Subclinical Hypothyroidism

S u b c l i n i c a l H y p o t h y ro i d i s m
a n d T h y ro i d A u t o i m m u n i t y
in Pregnancy: To Treat or Not to Treat
a,b c,
Spyridoula Maraka, MD, MS , Chrysoula Dosiou, MD, MS *
KEYWORDS
Thyroid peroxidase antibody Thyroglobulin antibody Euthyroid Hypothyroidism
Pregnancy Levothyroxine Thyroid hormone replacement
KEY POINTS
Subclinical hypothyroidism in pregnancy is associated with adverse maternal and
offspring outcomes.
Current evidence shows obstetrical benefits of levothyroxine treatment of pregnant
women with a thyroid-stimulating hormone (TSH) level greater than 4 mU/L.
Thyroid autoimmunity in women is common and independently associated with infertility
and adverse obstetric outcomes.
Women with thyroid autoimmunity are at risk of developing subclinical/overt
hypothyroidism.
Recent randomized controlled trials do not show obstetrical benefits of levothyroxine
treatment of euthyroid women with thyroid autoimmunity during gestation. There are
not enough data to determine whether treatment of women with TSH 2.5 to 4 mU/L and
thyroid autoimmunity is beneficial or harmful overall or in specific subgroups of women.
INTRODUCTION
Subclinical hypothyroidism (SCH) in pregnancy is defined as the presence of an

elevated maternal thyrotropin (thyroid-stimulating hormone [TSH]) concentration with
a normal free thyroxine (FT4) concentration.1 Guidelines recommend using assay-
specific and trimester-specific reference ranges for TSH and FT4,1 but their availability
is currently unknown. If pregnancy-specific TSH reference ranges are not available, an
a
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine,
University of Askansas for Medical Sciences, 4301 West Markham Street, Slot 587, Little Rock,
AR 72205, USA; b Section of Endocrinology, Medicine Service, Central Arkansas Veterans
Healthcare System, Little Rock, AR, USA; c Division of Endocrinology, Department of Internal
Medicine, Stanford University School of Medicine, Stanford, CA, USA
* Corresponding author. Division of Endocrinology, Department of Medicine, Stanford Univer-
sity School of Medicine, 300 Pasteur Drive, S025, Stanford, CA 94305.
E-mail address: cdosiou@stanford.edu
Endocrinol Metab Clin N Am 53 (2024) 363–376

https://doi.org/10.1016/j.ecl.2024.05.010 endo.theclinics.com
0889-8529/24/ª 2024 Elsevier Inc. All rights are reserved, including those for text and data mining,
AI training, and similar technologies.
Downloaded for Anonymous User (n/a) at R4L.Ghana [CK] from ClinicalKey.com by Elsevier on August 03, 2024.
For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
364 Maraka & Dosiou
upper reference limit of 4.0 mU/L may be used.1 Depending on the TSH cutoff, the
prevalence of SCH in pregnancy varies significantly (1.2%–42.9%).2 SCH has been
associated with adverse maternal and offspring outcomes, but the effectiveness of lev-
othyroxine (LT4) treatment to improve outcomes is not well established.3
Thyroid autoimmunity, defined as antibodies against thyroid peroxidase (TPOAb) or
thyroglobulin (TGAb), affects approximately 11% of reproductive-age women.4 In this
discussion, we will not address autoimmunity against the TSH receptor, as the focus is
on autoimmunity associated with hypothyroidism. Overall, 5% to 14% of women have
TPOAb, 3% to 18% have TGAb,5 while 10% have antibodies against both antigens.6
Antibody positivity and titers are positively associated with TSH increase in preg-
nancy.7 The risk of both overt hypothyroidism (OH) and SCH in pregnancy is highest
in the presence of both autoantibodies (odds ratio [OR] 44.69 [95% confidence interval
(CI) 23.47–85.10] for OH, OR 6.26 [95% CI 4.29–9.13] for SCH) and is highly associ-
ated with the antibody titer.8 Thyroid autoimmunity has been independently associ-
ated with adverse pregnancy outcomes and the effectiveness of LT4 treatment has
been studied in recent randomized controlled trials (RCTs).
This review discusses the best available evidence on the impact of SCH and thyroid
autoimmunity on pregnancy and the effect of LT4 treatment.
DISCUSSION
Subclinical Hypothyroidism
Impact of subclinical hypothyroidism on maternal and offspring outcomes
Thyroid hormones regulate key metabolic and anabolic processes in both mother and
fetus throughout pregnancy.9,10 SCH has been associated inconsistently with an
increase in the risk of adverse pregnancy and offspring outcomes in individual observa-
tional studies.3 In a systematic review and meta-analysis of 18 cohort studies
comparing approximately 4000 pregnant women with SCH to euthyroid women,
women with SCH were more likely to have pregnancy loss, placental abruption, prema-
ture rupture of membranes, and neonatal death.3 However, there were significant differ-
ences in how SCH was defined and the gestational age at thyroid function screening,
which could significantly influence the results. Moreover, common limitations of obser-
vational studies include lack of sample representation (nonpopulation-based studies)
and lack of adjustment for important confounders.3 Recently, individualized participant
data (IPD) meta-analyses of prospective cohorts of pregnant women have allowed to
uniformly define thyroid dysfunction and perform rigorous statistical analyses,
increasing our confidence in the estimate results.
An IPD meta-analysis of 19 prospective cohort studies including 47,045 pregnant
women found that SCH was associated with preterm birth (absolute risk difference
1.4% [95% CI 0.0–3.2]; OR 1.29 [95% CI 1.01–1.64]), but not with very preterm birth
(gestational age <32 weeks) compared with euthyroidism.11 Sensitivity analysis
showed that the association of SCH with preterm birth was no longer apparent after
additional adjustment for TPOAb positivity, suggesting that it is the TPOAb positivity
that underlies any associations of SCH with preterm birth. Another IPD meta-
analysis of 19 prospective cohort studies showed that among 39,826 pregnant
women, SCH was associated with a higher risk of preeclampsia (3.6% vs 2.1%; OR
1.53 [95% CI 1.09–2.15]) compared with euthyroidism.12 In continuous analyses,
both a higher and a lower TSH concentration were associated with a higher risk of pre-
eclampsia. Given the absence of clinical trials on the effects of different TSH treatment
targets on adverse pregnancy outcomes, these indirect data suggest that an optimal
TSH target for treatment could be in the middle of the reference range and highlight the
SCH and Thyroid Autoimmunity in Pregnancy 365
relevance of monitoring thyroid function during pregnancy in women treated with LT4
to avoid undertreatment or overtreatment. Both IPD meta-analyses were adjusted for
important confounders (maternal age, body mass index [BMI], ethnicity, smoking, par-
ity, gestational age at sampling, and fetal sex).11,12 Moreover, an IPD meta-analysis of
20 prospective cohort studies including 48,145 mother–child pairs found that SCH
was associated with a higher risk of small for gestational age compared with euthyr-
oidism (absolute risk difference 2.4% [95% CI 0.4–4.8]; OR 1.24 [95% CI 1.04–1.48])
and lower mean birthweight (adjusted risk difference -38 g [95% CI 61 to 15]).13
Analysis was adjusted for maternal age, BMI, ethnicity, smoking, parity, gestational
age at sampling, fetal sex, and gestational age at birth. Interestingly, the authors found
an inverse, dose–response relationship of maternal FT4 (even within the normal range)
with birthweight, where higher FT4 concentration was associated with lower birth-
weight. This result also prompts for careful consideration of potential risks of LT4 ther-
apy and overtreatment during pregnancy.
Finally, of special interest is the potential impact of SCH on the neurodevelopment
of the offspring. An aggregate meta-analysis of 11 cohort studies showed that SCH
was associated with higher risk for child intellectual impairment (OR 2.14 [95% CI
1.20–3.83]) compared with euthyroidism.14 Another aggregate meta-analysis of 15
cohort studies found that SCH in pregnancy was significantly associated with lower
score on mental developmental index (relative risk [RR] 6.08 [95% CI 9.57 to
2.58]) and psychomotor developmental index (RR 7.29 [95% CI 10.30 to
4.28]) of the offspring compared with euthyroid women’s offspring at 12 to 30 months
of age.15 However, an IPD meta-analysis of 3 prospective population-based birth
cohort studies including 9036 mother–child pairs showed that maternal TSH in early
pregnancy was not independently associated with nonverbal intelligence quotient
(IQ) at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, or autistic traits at 5 to
8 years of age (adjusted for maternal age, educational level, ethnicity, parity, prepreg-
nancy BMI, smoking, gestational age at sampling, and child sex).16
Effects of treatment on maternal and offspring outcomes

Although SCH has been associated with multiple adverse maternal and offspring out-
comes, the important question is whether LT4 treatment is effective in reducing the
risk for these adverse outcomes.
A prospective study comparing the ability of universal screening versus case-finding
to detect thyroid dysfunction provided indirect evidence.17 Based on the presence of
risk factors for thyroid dysfunction, 4562 women were randomized by the 11th week
of pregnancy to universal screening versus case-finding. Women in the universal
screening arm were checked for thyroid dysfunction and started on LT4 therapy if
they had TSH greater than 2.5 mU/L and were TPOAb1. In the case-finding arm, only
high-risk women were checked, whereas the low-risk group had their stored serum
analyzed at the end of pregnancy, resulting in 34 women with hypothyroidism remaining
untreated. There was no significant difference between the composite endpoint of
adverse obstetrical and neonatal outcomes in the universal screening vs the case-
finding group. Considering only the cohorts of low-risk women, complications were
less likely among women in the universal screening than those in the case-finding group
(OR 0.43 [95% CI 0.26–0.70]), driven by the events that happened to the untreated pa-
tients with hypothyroidism.
Since then, multiple RCTs have assessed the effects of LT4 treatment on maternal
and offspring outcomes (Table 1). In the controlled antenatal thyroid screening
(CATS) study, 21,846 women were randomized at a median of 12 weeks 3 days of
gestation to a group screened for thyroid dysfunction or to a control group who had their
366
Maraka & Dosiou

Table 1
Summary of the outcomes from randomized controlled trials of levothyroxine treatment of subclinical hypothyroidism during pregnancy
Nazarpour Casey Nazarpour Hales et al,19 Nazarpour

Study Characteristics Lazarus et al,18 2012b et al,22 2017 et al,20 2017 et al,21 2018 2018b et al, 2023
Country United Kingdom Iran United States Iran United Kingdom Iran
and Italy and Italy
LT4 group (N 5) 186 56 339 183 63 189
Control group (N 5) 197 58 338 183 51 168
Population TSH >97.5th percentile TSH 2.5–10 mU/L TSH 4.0 mU/L TSH 2.5–10 mU/L TSH >97.5th percentile TSH 2.5–10 mU/L
FT4 2.5 percentile Normal FT4 index Normal FT4 Normal FT4 index FT4 2.5th percentile Normal FT4 index
TPOAb1 TPOAb
Maternal outcomes
Pregnancy lossa N/A - - - N/A N/A
Preterm delivery N/A U - Uc N/A N/A
Placental abruption N/A - - - N/A N/A
Gestational diabetes N/A N/A - N/A N/A N/A
Gestational N/A N/A - N/A N/A N/A
hypertension N/A N/A - N/A N/A N/A
Preeclampsia
Neonatal/offspring outcomes
Neonatal birth weight N/A - - - N/A N/A
Head circumference N/A - - - N/A N/A
Neonatal admission N/A U - - N/A N/A
Apgar score N/A N/A - N/A N/A N/A
Neonatal death N/A N/A - N/A N/A N/A
Offspring IQ - N/A - N/A - N/A
Development/behavior - N/A - N/A N/A -
UPositive effect, -, Neutral effect

Abbreviations: FT4, free thyroxine; LT4, levothyroxine; N/A, not assessed; SCH, subclinical hypothyroidism; TPOAb, thyroid peroxidase antibody; TSH, thyroid-
stimulating hormone.
a
Includes miscarriage and stillbirth.
b
These studies investigated the effect of LT4 on pregnant women with TSH >97.5th percentile, FT4 <2.5th percentile, or both; we present the data on the sub-
group with SCH.
c
The positive effect was significant in the subgroup who had TSH 4 to 10 mU/L.
stored serum analyzed at the end of pregnancy (untreated).18 Treatment with 150 mcg
of LT4 was started at a median of 13 weeks 3 days of gestation in screened women
found to have a TSH level greater than 97.5th percentile, an FT4 level less than 2.5th
percentile, or both. Treatment was adjusted to achieve a target TSH of 0.1 to 1.0 mU/
L. There was no difference between groups in the IQ of children at 3 years of age (treated
mean IQ 99 vs untreated mean IQ 100) and the percentage of children with IQ less than
85. A subgroup analysis including only women with SCH had similar results. Study lim-
itations included the late initiation of LT4 therapy (possibly too late in gestation to have a
major influence on brain development), the relatively high, fixed LT4 dosing that could
have negatively impacted IQ, the questionable accuracy of IQ testing in 3 year old chil-
dren, and inadequate power to detect subtle differences in cognition. Data from the
CATS-II study showed that LT4 therapy did not improve child cognition at age 9.5 years,
confirming long term the CATS study results.19 In another multicenter RCT, pregnant
women with SCH (TSH >4.0 mU/L, normal FT4 levels) were randomized to LT4 treat-
ment versus placebo.20 There was no benefit of LT4 treatment regarding offspring IQ
at 5 years, selected adverse pregnancy outcomes (preterm delivery, gestational hyper-
tension, preeclampsia, gestational diabetes, and placental abruption), and adverse
neonatal outcomes (neonatal death, low Apgar score, admission to the neonatal inten-
sive care unit, low birth weight, and congenital malformations). A post hoc analysis
found no significant interaction according to TPOAb level. However, LT4 therapy was
initiated at 17 weeks of gestation on average. Due to the late randomization, the study
was not able to adequately assess the outcome of miscarriage. Another single-blinded
RCT showed that there was no beneficial effect of LT4 therapy in reducing preterm de-
livery in SCH TPOAb women with TSH of 2.5 to 10.0 mU/L.21 However, a subgroup
analysis showed that LT4 could decrease this complication using a TSH cutoff greater
than 4.0 mU/L (RR 0.38 [95% CI 0.15–0.98]; P 5 .04). Similarly, the Tehran Thyroid and
Pregnancy Study showed a 70% and 83% decrease in preterm delivery and neonatal
hospital admissions, respectively, in LT4-treated pregnant women who were TPOAb1
compared with untreated women (TSH 2.5–10.0 mU/L).22 Subgroup analysis showed
that the benefit of LT4 treatment was observed only among TPOAb1 women with
TSH greater than 4.0 mU/L. A follow-up of these trials showed that there was no differ-
ence in the neurodevelopmental score of offspring at 3 years in mothers with SCH ran-
domized to LT4 treatment versus no treatment.23
With regard to pregnancy loss, the best available evidence is from a US national
cohort study, which compared 843 pregnant women with SCH who received thyroid
hormone treatment with 4562 women who remained untreated.24 The study showed
that LT4 therapy was not only associated with decreased risk of pregnancy loss
(OR 0.45 [95% CI 0.30–0.65]) but also with higher risk of preterm delivery (OR 1.60
[95% CI 1.14–2.24]), gestational diabetes (OR 1.37 [95% CI 1.05–1.79]), and pre-
eclampsia (OR 1.61 [95% CI 1.10–2.37]). A stratified analysis showed that the treated
women with a higher TSH level (4.1–10 mU/L) were the ones who had the benefit of
fewer pregnancy losses and not the ones with milder TSH elevation (2.5–4.0 mU/L).
This lack of benefit together with the noted risk of adverse events raised the concern
of possible overtreatment of women with TSH 2.5 to 4.0 mU/L. Study limitations
included the retrospective observational design, the potential for misclassification of
treatment and confounders, lack of data on gestational age at initiation of LT4 therapy
and TPOAb status, and possible selection bias.
Thyroid Autoimmunity
Two significant physiologic events affect the phenotype of thyroid autoimmunity dur-
ing pregnancy. First, the pregnant state poses a “stress test” for the thyroid, due to a
368 Maraka & Dosiou
number of changes that cause an increased demand for thyroid hormone by up to

50% by midgestation.25 Women who are already on thyroid hormone prepregnancy
need to therefore increase their dose,26–28 while euthyroid women with autoimmunity
have a 16% to 19% risk of developing hypothyroidism.6,29 Higher baseline TSH and
TPOAb titers are associated with greater risk.6 Second, progesterone induces a state
of immunotolerance, shifting the immune response from a Th1 to a more dominant Th2
profile, while increasing the population of regulatory T cells.30 Consequently, thyroid
antibody titers decrease during gestation,31 by an average of 60%.6,29 The reverse
happens in the postpartum phase, where the sudden drop in progesterone results
in flares of autoimmune disease, manifesting as postpartum thyroiditis in 50% of
women.32,33 These changes influence disease presentation as well as the levels of thy-
roid autoantibodies.
Impact of thyroid autoimmunity on obstetrical outcomes and potential mechanisms

Thyroid autoimmunity is independently associated with an increased risk of infer-
tility,34 low ovarian reserve,35,36 and lower live birth rates,37 as well as obstetrical
and fetal complications, even in the absence of overt thyroid dysfunction. In a land-
mark article in 1990, Stagnaro-Green and colleagues first described the association
of thyroid autoimmunity with spontaneous miscarriage.38 Meta-analyses of more
than 10 cohort studies have confirmed a 2 to 4 fold increase in risk of mostly first
trimester miscarriage in the presence of thyroid autoimmunity.39,40 The effect of auto-
immunity appears to be additive to that of TSH elevation alone.41 Thyroid autoimmu-
nity is also associated with an increased risk for recurrent miscarriages,42 4 fold
increase in the incidence of placental abruption,43 and an increased risk of preterm
birth.11,39,41 Traditionally, these risks have been predominantly thought to be due to
a relative thyroid hormone insufficiency at the level of the placental-fetal unit, due to
limited thyroidal reserve. This possibility was supported by the observation that sup-
plementation with thyroid hormone improved obstetric outcomes in initial RCTs17,29 as
well as the fact that TPOAb positivity blunts the normal thyroidal response to human
chorionic gonadotropin (HCG).44 Alternatively, the antibodies themselves may be
directly pathogenic to ovarian antigens45 or be a marker of more generalized autoim-
munity that adversely affects pregnancy success.46 The antibodies may also directly
affect oocyte health, as studies of women undergoing assisted reproductive technol-
ogy (ART) have shown that the quality of the embryos obtained from oocytes of
TPOAb1 women is inferior to that obtained from TPOAb women.47
Effects of treatment on obstetrical outcomes

Prior to the latest American Thyroid Association (ATA) clinical guidelines for the man-
agement of thyroid disease in pregnancy,1 2 RCTs from Italy investigated the effect of
LT4 on obstetrical outcomes in euthyroid women with thyroid autoimmunity. A 2006
RCT of 115 TPOAb1 euthyroid patients (TSH <4.2 mU/L) showed a beneficial effect
of LT4 treatment on reducing miscarriage rates from 13.8% to 3.5% and preterm de-
livery rates from 22.4% to 7%.29 A follow-up RCT study of 393 women with thyroid
autoimmunity and a TSH less than 2.5 mU/L, showed that LT4 had no effect on
miscarriage or preterm delivery rates.48 A limitation of the second study was that
49% of women in the control group were also treated with LT4 starting in the second
or third trimester (per protocol design, treatment was initiated if TSH rose to >3 mU/L);
this could have skewed results toward the null hypothesis.
Since 2017, 3 large RCTs have failed to show an obstetrical benefit of LT4 supple-
mentation in euthyroid patients with thyroid autoimmunity (POSTAL,49 TABLET,50 and
T4LIFE51; Table 2). The TABLET trial showed that 952 women with a history of
Table 2
Randomized controlled trials of levothyroxine impact on obstetrical outcomes in euthyroid women with thyroid autoimmunity
Trial, Year Negro et al,29 2006a Negro et al,48 2016 POSTAL,49 2017 TABLET,50 2019c T4LIFE,51 2022d
Location Italy Italy China United Kingdom Netherlands, Belgium,
and Denmark
N 115 393 600 952 187e
Population All pregnant women, All pregnant women, Undergoing IVF, h/o miscarriage or h/o RPL, conceiving
TPOAb >100 kIU/L, TPOAb >16 IU/mL excluded RPL, infertility, conceiving both naturally and
TSH 0.27–4.2 mU/L, TSH 0.5–2.5 mU/L, TPOAb >60 IU/mL, naturally or with ART, with ART, TPOAb
control 5 no control 5 no treatmentb TSH 0.5–4.78 mU/L, TPOAb greater than greater than
treatment control 5 no treatment individual laboratory individual laboratory
thresholds, TSH thresholds, TSH
0.44–3.63 mU/L, within individual
control 5 placebo laboratory ref range,
control 5 placebo
SCH and Thyroid Autoimmunity in Pregnancy

Clinical pregnancy (%)
Control NA NA 37.7 58.3 78
LT4 NA NA 35.7 56.6 73
Miscarriage (%)
Control 13.8 14.9 10.6 29.6 33
LT4 3.5* 11.6 10.3 28.2 23
Live birth (%)
Control NA NA 32.3 37.9 48
LT4 NA NA 31.7 37.4 50
Preterm delivery (%)
Control 22.4 10.8 19.6 NA 4
LT4 7.0* 6.9 22.1 NA 6
(continued on next page)
369
370
Maraka & Dosiou

Table 2
(continued )
Trial, Year Negro et al,29 2006a Negro et al,48 2016 POSTAL,49 2017 TABLET,50 2019c T4LIFE,51 2022d
TSH, prepregnancy Median (IQR) Mean (SD) Median (IQR)
(mU/L)
Control NA NA 2.12 (1.50, 2.80) 0.652 (0.418) 2.00 (1.36, 2.70)
LT4 NA NA 2.94 (2.04, 3.74) 0.674 (0.422) 2.10 (1.40, 3.11)
TSH trimester 1 (mU/L) Mean (SD) Mean (SD) — Mean (SD) Median (IQR)
Control 1.7 (0.5) 1.37 (0.5) NA 0.573 (0.766) 1.79 (1.30, 2.68)
LT4 1.6 (0.5) 1.42 (0.5) NA 0.141 (0.967)* 1.37 (0.65, 2.16)**
TSH trimester 2 (mU/L) Mean (SD) Mean (SD) — Mean (SD) Median (IQR)
Control 2.3 (0.5) 1.8 (0.8) NA 0.385 (0.626) 1.90 (1.14, 2.40)
LT4 1.1 (0.4)* 1.23 (0.5)* NA 0.177 (0.634)* 1.52 (0.92, 1.93)**
TSH trimester 3 (mU/L) Mean (SD) Mean (SD) — Mean (SD) —
Control 2.5 (0.6) 2.49 (1.1) NA 0.327 (0.519) NA
LT4 1.2 (0.4)* 1.47 (0.8)* NA 0.123 (0.552)* NA
Primary trial outcome in bold. Difference between control and LT4 groups not statistically significant unless indicated by * (P < .05). For **, study text indicates
value is lower than control but does not provide statistics.
Abbreviations: ART, assisted reproductive technologies; IQR, interquartile range; IVF, in vitro fertilization; LT4, levothyroxine; RPL, recurrent pregnancy loss; SD,
standard deviation; TPOAb, thyroid peroxidase antibody; TSH, thyroid-stimulating hormone.
Power calculations.
Negro 2016: N 5 318 needed to detect a 50% decrease in miscarriage (from 24% to 12%).
POSTAL: N 5 600 needed to have 80% power to detect a 50% decrease in miscarriage rates (from 30% to 15%).
TABLET: N 5 900 needed to have 80% power to detect 10% difference in live birth rates (from 55% to 65%).
T4LIFE: N 5 240 needed to have 80% power to detect 20% difference in live birth rates (from 55% to 75%).
a
Study did not define a primary outcome.
b
49% of “no treatment” group received treatment with LT4 starting in trimesters 2 or 3, when TSH >3.0 mU/L.
c
10% discontinued trial agent because of abnormal TFTs.
d
9% discontinued trial because of hypothyroidism.
e
Trial stopped prematurely, not meeting recruitment goals.
miscarriage or subfertility randomized to 50 mcg LT4 preconception and throughout

pregnancy had no difference in live births after 34 weeks.50 Similar data were obtained
in the POSTAL trial,49 which randomized 600 subfertile women undergoing ART, and
the T4LIFE trial,51 investigating the effect of LT4 in 187 women with recurrent miscar-
riage history. All 3 RCTs had significant limitations, such as studying very specific yet
varied populations of women, limited power to detect clinically relevant differences in
important subgroups, and including women with borderline thyroid autoimmunity and
TSH in the lower range of normal, which might have diluted the potential benefit of LT4
(see Table 2). In fact, median TSH was well below 2.5 mU/L at enrollment and stayed
less than 2.5 mU/L in all trimesters in the studies that checked serial values, while the
mean TSH was less than 0.7 mU/L at enrollment and stayed less than 0.6 mU/L
throughout pregnancy in the placebo group in the TABLET study.50 Thyroid antibody
titers were assessed with 22 different assays in the TABLET trial and 15 assays in the
T4LIFE trial and all borderline or indeterminate values were considered positive. This
could have resulted in misclassification of patients without true thyroid autoimmunity
in the study group, biasing results toward the null hypothesis. Nevertheless, the recent
RCTs suggest that relative thyroid insufficiency is not the only mechanism at play in
euthyroid women with thyroid autoimmunity, but there are likely multiple pathogenetic
pathways involved, in different patient populations, and depending on the severity of
the thyroid destruction.
The TABLET, POSTAL and T4LIFE RCTs, despite their limitations, all show that
treatment of euthyroid TPOAb1 women with TSH less than 2.5 mU/L and history of
infertility, miscarriage, RPL, or undergoing ART do not benefit from LT4 treatment.
The results are consistent with prior ATA pregnancy guidelines that do not support
treatment of this population and in fact do not recommend TPOAb testing for TSH
less than 2.5 mU/L.1 It is important to note, however, that these studies do not have
sufficient data to address the effect of treatment in women with TSH 2.5 to 4.0 mU/
L, or in certain subsets such as women with spontaneous pregnancy versus ART,
women with very high TPOAb titers, or women with limited thyroid reserve. In fact, a
recent meta-analysis showed that LT4 treatment reduced the risk of pregnancy loss
(RR 0.61 [95% CI 0.39–0.96]) and preterm birth (RR 0.49 [95% CI 0.30–0.79]) in women
with thyroid autoimmunity undergoing natural conception but not in pregnancies
achieved through ART (RR 0.68 [95% CI 0.40–1.15] and RR 1.20 [95% CI 0.68–
2.13], respectively).52 Another meta-analysis raises the possibility that only women
with high TPOAb titers might be at risk for miscarriage and therefore benefit from treat-
ment. Miscarriage rates were not elevated in women when a TPOAb cutoff of greater
than 34 IU/mL was used to define positivity (RR 0.61 [95% CI 0.35–1.08]) while they
were significantly elevated when a cutoff of greater than 100 IU/mL was used (RR
2.12 [95% CI 1.52–2.96]).53 There could also be a subgroup of women in whom thyroid
autoimmunity causes a limited thyroid reserve, and who would thus benefit from LT4
treatment. In a study of patients with thyroid autoimmunity and preterm delivery, the
FT4 response to HCG was found to be associated with the risk for preterm delivery.
TPOAb1 women who had an expected FT4 response to HCG did not have increased
rates of preterm delivery (OR 0.56), whereas those with suboptimal response to HCG
had an OR greater than 2 for preterm delivery.44 It is possible that LT4 treatment would
benefit the latter group, but not the former. Finally, the follow-up to the TABLET trial
has yielded some important information regarding the risk of developing hypothyroid-
ism in women with thyroid autoimmunity in the short term and the implications of lack
of treatment. When the TABLET participants were followed for 1 year after enrollment,
7.4% developed SCH or OH (27 out of 470 in the LT4 group vs 43 out of 470 in the
placebo group): 84% preconception (most in the first 3 months) and 16% in the first
372 Maraka & Dosiou
trimester of pregnancy.54 Baseline TSH and TPOAb levels were predictive of the
development of SCH/OH (TSH 3 mU/L in patients who developed SCH/OH vs 2
mU/L in those who didn’t, TPOAb 213 IU/mL vs 182 IU/mL), while LT4 treatment pre-
conception reduced the occurrence of SCH/OH by 40%.54 In subgroup analysis, the
group of women with untreated SCH (N 5 20) was found to have a lower chance of live
birth compared with the group of women with treated SCH/OH (N 5 50; RR 0.31 [95%
CI 0.10–0.91]).54 Given the earlier data suggesting that the population of euthyroid
women with thyroid autoimmunity is not uniform, as well as the limitations of existing
RCTs, further studies are needed to identify the subsets of euthyroid TPOAb1 women
that may benefit from LT4 treatment during pregnancy.
Treatment Recommendations/Considerations
The most recent clinical guidelines recommend treatment of all pregnant women with
OH and pregnant women with SCH with TSH greater than 10 mU/L, with a goal TSH
between the lower limit of the trimester-specific reference range and 2.5 mU/L.1 For
women with TSH less than 10 mU/L, the American Congress of Obstetricians and Gyne-
cologists does not recommend treatment55 and the ATA recommendations depend on
the TPOAb status.1 For women with TPOAb positivity, LT4 treatment is recommended
for TSH between the upper limit of pregnancy-specific reference range (ULRR) and 10
mU/L and is to be considered for TSH between 2.5 mU/L and the ULRR. In women
without thyroid autoimmunity, they recommend to consider treatment in those with
TSH between the ULRR and 10 mU/L.1 Our opinion is that LT4 treatment of all pregnant
women with TSH greater than 4 mU/L is justified based on the evidence we presented in
this review. For euthyroid women with thyroid autoimmunity further research is needed
to identify whether there are certain subgroups that may benefit from LT4 therapy.
In addition to treatment algorithms, awareness of TPOAb positivity is critical in
pregnancy. For TPOAb1 women who are euthyroid prepregnancy, knowledge of the
underlying autoimmunity allows for appropriate monitoring for the development of hy-
pothyroidism preconception, during pregnancy, and in the postpartum phase. Moni-
toring thyroid function every 3 months preconception can promptly diagnose SCH/
OH, if it occurs. During pregnancy, ATA guidelines recommend thyroid function moni-
toring every 4 weeks until midgestation, while therapy with LT4 should be initiated if
SCH/OH develops.1 These women should also be educated about the possibility of
postpartum thyroiditis and have thyroid function assessed at regular intervals in the
postpartum year.1 Importantly, women with Hashimoto’s disease who undergo ART
can have significant alterations in thyroid tests in the process and before conception,
as a result of the hormonal preparations needed in their fertility cycles.56,57 Evaluation
of thyroid function should be performed ideally before hormonal manipulation starts or
a few weeks after controlled ovarian hyperstimulation, as the results at other times
may be difficult to interpret.1
SUMMARY AND FUTURE DIRECTIONS
SCH is associated with adverse maternal and offspring outcomes. LT4 has been
shown to improve pregnancy outcomes in women with TSH greater than 4 mU/L,
but this effect was not found in RCTs with mean gestational age at randomization
after the first trimester. Thyroid autoimmunity is associated with infertility and adverse
obstetric outcomes independent of thyroid dysfunction. Existing studies, however, do
not offer definitive answers for the potential benefit of treatment of euthyroid women
with thyroid autoimmunity. Nevertheless, recent RCTs suggest that there is no clear
obstetrical benefit to treating women with TSH less than 2.5 mU/L. To develop new
evidence-based recommendations for patients with TSH 2.5 to 4.0 mU/L who are
TPOAb1, further studies are needed to determine:
a. what are the effects of LT4 on obstetrical outcomes in patients with thyroid auto-
immunity and TSH 2.5 to 4.0 mU/L?
b. Are there different outcomes in patients with high TPOAb levels?
c. Are there different outcomes in spontaneous versus ART pregnancies?
d. What factors predict the development of SCH/OH during gestation in women with
thyroid autoimmunity?
e. Are there ways to assess thyroidal reserve preconception?
A starting point could be to combine IPD from the TABLET, POSTAL, and T4LIFE
trials for analysis, as recruitment for large RCTs in pregnancy is challenging. In addi-
tion, it would be useful to develop a way to test the adequacy of thyroid reserve in
patients with thyroid autoimmunity in efforts to predict which patients would be able
to mount an appropriate HCG response to fulfill the demands of pregnancy.
CLINICS CARE POINTS
Women with SCH should be treated with LT4 if TSH is greater than 4.0 mU/L.
Women with thyroid autoimmunity should be monitored with regular thyroid function tests
preconception and during gestation.
Further research is needed to identify whether there are subgroups of euthyroid women
with thyroid autoimmunity who may benefit from LT4 therapy.
DISCLOSURE
The authors have nothing to disclose.
REFERENCES
1. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thy-
roid Association for the Diagnosis and Management of Thyroid Disease During
Pregnancy and the Postpartum. Thyroid 2017;27(3):315–89.
2. Dong AC, Stagnaro-Green A. Differences in Diagnostic Criteria Mask the True
Prevalence of Thyroid Disease in Pregnancy: A Systematic Review and Meta-
Analysis. Thyroid 2019;29(2):278–89.
3. Maraka S, Ospina NM, O’Keeffe DT, et al. Subclinical Hypothyroidism in Preg-
nancy: A Systematic Review and Meta-Analysis. Thyroid 2016;26(4):580–90.
4. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid anti-
bodies in the United States population (1988 to 1994): National Health and Nutrition
Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87(2):489–99.
5. De Leo S, Pearce EN. Autoimmune thyroid disease during pregnancy. Lancet
Diabetes Endocrinol 2018;6(7):575–86.
6. Glinoer D, Riahi M, Grun JP, et al. Risk of subclinical hypothyroidism in pregnant
women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol
Metab 1994;79(1):197–204.
7. Bliddal S, Derakhshan A, Xiao Y, et al. Association of Thyroid Peroxidase Anti-
bodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An In-
dividual Participant Data Meta-Analysis. Thyroid 2022;32(7):828–40.
374 Maraka & Dosiou
8. Sun J, Teng D, Li C, et al. Association between iodine intake and thyroid autoan-
tibodies: a cross-sectional study of 7073 early pregnant women in an iodine-
adequate region. J Endocrinol Invest 2020;43(1):43–51.
9. Fowden AL, Forhead AJ. Endocrine mechanisms of intrauterine programming.
Reproduction 2004;127(5):515–26.
10. Bernal J, Nunez J. Thyroid hormones and brain development. Eur J Endocrinol
1995;133(4):390–8.
11. Consortium on Thyroid and Pregnancy-Study Group on Preterm Birth, Korevaar T,
Derakhshan A, Taylor PN, et al. Association of Thyroid Function Test Abnormal-
ities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and
Meta-analysis. JAMA 2019;322(7):632–41.
12. Toloza FJK, Derakhshan A, Mannisto T, et al. Association between maternal thyroid
function and risk of gestational hypertension and pre-eclampsia: a systematic re-
view and individual-participant data meta-analysis. Lancet Diabetes Endocrinol
2022;10(4):243–52.
13. Derakhshan A, Peeters RP, Taylor PN, et al. Association of maternal thyroid func-
tion with birthweight: a systematic review and individual-participant data meta-
analysis. Lancet Diabetes Endocrinol 2020;8(6):501–10.
14. Thompson W, Russell G, Baragwanath G, et al. Maternal thyroid hormone insuf-
ficiency during pregnancy and risk of neurodevelopmental disorders in offspring:
A systematic review and meta-analysis. Clin Endocrinol (Oxf) 2018;88(4):575–84.
15. Liu Y, Chen H, Jing C, et al. The Association Between Maternal Subclinical Hypo-
thyroidism and Growth, Development, and Childhood Intelligence: A Meta-anal-
ysis. J Clin Res Pediatr Endocrinol 2018;10(2):153–61.
16. Levie D, Korevaar T, Mulder TA, et al. Maternal Thyroid Function in Early Pregnancy
and Child Attention-Deficit Hyperactivity Disorder: An Individual-Participant Meta-
Analysis. Thyroid 2019;29(9):1316–26.
17. Negro R, Schwartz A, Gismondi R, et al. Universal screening versus case finding
for detection and treatment of thyroid hormonal dysfunction during pregnancy.
J Clin Endocrinol Metab 2010;95(4):1699–707.
18. Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and child-
hood cognitive function. N Engl J Med 2012;366(6):493–501.
19. Hales C, Taylor PN, Channon S, et al. Controlled Antenatal Thyroid Screening II:
Effect of Treating Maternal Suboptimal Thyroid Function on Child Cognition. J Clin
Endocrinol Metab 2018;103(4):1583–91.
20. Casey BM, Thom EA, Peaceman AM, et al. Treatment of Subclinical Hypothyroid-
ism or Hypothyroxinemia in Pregnancy. N Engl J Med 2017;376(9):815–25.
21. Nazarpour S, Ramezani Tehrani F, Simbar M, et al. Effects of Levothyroxine on
Pregnant Women With Subclinical Hypothyroidism, Negative for Thyroid Peroxi-
dase Antibodies. J Clin Endocrinol Metab 2018;103(3):926–35.
22. Nazarpour S, Ramezani Tehrani F, Simbar M, et al. Effects of levothyroxine treat-
ment on pregnancy outcomes in pregnant women with autoimmune thyroid dis-
ease. Eur J Endocrinol 2017;176(2):253–65.
23. Nazarpour S, Ramezani Tehrani F, Sajedi F, et al. Lack of beneficiary effect of lev-
othyroxine therapy of pregnant women with subclinical hypothyroidism in terms of
neurodevelopment of their offspring. Arch Gynecol Obstet 2024;309(3):975–85.
24. Maraka S, Mwangi R, McCoy RG, et al. Thyroid hormone treatment among preg-
nant women with subclinical hypothyroidism: US national assessment. BMJ 2017;
356:i6865.
25. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J
Med 1994;331(16):1072–8.
26. Mandel SJ, Larsen PR, Seely EW, et al. Increased need for thyroxine during preg-
nancy in women with primary hypothyroidism. N Engl J Med 1990;323(2):91–6.
27. Kaplan MM. Monitoring thyroxine treatment during pregnancy. Thyroid. Summer
1992;2(2):147–52.
28. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of in-
creases in levothyroxine requirements during pregnancy in women with hypothy-
roidism. N Engl J Med 2004;351(3):241–9.
29. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid preg-
nant women with autoimmune thyroid disease: effects on obstetrical complica-
tions. J Clin Endocrinol Metab 2006;91(7):2587–91.
30. Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy.
Am J Reprod Immunol 2010;63(6):445–59.
31. Feldt-Rasmussen U, Hoier-Madsen M, Rasmussen NG, et al. Anti-thyroid perox-
idase antibodies during pregnancy and postpartum. Relation to postpartum
thyroiditis. Autoimmunity 1990;6(3):211–4.
32. Premawardhana LD, Parkes AB, Ammari F, et al. Postpartum thyroiditis and long-
term thyroid status: prognostic influence of thyroid peroxidase antibodies and ul-
trasound echogenicity. J Clin Endocrinol Metab 2000;85(1):71–5.
33. Premawardhana LD, Parkes AB, John R, et al. Thyroid peroxidase antibodies in
early pregnancy: utility for prediction of postpartum thyroid dysfunction and impli-
cations for screening. Thyroid 2004;14(8):610–5.
34. Quintino-Moro A, Zantut-Wittmann DE, Tambascia M, et al. High Prevalence of
Infertility among Women with Graves’ Disease and Hashimoto’s Thyroiditis. Int J
Endocrinol 2014;2014:982705.
35. Chen CW, Huang YL, Tzeng CR, et al. Idiopathic Low Ovarian Reserve Is Asso-
ciated with More Frequent Positive Thyroid Peroxidase Antibodies. Thyroid 2017;
27(9):1194–200.
36. Korevaar T, Minguez-Alarcon L, Messerlian C, et al. Association of Thyroid Func-
tion and Autoimmunity with Ovarian Reserve in Women Seeking Infertility Care.
Thyroid 2018;28(10):1349–58.
37. Seungdamrong A, Steiner AZ, Gracia CR, et al. Preconceptional antithyroid perox-
idase antibodies, but not thyroid-stimulating hormone, are associated with
decreased live birth rates in infertile women. Fertil Steril 2017;S0015-0282(17):
31748–X.
38. Stagnaro-Green A, Roman SH, Cobin RH, et al. Detection of at-risk pregnancy by
means of highly sensitive assays for thyroid autoantibodies. JAMA 1990;264(11):
1422–5.
39. Thangaratinam S, Tan A, Knox E, et al. Association between thyroid autoanti-
bodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ
2011;342:d2616.
40. Chen L, Hu R. Thyroid autoimmunity and miscarriage: a meta-analysis. Clin Endo-
crinol (Oxf) 2011;74(4):513–9.
41. Liu H, Shan Z, Li C, et al. Maternal subclinical hypothyroidism, thyroid autoimmu-
nity, and the risk of miscarriage: a prospective cohort study. Thyroid 2014;24(11):
1642–9.
42. Xie J, Jiang L, Sadhukhan A, et al. Effect of antithyroid antibodies on women with
recurrent miscarriage: A meta-analysis. Am J Reprod Immunol 2020;83(6):e13238.
43. Abbassi-Ghanavati M, Casey BM, Spong CY, et al. Pregnancy outcomes in
women with thyroid peroxidase antibodies. Obstet Gynecol 2010;116(2 Pt 1):
381–6.
376 Maraka & Dosiou
44. Korevaar T, Steegers EA, Pop VJ, et al. Thyroid Autoimmunity Impairs the Thyroidal
Response to Human Chorionic Gonadotropin: Two Population-Based Prospective
Cohort Studies. J Clin Endocrinol Metab 2017;102(1):69–77.
45. Monteleone P, Faviana P, Artini PG. Thyroid peroxidase identified in human gran-
ulosa cells: another piece to the thyroid-ovary puzzle? Gynecol Endocrinol 2017;
33(7):574–6.
46. Miko E, Meggyes M, Doba K, et al. Characteristics of peripheral blood NK and
NKT-like cells in euthyroid and subclinical hypothyroid women with thyroid auto-
immunity experiencing reproductive failure. J Reprod Immunol 2017;124:62–70.
47. Andrisani A, Sabbadin C, Marin L, et al. The influence of thyroid autoimmunity on
embryo quality in women undergoing assisted reproductive technology. Gynecol
Endocrinol 2018;34(9):752–5.
48. Negro R, Schwartz A, Stagnaro-Green A. Impact of Levothyroxine in Miscarriage
and Preterm Delivery Rates in First Trimester Thyroid Antibody-Positive Women
With TSH Less Than 2.5 mIU/L. J Clin Endocrinol Metab 2016;101(10):3685–90.
49. Wang H, Gao H, Chi H, et al. Effect of Levothyroxine on Miscarriage Among
Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing
In Vitro Fertilization and Embryo Transfer: A Randomized Clinical Trial. JAMA
2017;318(22):2190–8.
50. Dhillon-Smith RK, Middleton LJ, Sunner KK, et al. Levothyroxine in Women with
Thyroid Peroxidase Antibodies before Conception. N Engl J Med 2019;380(14):
1316–25.
51. van Dijk MM, Vissenberg R, Fliers E, et al. Levothyroxine in euthyroid thyroid
peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial):
a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lan-
cet Diabetes Endocrinol 2022;10(5):322–9.
52. Rao M, Zeng Z, Zhou F, et al. Effect of levothyroxine supplementation on preg-
nancy loss and preterm birth in women with subclinical hypothyroidism and thy-
roid autoimmunity: a systematic review and meta-analysis. Hum Reprod Update
2019;25(3):344–61.
53. Zhang S, Yang M, Li T, et al. High level of thyroid peroxidase antibodies as a detri-
mental risk of pregnancy outcomes in euthyroid women undergoing ART: A meta-
analysis. Mol Reprod Dev 2023;90(4):218–26.
54. Gill S, Cheed V, Morton VAH, et al. Evaluating the Progression to Hypothyroidism
in Preconception Euthyroid Thyroid Peroxidase Antibody-Positive Women. J Clin
Endocrinol Metab 2022;108(1):124–34.
55. American College of O, Gynecologists’ Committee on Practice B-O. Thyroid Dis-
ease in Pregnancy: ACOG Practice Bulletin, Number 223. Obstet Gynecol 2020;
135(6):e261–74.
56. Li L, Li L, Li P. Effects of controlled ovarian stimulation on thyroid function during
pregnancydagger. Biol Reprod 2022;107(6):1376–85.
57. Busnelli A, Cirillo F, Levi-Setti PE. Thyroid function modifications in women under-
going controlled ovarian hyperstimulation for in vitro fertilization: a systematic re-
view and meta-analysis. Fertil Steril 2021;116(1):218–31.

Subclinical Hypothyroidism

Uploaded by

Copyright:

Available Formats

Subclinical Hypothyroidism

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Subclinical Hypothyroidism

Uploaded by

Copyright:

Available Formats

S u b c l i n i c a l H y p o t h y ro i d i s m

Subclinical hypothyroidism (SCH) in pregnancy is defined as the presence of an

Endocrinol Metab Clin N Am 53 (2024) 363–376

Effects of treatment on maternal and offspring outcomes

Maraka & Dosiou

Nazarpour Casey Nazarpour Hales et al,19 Nazarpour

UPositive effect, -, Neutral effect

number of changes that cause an increased demand for thyroid hormone by up to

Impact of thyroid autoimmunity on obstetrical outcomes and potential mechanisms

Effects of treatment on obstetrical outcomes

SCH and Thyroid Autoimmunity in Pregnancy

(continued on next page)

Maraka & Dosiou

miscarriage or subfertility randomized to 50 mcg LT4 preconception and throughout

SUMMARY AND FUTURE DIRECTIONS

CLINICS CARE POINTS

The authors have nothing to disclose.

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.