switch in TRAb activity from stimulating to blocking
(or vice versa) has been reported during pregnancy8
• TRAbs freely cross the placenta; the fetal thyroid gland is
functional by week 16–20 of gestation; therefore, stimulation
of the gland by TRAbs could cause fetal hyperthyroidism and
goitre beginning around the 20th week of pregnancy
• Anti-thyroid drugs can also cross the placenta and control
fetal hyperthyroidism, and could be responsible for fetal
hypothyroidism
• After delivery, anti-thyroid drugs are cleared from the
neonate’s circulation within a week, whereas TRAbs persist
for longer and could be responsible for neonatal
hyperthyroidism
Monitoring
• Neonatal hyperthyroidism occurs in 1–5% of neonates born
to mothers with Graves’ disease, but the prevalence of fetal
hyperthyroidism is not well established3
• American Thyroid Association guidelines recommend
assessing the TRAb status of women with a history of
Graves’ disease in early pregnancy, and when investigating
the cause of newly diagnosed thyrotoxicosis in pregnancy
• If maternal TRAb concentrations are low or undetectable,
further TRAb testing is generally not necessary; however, if
maternal TRAb concentrations are high, TRAb testing
should be repeated at 18–22 weeks gestation1
• The risk of fetal and neonatal hyperthyroidism is particularly
high when mothers have elevated TRAb concentrations9
• According to a retrospective study,7 a concentration of
TSH-binding inhibitory immunoglobulins higher
than 5 IU/L (around three times the upper limit of normal
for the assay) in a pregnant woman during the second or
third trimester of pregnancy is a predictor for neonatal
hyperthyroidism, with a sensitivity of 100% and a
specificity of 43%;7 in these women, serial ultrasound
assessments to look for signs of fetal hyperthyroidism and
consultation with a specialist of maternal–fetal medicine
are recommended

Multiparity does not seem to be associated with thyroid observed in several studies.10,13,14,20,21 These studies reported
autoimmunity.25 higher baseline TSH concen­ trations in women with
A decrease in both the prevalence and titres of thyroid thyroid autoimmunity than women who were negative for
antibodies during the course of pregnancy has been antibodies. TSH concen­trations remained high for women

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Concentration
1st trimester
Conception
Figure 2: Changes in the concentration of TAbs and TSH during pregnancy
General changes in the concentrations of hCG and TAbs, and TSH in TAbs-positive and TAbs-negative women, throughout pregnancy. hCG=human chorionic
gonadotropin. TAbs=thyroid antibodies. TSH=thyroid-stimulating hormone.
with thyroid auto­immunity throughout pregnancy, with a
further increase at parturition, despite a decrease in
autoantibody concen­trations.10,13,21 The decrease or disap­
pearance of anti-thyroid antibodies during gestation could
be explained by a state of immune tolerance, which is
typically induced by pregnancy. Nevertheless, the physio­
logical modifications that occur in pregnancy, which lead
to an increased demand for production of thyroid
hormone, might overcome the beneficial effect of the
decrease in antibodies (figure 2). Thyroid antibodies can
cross the placenta (figure 3); however, neither thyro­
peroxidase nor thyroglobulin antibodies are thought to
affect fetal thyroid function.26
Thyroid autoimmunity and miscarriage
Miscarriage is defined as spontaneous pregnancy loss
occurring before 20 weeks of gestation. Most miscarriages
occur before 10 weeks of gestation, particularly in the very
first few weeks of pregnancy. This is important because
many studies that assessed thyroid antibody status after
the first 10 weeks of gestation could have underestimated
the risk of early miscarriage. Miscarriage affects 15–25% of
pregnancies.27 Recurrent pregnancy loss is defined as three
or more consecutive miscarriages and occurs in 1% of
pregnancies; if two or more losses are included in the
definition, recurrent pregnancy loss occurs in up to 5% of
pregnancies. The proven causes of recurrent pregnancy
loss are few, but they include karyotype abnormalities,
antiphospholipid syndrome, uterine malformations, and
cervical incom­ petence. More than 50% of cases are
considered idio­pathic.27
Sporadic spontaneous miscarriage
An association between thyroid autoimmunity and mis­
carriage was first described in 1990 when Stagnaro-Green
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Review
TSH if TAb positive hCG
TSH if TAb negative Thyroid antibodies
2nd trimester 3rd trimester
Delivery
Time
and colleagues28 reported twice as many miscarriages for
euthyroid pregnant women who were thyroid auto­
antibody positive (17·0%) compared with those who were
thyroid autoantibody negative (8·4%, p=0·01). Most, but
not all,29 subsequent studies have confirmed these data.
A meta-analysis30 including 12 case-control studies and
19 prospective cohort studies found that the pooled odds
ratio (OR) for miscarriage in women with thyroid
autoantibodies was 1·8 (95% CI 1·25–2·60) for case-
control studies and 3·9 (2·48–6·12) for cohort studies.
A clear association does thus seem to exist between
thyroid autoimmunity and risk of sporadic spontaneous
miscarriage.
Recurrent miscarriage
The association between thyroid autoimmunity and
recurrent pregnancy loss is less clear than that between
thyroid autoimmunity and sporadic miscarriage. Some
studies have shown an association between thyroid
autoimmunity and both pregnancy losses of three or
more31,32 and two or more;33 however, this finding has not
been universal.34,35 A meta-analysis36 inclu­ding eight studies
reported an increased risk of recurrent miscarriage in
euthyroid women with thyroid antibodies compared with
euthyroid women without thyroid anti­ bodies (OR 2·3,
95% CI 1·5–3·5).
Causes and pathogenesis of miscarriage in women with
thyroid autoantibodies
Although an association between antibody positivity and
miscarriage has been reported,28–30 a causal relationship
has not been proven. Older age is considered an inde­
pendent risk factor for miscarriage, and women with
thyroid antibodies are typically older than women
without antibodies.37 Nevertheless, a meta-analysis
 Review
Placenta Fetus
Thyroid-releasing hormone,
anti-thyroid drugs, TRAbs,
thyroperoxidase and
thyroglobulin antibodies,
and iodine
Tri-iodothyronine,
thyroxine, and
levothyroxine
TSH, hCG,
and thyroglobulin
Figure 3: Transplacental passage of thyroid antibodies, thyroid hormones, and hormones regulating thyroid
function, and thyroid and anti-thyroid drugs
Thyroid-releasing hormone, anti-thyroid drugs, TRAbs, thyroperoxidase and thyroglobulin antibodies, and
iodine can actively cross the placental barrier (solid arrow). Maternal thyroxine and levothyroxine can cross the
placental barrier (dashed arrow); however, the degree to which tri-iodothyronine can cross the placenta is still
not well understood. Maternal TSH, hCG, and thyroglobulin are not able to cross the placenta. hCG=human
chorionic gonadotropin. TSH=thyroid-stimulating hormone. TRAbs=TSH receptor antibodies.
confirmed the higher risk of miscarriage in women with
thyroid antibodies than those without after exclusion of
studies that did not use age-matched control groups
(OR 5·4, 95% CI 1·8–16).36 A high TSH concen­tration is
also a risk factor for miscarriage.38,39 Although only
euthyroid women were enrolled in studies examining the
effects of thyroid autoimmunity on miscarriage risk,
women with thyroid antibodies typically had higher
baseline TSH concen­ trations than those who were
antibody negative. In a meta-analysis,37 the TSH concen­
trations of women who were positive for thyroid
antibodies were on average 0·61 mIU/L higher than
those of women who were negative for antibodies
(p<0·0001). The presence of antibodies could be a sign of
subtle thyroid dysfunction and a failure of the thyroid to
respond to the increased demand for thyroid hormone
during pregnancy.40 A prospective cohort study39 showed
an additive effect of both thyroid autoimmunity and a
mild increase in TSH on miscarriage risk, indicating
that women who are antibody positive have an increased
risk of miscarriage at a lower TSH threshold. If mild
hypo­thyroidism is a cause of the observed association
between thyroid autoimmunity and miscarriage, treat­
ment with levothyroxine could be effective in lowering
the risk of miscarriage.
578 www.thelancet.com/diabetes-endocrinology Vol 6 July 2018
Another possible explanation for the observed asso­
ciation between thyroid autoimmunity and miscarriage is
the association of thyroid autoimmunity with other
autoimmune diseases—eg, systemic lupus erythema­tosus
and antiphospholipid antibody syndrome. Studies have
not found an association between thyroid antibodies and
antiphospholipid antibodies or antinuclear antibodies in
women with a history of recurrent pregnancy loss;33,41
however, an association of thyroid autoimmunity with
non-organ-specific antibodies has been described.41
Thyroid antibody positivity seems likely to be part of a
more generalised immune dysfunction. This postulation
is supported by the increased concentrations of CD5+ and
CD20+ B-lymphocyte cells that have been found in women
who have miscarried, cells that are involved in the
development of autoimmune disease.42 Moreover,
dominant type-1 helper (Th1) cell immune responses have
been seen in recurrent pregnancy loss and in failure of
embryonic implantation.43 Kim and colleagues41 reported
that in women with recurrent pregnancy loss, Th1 and
type-2 helper (Th2) cell cytokine-expressing CD3+-to-CD4+
cell ratios were higher in those who were thyroid antibody
positive than in those who were antibody negative.41 The
Th1-cell responses—in particular the secretion of
interferon γ, interleukin 2, and tumour-necrosis factor α
by Th1 cells—trigger thrombotic and inflammatory
processes at the maternal uteroplacental blood vessels
and could lead to miscarriage either directly through
T lymphocytes, or mediated by the migration of cytotoxic
natural killer (NK) cells into the uterus.44 Therefore, thyroid
antibodies might be non-specific markers for autoimmune
disease and not directly linked to the cause of miscarriage.
Some studies have found an increased proportion of fetal
resorption (ie, miscarriage) in mice with induced thyro­
peroxidase antibodies45 and thyroglobulin anti­ bodies,46
implying a direct pathogenic effect, but additional studies
are needed to confirm these findings.
Another hypothesis concerns the possible cross-reactivity
between TRAbs and receptors for hCG.47 TRAbs, in
particular TSH-receptor blocking antibodies, are found in
women with Graves’ disease and in up to 10% of patients
with Hashimoto’s thyroiditis. TRAbs might inhibit the
luteinising hormone and choriogonadotropin (LHCG)
receptor in the corpus luteum, decreasing progesterone
and oestrogen production, which is necessary for the
maintenance of pregnancy during the first trimester.48
Management of miscarriage risk in euthyroid women
with thyroid autoantibodies
The treatments studied in pregnant women who are
positive for thyroid antibodies to date are levothyroxine
and intravenous immunoglobulins.
The rationale for the use of levothyroxine, which is a
manufactured form of thyroid hormone, to reduce mis­
carriage risk in women with thyroid autoimmunity
is because of the possible association between thyroid
autoimmunity and subtle hypot­ hyroidism during

pregnancy. Although the incidence of miscarriage is
lower among euthyroid women with thyroid antibodies
who are given levothyroxine than untreated women in a
randomised controlled trial21 and in retrospective
observational studies,49–51 these results are not conclusive.
Previous studies have included euthyroid women with
TSH concentrations at the high end of the normal
range, up to 3·5–5·0 IU/L. When only women with thyro­
peroxidase antibodies and a serum TSH concentration
lower than 2·5 IU/L in the first trimester are included,
the benefit of levothyroxine therapy is uncertain. In a 2016
randomised study,52 levothyroxine therapy decreased the
incidence of miscarriage in women with thyroperoxidase
antibodies (from 14·9% to 11·6%), but this change was
not statistically significant.52 Additionally, a randomised
con­trolled trial53 that enrolled euthyroid and subclinically
hypothyroid women (TSH concentration ≤10 mIU/L)
with thyroid autoimmunity showed that levothyroxine
treatment had no effect on the risk of miscarriage
(3·6% in the group given levothyroxine vs 3·4% in
the untreated group).53 Similarly, a meta-analysis did not
report a significant reduction in the prevalence of
miscarriage in euthyroid women who were positive for
thyroid antibodies and given levothyroxine.54
Guidelines do not definitively recommend or oppose
levothyroxine therapy in euthyroid women who are
positive for thyroid antibodies during pregnancy.1,55
However, two randomised multicentre clinical trials
are ongoing.56,57 In the Thyroid AntiBodies and
LEvoThyroxine (TABLET) trial56 in the UK, euthyroid
women with thyroperoxidase antibodies and a history of
infertility or miscarriage are enrolled to compare
livebirth rates between women given levothyroxine
and women given placebo. The T4Life trial57 in the
Netherlands will assess the effects of levothyroxine
treatment on livebirth rates in euthyroid women who
are pregnant and with a history of recurrent miscarriage.
In the absence of definitive data, our own practice is to
offer low-dose levothyroxine therapy—a low-risk inter­
vention—to euthyroid women who are pregnant and
positive for thyroperoxidase anti­bodies.
The alternative treatment is via intravenous immuno­
globulins. If the fetal loss in euthyroid women who are
antibody positive is explained by underlying generalised
autoimmune activity, intravenous immunoglobulins
should modulate the switch from the Th1 to Th2 cell
response and allow a successful pregnancy.58 Several
studies have examined this treatment, but all have had
substantial limitations.59–61
In a study directly comparing treatment with levo­
thyroxine and intravenous immunoglobulins, higher
livebirth rates were seen in women given levothyroxine
than with intra­venous immunoglobulins.61 ATA guide­
lines recommend against the use of intravenous
immunoglobulins for euthyroid women who are antibody
positive with recurrent miscarriages,1 and we agree that
the evidence for any benefit is insufficient.
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Thyroid autoimmunity and preterm delivery
Preterm delivery is defined as birth occurring before
37 weeks of gestation, whereas very premature delivery is
defined as birth occurring before 34 weeks. In 2013, the
incidence of preterm delivery in the USA was 11·4% and
the incidence of very premature delivery was 3·4%;62 the
European incidence of preterm delivery in 2008 ranged
from 5·5% to 11·1%.63 Preterm births are the leading
cause of perinatal mortality and long-term morbidity.
Some preterm births are due to infection, inflammation,
uteroplacental ischaemia or haemorrhage, or uterine
overdistension. Nevertheless, in most cases, a clear cause
is not known and several risk factors, including thyroid
autoimmunity, have been proposed. The first study to
report an association between thyroid autoimmunity and
premature delivery was published by Glinoer and
colleagues in 1994.10 This study showed that women with
thyroid antibodies had a significantly higher risk for
premature delivery than women without thyroid
antibodies (16% vs 8%; p<0·005). Although subsequent
studies have had inconsistent results, a meta-analysis
published in 2011,30 including five cohort studies,
confirmed an association between the presence of
thyroid antibodies and premature delivery (OR 2·07,
95% CI 1·17–3·68; p=0·01). A 2012 meta-analysis64 of
prospective cohort studies confirmed this association,
reporting that the overall relative risk (RR) of premature
delivery in euthyroid women with thyroid antibodies
was 1·98 (95% CI 1·29–3·04; p=0·002). The pathophysio­
logical mechanisms underlying this association are
unknown but are suspected to include subtly impaired
thyroid function,65 a direct effect of thyroid antibodies or
a more generalised autoimmune dysfunction, or a com­
bination of these factors.
Management of preterm delivery risk in euthyroid
women with thyroid autoantibodies
Levothyroxine treatment has been reported to lower the
risk for preterm delivery in women with thyroid
antibodies in two randomised clinical trials.21,53 However,
one of these studies53 enrolled women with baseline TSH
concen­ trations of up to 10·0 mIU/L, and secondary
analyses showed that the beneficial effect of levothyroxine
was present only in women with TSH concentrations
higher than 4·0 mIU/L. In another trial52 that was
restricted to women with a TSH concentration below
2·5 mIU/L and with thyroperoxidase antibodies, the
participants were randomised into two groups; one
group received levothyroxine (0·5 µg/kg per day of
levothyroxine if TSH concentration was 0·5–1·5 mIU/L
and 1 µg/kg per day if TSH concentration was
1·5–2·5 mIU/L) and the other group was not treated
in the first trimester, but received levothyroxine later
in gestation if their TSH concentration was above
3·0 mIU/L. This study reported that treatment with
levothyroxine had no effect on the risk for preterm
delivery. Thus far, the evidence for or against treatment
 Review
of euthyroid women who are positive for thyroid
antibodies with levothyroxine to prevent preterm delivery
is insufficient.1 The ongoing TABLET trial56 in the UK
will examine preterm birth as a secondary outcome.
Thyroid autoimmunity and infertility
Infertility is the failure to achieve a successful pregnancy
after 12 months of regular unprotected intercourse or
therapeutic donor insemination. Infertility could be due to
both known male (eg, sperm-production disorders or
ejaculatory disturbances) and female (eg, ovulation
disturbances, tuboperitoneal disorders, and endometriosis)
factors, although it could be due to multiple causes or be
un­explained. A meta-analysis36 of four studies reported
that euthyroid women who were positive for thyroid
antibodies had a slightly, but significantly, increased risk of
unexplained infertility compared with those who were
antibody negative (RR 1·47, 95% CI 1·06–2·02). Larger
studies are needed to confirm this finding. Our under­
standing of the association between thyroid auto­immunity
and infertility remains poor because little data on this
subject exist and studies aiming to investigate this
association have enrolled women with different underlying
causes of infertility. For this reason, guidelines do not
recommend levothyroxine to improve the fertility of
euthyroid women with thyroid antibodies who are
attempting a natural conception.1
Pathogenic mechanisms that could underlie the
association between thyroid autoimmunity and infertility
are unclear. Because infertility has multiple causes,
various mechanisms could be involved. The zona
pellucida has been hypothesised to be the target of thyroid
antibodies, since it expresses antigens that are shared by
thyroid tissue.47 Moreover, Monteleone and colleagues66
found thyroid antibodies in the ovarian follicular fluid of
women with thyroid autoimmunity, and showed that
these women had a substantially lower proportion of both
oocyte ferti­lisation and grade-A em­bryos than did women
without thyroid antibodies. Although the incidence of
pregnancy in this study was higher in women who
were antibody negative (43% vs 29%), this difference was
not statistically significant. Monteleone and colleagues
post­ulated that the thyroid antibodies that were detected
in the follicular milieu of the ovulatory follicles could
reduce oocyte quality and fertilisation potential by an
antibody-mediated cytotoxic effect.
Thyroid autoimmunity and assisted reproductive
technology
Several studies have investigated whether thyroid auto­
immunity could affect assisted reproductive tech­nology
outcomes. Studies have enrolled women with different
causes of infertility, undergoing either their first or
subsequent assisted reproductive cycles, and with various
assisted repro­ductive technology protocols, so comparison
between studies can be difficult. The two main outcomes
assessed are typically the proportion of women who have a
580 www.thelancet.com/diabetes-endocrinology Vol 6 July 2018
clinical pregnancy and the proportion who have a
miscarriage. A few small studies67,68 have reported an
association between thyroid autoimmunity and lower
likelihood of pregnancy in women undergoing assisted
reproductive technology cycles. However, most studies in
euthyroid women undergoing assisted repro­ductive cycles
have not found a significantly different likelihood of
pregnancy in women with thyroid anti­bodies,69–72 and three
meta-analyses36,73,74 support an absence of association.
Studies examining the risk of miscarriage in euthyroid
women with thyroid autoimmunity who undergo assisted
reproduction have had conflicting results.68–72,75 However,
two meta-analyses73,74 have shown a significantly increased
risk of miscarriage in women who are positive for thyroid
antibodies who are undergoing assisted reproductive
treatment.73,74 In one of these meta-analyses,74 12 studies
were examined and reported an OR for miscarriage of
1·44 (95% CI 1·06–1·95; p=0·02) in women with thyroid
antibodies compared with those without antibodies. This
association was independent of age and baseline TSH
concentrations. The analysis found no effect from thyroid
antibodies on the mean number of oocytes retrieved or
the likelihood of fertilisation and implantation. Although
data are not definitive, thyroid antibodies seem to have
a more pronounced effect over the course of pregnancy
than on fertilisation potential or implantation capacity.
Treatment of women who are positive for thyroid
antibodies and undergoing assisted reproductive
treatment
Several studies have investigated interventions that are
aimed at improving assisted reproductive technology
outcomes in women who are positive for thyroid anti­
bodies. The beneficial effects of levothyroxine in euthyroid
women with thyroid autoimmunity who are undergoing
assisted reproduction were assessed in a retrospective
study76 and a small randomised clinical trial.77 Neither
study reported improved likelihood of pregnancy or
miscarriage in the women who were given levo­
thyroxine.76,77 In a prospective study,78 intravenous im­
munoglobulins, in addition to aspirin and heparin,
increased the likelihood of birth in women who were
infertile with thyroid autoimmunity compared with a
group of similar women given only aspirin and heparin
(51% vs 27%; p=0·027). Two small randomised clinical
trials79,80 have investigated glucocorticoid treatment in
women with thyroid autoimmunity. The proportion of
clinical pregnancies and births were signi­ficantly higher
in women given prednisolone than women who were
not.79,80 Although positive findings have been reported
with glucocorticoid treatment, larger studies are necessary
to confirm these preliminary data. Additionally, caution is
needed in using corticosteroids in early pregnancy, since
risks in this context are not well understood. Despite the
paucity of evidence, the ATA guidelines suggest that low
doses of levothyroxine should be considered in euthyroid
women who are thyroid antibody positive and undergoing

assisted reproductive treatment. Given that the potential
benefits outweigh the minimal risks, our practice is to
offer patients this option.1
Thyroid autoimmunity and neonatal outcomes
Child neurodevelopment
A link between thyroid autoimmunity in pregnant
women and impaired neurodevelopment in their children
has been reported in several studies.81–86 Children of
euthyroid mothers who have thyroperoxidase antibodies
during the late stage of gestation have been reported to
have lower scores on general cognitive and motor scales
than those of euthyroid mothers without thyroperoxidase
antibodies,81,82 although this finding has not been observed
in all cohorts.83,84
Wasserman and colleagues85 assessed the concen­tration
of thyroperoxidase antibodies of pregnant women during
their third trimester and reported that children of mothers
who were positive for thyroperoxidase antibodies had
lower IQ scores than those of mothers who were negative
for these antibodies.85 The investigators found that this
association was prominent in children at age 4 years and
was attenuated at 7 years. A strong association was found
between sensorineural hearing loss and IQ scores.86 The
investigators speculated that the lower IQ scores in these
children might be mediated by senso­ rineural hearing
loss, since they had previously reported a significant
association between sensorineural hearing loss in children
and high concentrations of maternal thyroperoxidase
antibodies during the third trimester (prevalence OR 7·5,
95% CI 2·4–23·3). A single study84 has shown an increased
risk for externalising problems, in particular attention
deficit hyperactivity disorder, at age 3 years in the children
of mothers who are positive for thyroperoxidase
antibodies.84 However, whether thyroid antibodies have a
direct effect on neurodevelopment, or whether these
effects are mediated by subtle hypothyroidism or a more
generalised autoimmune dysfunction, is still unclear.
Other neonatal complications
Other neonatal complications have been reported in
relation to maternal thyroid autoimmunity, although
these are less well established and require confirmation
in larger prospective studies. Children of mothers who
are positive for thyroperoxidase antibodies have been
reported to have a significantly increased risk for
intrauterine growth retardation, which can probably be
explained by an increased prevalence of preterm births
among these women, and for being large for their
gestational age, which could be mediated by a higher
maternal body-mass index and placental weight.87
However, an association between high concentrations of
maternal thyroperoxidase antibodies and intrauterine
growth retardation has not been found via meta-analysis.88
In one study,87 mothers who were positive for thyroid
antibodies were found to have a significantly greater risk
for perinatal mortality than those who were negative for
www.thelancet.com/diabetes-endocrinology Vol 6 July 2018 581
Review
thyroid antibodies; however, these findings were not
supported by studies done by Abbassi-Ghanavati and
colleagues18 or Negro and colleagues.89 Negro and
colleagues did not find any association between maternal
thyroid antibodies and neonatal complications, except for
a risk of respiratory distress in infants of mothers who
were positive for thyroid antibodies that was three times
higher than offspring of mothers who were negative
for thyroid antibodies—a finding which requires
confirmation in additional studies.89
Thyroid autoimmunity and other maternal
complications
Thyroid autoimmunity has been associated with
post-partum depression and with depression during
pregnancy;90 however, the underlying mechanisms have
not been elucidated. A murine model91 showed no
difference between thyroid hormone concentrations at
the prefrontal cortex in animals with thyroid auto­
immunity, but did show a local reduction in serotonin
and in the brain-derived neurotrophic factor, which
mediate neuroplastic events and are linked to cognitive
and social behaviour. Other hypotheses link depression
to the increased production of proinflam­matory cytokines
in autoimmune disorders.92
A slightly increased risk of gestational diabetes was
reported in one study93 comparing euthyroid women
with thyroperoxidase antibodies with women without
thyroperoxidase anti­bodies (adjusted RR 1·65, 95% CI
1·43–1·92), but a meta-analysis did not find such
an association.94 The best-described late pregnancy com­
plications associated with thyroid autoimmunity are
placental abruption and premature rupture of
membranes. Risk of placental abruption, which is the
premature separation of a normally implanted placenta,
was found to be signi­ ficantly increased in pregnant
women who were positive for thyroperoxidase anti­
bodies compared with those who were negative for
thyroperoxidase antibodies.18 This association was also
reported in the First and Second Trimester Risk of
Aneuploidy (FaSTER) study.95 This observational study
showed an increased risk for placental abruption in
women with thyroperoxidase antibodies. The adjusted
OR for placental abruption among women with
thyroperoxidase antibodies during the first trimester
was 1·78 (95% CI 0·96–3·3) and during the second
trimester it was 2·14 (1·18–3·89). Pregnant women who
were positive for thyroglobulin antibodies had a slightly,
but non-significantly, increased risk for placental
abruption compared with those who were negative for
thyroglobulin antibodies; however, when the patient was
positive for both thyroperoxidase and thyroglobulin
antibodies the risk was even higher, with an OR of
2·10 (95% CI 0·91–4·86) during the first trimester and
2·73 (1·17–6·33) during the second trimester.95 The
FaSTER study also reported an association between
thyroid autoimmunity and premature rupture of
 Review

Association Treatment to prevent the complication

Sporadic miscarriage Association reported Benefit of levothyroxine therapy is uncertain; guidelines do
not recommend for or against treatment
Recurrent miscarriage Association reported, but less robust than that of Benefit of levothyroxine therapy is uncertain; guidelines do
sporadic miscarriage not recommend for or against treatment
Premature delivery Association reported Benefit of levothyroxine therapy is uncertain; guidelines do
not recommend for or against treatment
Infertility Mixed results, association is unclear Not recommended
Failure of assisted reproductive technology No association Benefit of levothyroxine therapy is uncertain; guidelines suggest
considering low-dose levothyroxine treatment, although they
do not recommend glucocorticoid treatment in these women
Impaired newborn neurodevelopment Mixed results, an association seems to be apparent NA
Intrauterine growth retardation Few and mixed results NA
Perinatal mortality Few and mixed results NA
Newborn respiratory distress Few and mixed results NA
Post-partum depression and depression Mixed results, an association seems to be apparent NA
during pregnancy
Gestational diabetes Few and mixed results NA
Placental abruption Mixed results, an association seems to be apparent NA
Premature rupture of membrane Few and mixed results NA
Post-partum thyroiditis Strong association Levothyroxine therapy and iodine supplementation did not
prevent post-partum thyroiditis; selenium supplementation
might be used with caution (see text)

NA=information not available.

Table: Associations of maternal thyroid antibodies with adverse outcomes and efficacy of treatment options for pregnancy and newborn complications

membranes.96 However, this relationship has been
inconsistent in subsequent studies.18,23,97,98
Post-partum thyroiditis
Post-partum thyroiditis is a form of autoimmune thyroid
dysfunction that most frequently occurs in women early
after delivery, around 6 weeks post partum,99 but can
occur up to 12 months post partum. Similar to other
types of thyroiditis, post-partum thyroiditis can present
with a thyrotoxic phase due to the release of stored
thyroid hormones from the thyroid gland, a subsequent
hypothyroid phase, and generally a restoration of
euthyroidism by the end of the first post-partum year.
However, not all women have the classic form of
post-partum thyroiditis, and only 30% of individuals
have been reported to present with a thyrotoxic phase.100
The overall incidence of post-partum thyroiditis is
thought to be around 8%;101 however, women who have
thyroid autoimmunity are at high risk. The presence of
thyroid antibodies during pregnancy is considered to be
one of the best predictors of post-partum thyroiditis.99,102
Women with thyroperoxidase antibodies have been
reported to have a 5·7 times greater risk of developing
post-partum thyroiditis than women without antibodies,101
and, in a prospective study,100 pregnant women who had
thyroid antibodies had an OR of developing post-partum
thyroiditis of 34·1 (95% CI 23·5–49·6). To be a sensitive
predictor, thyroid antibodies must be detected early in
pregnancy, in view of the known immunotolerance that
develops during gestation.102,103 Approximately half of all
women with post-partum thyroiditis will eventually
develop permanent hypothyroidism after the first
post-partum year.100,104
No clinical trials have compared treatment algorithms
for post-partum thyroiditis, including timing and choice
of patients to treat. During the thyrotoxic phase of
post-partum thyroiditis, symptomatic women can be
given β blockers, whereas anti-thyroid drugs are in­
effective. Hypothyroidism is usually mild and transient,
and treatment with levothyroxine should be considered
in women who are symptomatic. After 12 months,
levothyroxine should be tapered and usually can be
discontinued. Checking TSH concentrations annually is
recommended thereafter because of the high risk for
chronic hypothyroidism.100–104
Treatment for the prevention of post-partum
thyroiditis
Some interventional studies have aimed to prevent
post-partum thyroiditis in women with thyroid
antibodies. Treatment with levothyroxine and iodine
during preg­nancy did not reduce the risk of post-partum
thyroiditis in two randomised clinical trials.105,106 In
another trial,107 Negro and colleagues randomly assigned
euthyroid women who were pregnant and who had
thyroperoxidase antibodies to treatment with selenium
200 µg per day or placebo. The study showed a
significantly greater decrease in thyro­peroxidase antibody
concentrations over the course of pregnancy in women
taking selenium compared with women in the placebo

582 www.thelancet.com/diabetes-endocrinology Vol 6 July 2018


Search strategy and selection criteria
We searched PubMed for publications written in English
between 1980 and Aug 11, 2017, using the terms “thyroid
autoimmunity” or “thyroid antibody” combined with the
terms “miscarriage”, “pregnancy loss”, “preterm delivery”,
“premature delivery”, “infertility”, “assisted reproductive
technology”, “child neurodevelopment”, “intrauterine growth
retardation”, “perinatal mortality”, “depression during
pregnancy”, “postpartum depression”, “gestational diabetes”,
“placental abruption”, “premature rupture of membranes”,
“preeclampsia”, “postpartum thyroiditis”, “fetal
hyperthyroidism”, and “neonatal hyperthyroidism”. We also
used the reference lists of the publications identified by the
search strategy and textbooks. Most of the references were
selected from publications in the past 10 years, but we
included relevant older articles.
group. In the post-partum period, thyroperoxidase
antibody concentrations increased in both groups, but
the increase was more dramatic in the placebo group,
whose concentrations were twice as high as those of the
women given selenium. The women who were given
selenium had a significantly lower incidence of thyroid
dysfunction post partum, and of permanent hypo­
thyroidism, than the women who were given placebo.107
However, in a subsequent randomised clinical trial,108
Mao and colleagues compared treatment with selenium
60 µg per day with placebo, and reported that titres of
thyroperoxidase antibodies during pregnancy did not
differ between treatment groups.108 Unfortunately, a clear
comparison of the two studies is not feasible because of
the different enrolment criteria and selenium and iodine
intakes. Selenium has been advocated as a treatment in
patients with thyroid autoimmunity because of its
antioxidant and anti-inflammatory properties. However,
caution should be taken when giving selenium to
patients, since the risk of type 2 diabetes is in­
creased in women who are supple­mented with selenium,
as observed in a randomised clinical trial that included
1200 participants.109 Studies to better ascertain the role
of selenium in thyroid autoimmunity are ongoing,110 but
routine selenium supplementation during pregnancy is
not recommended.
Conclusions
The associations between thyroid autoimmunity and
miscarriage and between thyroid autoimmunity and
premature delivery are supported by convincing evidence,
but the mechanisms of these associations are unknown.
Similarly, uncertainty remains about the association of
thyroid autoimmunity with other obstetric complications
(table). Although some authors recommend screening for
thyroid antibodies during pregnancy, in view of both the
increased risk for the development of hypothyroidism in
pregnant women who are positive for antibodies and their
www.thelancet.com/diabetes-endocrinology Vol 6 July 2018 583
Review
increased risk for adverse obstetric outcomes, we concur
with current guidelines, which state that evidence is
insufficient to recommend for or against universal
screening for thyroid antibodies. However, while awaiting
ongoing trials, we think considering treatment with low
doses of levothyroxine is reasonable for euthyroid women
who are known to have thyroid antibodies during
pregnancy.1,55 Further studies are needed to better
understand the mechanisms underlying the observed
associations of thyroid autoimmunity with adverse
pregnancy outcomes and interventional trials are needed
to establish whether treatment is beneficial.
Contributors
Both authors contributed to the literature search, data analysis, and
data interpretation. SDL was the primary writer, both authors edited
the manuscript.
Declaration of interests
ENP has received honoraria and travel fees from Institut Biochimique SA
and Merck Serono; has consulted for the Scientific Consulting; and was
the recipient of a research grant regarding perchlorate from Sociedad
Química y Minera de Chile S.A. SDL declares no competing interests.
Acknowledgments
We thank Massimiliana Smiraglia for her assistance with the figures.
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