European Journal of Endocrinology (2008) 158 841–851 ISSN 0804-4643

CLINICAL STUDY

Screening pregnant women for autoimmune thyroid disease:

a cost-effectiveness analysis
Chrysoula Dosiou, Gillian D Sanders1, Sally S Araki2 and Lawrence M Crapo3
Division of Endocrinology, Department of Medicine, Stanford University Medical Center, 300 Pasteur Drive, S025, Stanford, California 94305, USA,
1
Department of Medicine, Duke Clinical Research Institute, Duke University, Durham, North Carolina 27705, USA, 2Center for Primary Care and
Outcomes Research, Stanford University, Stanford, California 94305, USA and 3Division of Endocrinology, Department of Medicine, Santa Clara Valley
Medical Center, San Jose, California 95128, USA
(Correspondence should be addressed to C Dosiou; Email: cdosiou@stanford.edu)

Abstract
Objective: Untreated maternal hypothyroidism during pregnancy can have adverse consequences on
maternal health and child intelligence quotient (IQ). Our objective was to examine the cost-
effectiveness of screening pregnant women for autoimmune thyroid disease.
Design: We developed a state-transition Markov model and performed a cost-effectiveness analysis of
screening pregnant US women, aged 15–45 years, with no known history of thyroid disease, in the first
trimester.
Methods: Three strategies were compared: 1) no screening, 2) one-time screening using anti-thyroid
peroxidase (anti-TPO) antibodies, and 3) one-time screening using TSH. Screening tests were added to
the laboratory tests of the first prenatal visit. Abnormal screening tests were followed by further testing
and subsequent thyroxine treatment of hypothyroid women.
Results: Screening pregnant women in the first trimester using TSH was cost-saving compared with no
screening. Screening using anti-TPO antibodies was cost-effective compared with TSH screening with
an incremental cost-effectiveness ratio of $15 182 per quality-adjusted life year. Screening using TSH
remained cost-saving across a wide range of ages at screening, costs of treatment, and probabilities of
adverse outcomes. The cost-effectiveness of anti-TPO screening compared with TSH screening was
mostly influenced by the probability of diagnosing hypothyroidism in unscreened subjects or subjects
with a normal screening test. Screening remained highly cost-effective in scenarios where we assumed
no improvement of child IQ outcomes by levothyroxine treatment.
Conclusion: Screening all pregnant women for autoimmune thyroid disease in the first trimester is cost-
effective compared with not screening.

European Journal of Endocrinology 158 841–851

Introduction as well as with decreased intelligence quotient (IQ) in

About 11% of women aged 15–45 years have thyroid
autoimmunity (1), while 2.2% of pregnant women have
elevated thyroid stimulating hormone (TSH) at 15–18
weeks of gestation, and 0.3% are overtly hypothyroid (2, 3).
In the mother, untreated hypothyroidism during
pregnancy increases the risk of gestational hypertension
and complications at delivery (4–6). Women with
elevated anti-thyroid peroxidase (TPO) antibody titers
are at increased risk of developing postpartum
thyroiditis (PPT) (7, 8). In women with unrecognized
high TSH during pregnancy, the median interval to
clinical diagnosis of hypothyroidism is 5 years (9);
therefore, many mothers have undiagnosed hypothyr-
oidism in the first years of their child’s life.
In the fetus, untreated maternal hypothyroidism is
associated with adverse perinatal outcomes such as low
birth weight and intrauterine growth retardation (4–6)
childhood (9–13). The drop in IQ is more pronounced in
children of mothers with the highest TSH levels (ten-point
drop); however, even milder maternal thyroid dysfunction
is associated with a five-point drop in IQ compared with
controls (14). Given that 2.2% of pregnant women have
an elevated TSH, out of about 4 000 000 pregnancies that
occur annually in the US (15) as many as 88 000 infants
are at risk for low IQ. Untreated maternal hypothyroidism
in those cases would result in 12 320 more infants per
year with IQ %85.
Though data from randomized trials are still lacking,
observational studies have concluded that treatment of
maternal hypothyroidism with thyroid hormone
reduces the incidence of gestational hypertension in
the mother (6) and improves IQ in the child (9, 10).
Additionally, diagnosing and treating women with
undiagnosed hypothyroidism could improve quality of
life in both patients and their children.

q 2008 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0882

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842 C Dosiou and others
These data make it imperative to consider screening
pregnant women. There have been two cost-effective-
ness analyses of screening the general population for
thyroid disease, in adults over 35 (16) and 60 years old
(17); both found screening to be cost-effective. The US
Preventive Services Task Force recently concluded that
population-wide screening for subclinical thyroid
dysfunction in adults is unwarranted, but excluded
pregnant women from their analysis (18). An expert
panel on subclinical thyroid disease also recommended
against population-wide screening, but found the
evidence insufficient to recommend for or against
routine screening in pregnant women, and instead
recommended aggressive case finding (19). The Amer-
ican College of Obstetrics and Gynecology has a similar
position (20). On the other hand, both the American
Association of Clinical Endocrinologists (AACE) inde-
pendently and a consensus panel with representatives
from the American Thyroid Association, AACE, and
the Endocrine Society have endorsed routine thyroid
screening before or during pregnancy (21, 22). Finally,
the recent Endocrine Society clinical practice guidelines
for the management of thyroid dysfunction during
pregnancy support targeted thyroid disease case-
screening instead (23). Despite the lack of consensus
among professional organizations, a recent study
examining current practice in Maine has found that
routine TSH testing is performed in 48% of all
prenatal care practices and 76% of urban obstetric
practices (24).
Our analysis was undertaken to determine whether it
would be cost-effective to perform universal screening
for autoimmune thyroid dysfunction in pregnant
women using either anti-TPO antibodies or TSH.
Methods
Decision model
A Markov model (25, 26) was developed using the
TreeAge Pro 2004 Suite program (Williamstown, MA,
USA) to investigate the difference in costs and health
benefits between two strategies of screening pregnant
women for autoimmune thyroid disease and not
screening (Fig. 1). We used a modified societal
perspective and ran a lifetime analysis using a discount
rate of 3%. We adhered to the recommendations of the
Panel on Cost-Effectiveness in Health and Medicine (27).
Only women with no known history of thyroid disease
were included in the model. Three strategies were
evaluated: 1) no screening, 2) screening with anti-TPO
antibody, and 3) screening with TSH. Screening
occurred once in the woman’s lifetime, during the first
trimester of pregnancy, at the age of 25 (mean age of
mothers in their first pregnancy in the US) (15).
The screening test was added to the laboratory tests
obtained at the first prenatal visit (6–12 weeks of
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
gestation). The subjects who screened positive under-
went further testing, follow-up, and treatment. Regard-
less of screening status, women with autoimmune
thyroid disease and hypothyroidism were at risk for
gestational hypertension, PPT, and low IQ in their
children. Women with identified disease had these
complications ameliorated if treated appropriately.
After the first postpartum year, all women entered a
Markov cycle, in which they underwent annual
transitions between five health states (Fig. 2). The
likelihood of developing overt hypothyroidism differed
according to the subject’s underlying anti-TPO antibody
status and TSH level at screening (28).
Testing and treatment strategies
In screened patients, serum was saved at the initial
blood draw for further testing. In the first screening
strategy, if the anti-TPO antibody screen was positive,
serum was tested for TSH. If TSH was high, serum was
tested for free thyroxine (FT4); a diagnosis of subclinical
(normal FT4) or overt (low FT4) hypothyroidism was
reached, the patient was referred to an endocrinologist,
and treatment with levothyroxine was initiated. If the
TSH was not high, patients were followed with a
6-month postpartum visit and thyroid function tests
(TFTs: TSH and FT4), and thereafter with annual clinic
visits and TFTs.
In the second screening strategy, if the TSH was
elevated, serum was tested for FT4, a diagnosis of overt
or subclinical hypothyroidism was reached, the patient
was referred to an endocrinologist, and treatment with
levothyroxine was initiated. If the TSH level was
normal/low (under 95% percentile, corresponding to a
TSH %3 mU/ml (29, 30)), no further testing was
performed. If the TSH level was midrange (95–97.5th
percentile, i.e. 3–5 mU/ml (29, 30)), serum was tested
for anti-TPO antibodies. The subjects with positive anti-
TPO antibodies were followed with a 6-month post-
partum visit and TFTs, and thereafter with annual clinic
visits and TFTs.
Once patients were diagnosed with overt hypothy-
roidism, patients had three follow-up visits with TFTs
during the remainder of pregnancy, followed by three
more visits with TFTs at 3, 6, and 12 months
postpartum. Thereafter, they were followed with annual
visits and TFTs. Subclinically hypothyroid patients were
treated the same way as overtly hypothyroid patients
until the end of the first postpartum year. Thereafter,
thyroxine treatment was discontinued, they entered the
Markov model as patients with no overt disease, and
were followed with annual visits and TFTs. The patients
who were antibody positive with a normal TSH during
pregnancy had a follow-up visit with TFTs at 6 months
postpartum in order to assess for development of PPT
and were subsequently followed with annual visits
and TFTs.
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158 Thyroid screening in pregnancy is cost-effective 843

Figure 1 Simplified representation of the decision model to evaluate the cost-effectiveness of screening pregnant women with anti-TPO
Ab or TSH versus not screening. The square on the left represents a choice between alternative screening strategies: screening women
with anti-TPO Ab, screening with TSH, or not screening. Circles represent chance nodes. Patients who are screened with anti-TPO Ab can
come back as either Ab positive or Ab negative; patients who are Ab positive are then tested for TSH, which can be determined to be either
high or normal. Patients with high TSH have their FT4 tested, which can either be low or normal. All patients with high TSH are started on
treatment with levothyroxine, which women can either be compliant with or not. Similarly, women who are screened with TSH can come
back as testing high, midrange, or normal. If the TSH level is midrange, serum is tested for anti-TPO antibodies, and women with anti-TPO
Ab positivity receive lifelong follow-up. All women are assessed for the development of gestational hypertension, missed diagnosis of PPT,
and development of low IQ in their offspring. After screening, all women enter the Markov tree (Fig. 2), which represents the clinical events
that can occur during each annual period as a woman is followed for her lifetime. The costs and utilities associated with the different
screening strategies and the above outcomes were estimated and the incremental cost-effectiveness ratios (difference in cost/difference in
QALYs) were calculated between the different strategies to determine their relative cost-effectiveness. Anti-TPO Ab, anti-thyroid
peroxidase antibody; TSH, thyroid stimulating hormone, FT4, free thyroxine; Pos, positive; Neg, negative; Tx, treatment; PPT, postpartum
thyroiditis; IQ, intelligence quotient; QALYs, quality-adjusted life years.

Subjects who screened negative or were not screened
received no further testing. Disease was diagnosed and
treated only in symptomatic patients, with a delay, after
undergoing a medical workup for their symptoms.
Subjects diagnosed with overt hypothyroidism after
pregnancy were treated with levothyroxine, had three
follow-up visits with TFTs during the first year, and
annual visits with TFTs thereafter. Throughout the
model, women could be compliant or not with their
recommended treatment. Non-compliant patients
remained in the untreated overtly hypothyroid group
until they became compliant (mean of 2.5 years).
Probabilities
We derived the probabilities for the decision tree and
the Markov state transitions from epidemiology and
prevalence studies in peer-reviewed journals, after
extensive review of the literature (Table 1). The prevalence
of anti-TPO antibodies and high TSH were varied as a
function of maternal age (Table 2). Of the remaining
pregnant women, we assumed that 95% would have
normal/low TSH, and that the rest would have TSH in
the midrange. The probabilities of abnormal TFTs in the
various anti-TPO antibody and TSH subgroups were
calculated from studies of prevalence of hypothyroidism
in pregnant women (2, 3).
When probabilities were not available, they were
estimated using expert clinical judgment. We estimated
compliance with levothyroxine treatment to be 80 and
90% in non-pregnant and pregnant women respect-
ively. We estimated that unscreened patients with overt
or symptomatic subclinical hypothyroidism during
pregnancy would take on average 2.5 years to diagnose.

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844 C Dosiou and others
Figure 2 Markov health transition subtree. This Markov model
is used to capture long-term costs and utilities associated with
different health states. The ovals represent the possible health
states for women in our model, and the arrows represent possible
transitions. Women can either have no disease (where disease is
defined as overt hypothyroidism), can have disease but not be
diagnosed, have disease and be diagnosed and either be compliant
or not, or die from age-specific causes. Women transition annually
between these five health states over their lifetime. For example,
women without disease each year can either stay in the ‘no disease’
health state, can develop disease but be undiagnosed (‘disease-
undiagnosed’ state), can develop disease and be diagnosed and be
compliant with treatment (‘disease diagnosed – compliant’ health
state), can develop disease and be diagnosed but not be compliant
with treatment (‘disease diagnosed – non-compliant’ health state),
or die from age-specific causes (‘dead’ health state). Annual
transition probabilities between the different health states, costs,
and utilities associated with each health state were obtained from
the literature, or estimated, when not available.
This was based on clinical experience and was more
conservative than the median interval to diagnosis of
hypothyroidism in women with elevated TSH during
pregnancy (5 years) (9).
We varied all assumptions and parameter values
extensively in sensitivity analyses.
Costs
The costs for laboratory tests were obtained from the
2004 Medicare Clinical Laboratory Fee Schedule (31).
The costs for clinic visits were obtained from the 2004
Medicare payment amounts for services provided in a
facility (32) (Table 1). The cost of levothyroxine
treatment was obtained from the 2004 Redbook (33).
Screening cost consisted of an anti-TPO antibody titer
(CPT 86 376) or TSH test (CPT 84 443). The cost of the
initial visit to the endocrinologist was assumed to be
that of a 30-min outpatient consultation (CPT 99 242).
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
Hypothyroidism treatment costs were calculated for the
different scenarios described above using the costs of a
10-min follow-up outpatient visit (CPT 99 212), TSH
test (CPT 84 443), FT4 test (CPT 84 439), and annual
cost of levothyroxine treatment. The costs of gestational
hypertension were calculated as incremental costs
compared with a pregnancy with no gestational
hypertension (34). Costs for PPT and workup of
unscreened women with hypothyroidism were obtained
from the literature (16, 35). All costs were adjusted to
$2004 using the Gross Domestic Product Deflator
Inflation Calculator (http://www1.jsc.nasa.gov/bu2/
inflateGDP.html).
We estimated the cost of low IQ using data on the
relationship between cognitive ability and earning
potential (36). A one-point difference in IQ is associated
with about a 2% difference in earnings (range 1.76–
2.37%) (36). Based on estimates published elsewhere
(36), we assumed the discounted future earnings of a
2 year old to be $775 667 (adjusted to $2004). This
assumption would mean a loss of $15 513 in future
earnings per IQ point. Based on the follow-up to the
Haddow study (14), we assumed that children of
untreated overtly and subclinically hypothyroid
mothers have on average a 9.2- and 4.2-point
decrement in IQ respectively (after adjusting by 0.8
points for differences in socioeconomic status compared
with controls).
In the Markov tree, we only included lifetime costs
attributable to the diagnosis and treatment of hypothy-
roidism; we did not include future medical costs due to
other illnesses.
Patient preferences
Patient preferences for the different health states were
incorporated into the analysis using utilities, which
ranged from 0 to 1 (Table 1). A utility of 1 was assigned
to the ideal health state and 0 to the dead state.
Asymptomatic subclinical hypothyroidism and asymp-
tomatic PPT were assigned a utility of 1. Utilities for
overt hypothyroidism and PPT were obtained from the
literature (35, 37, 38). Symptomatic untreated sub-
clinical hypothyroidism was estimated to have a utility
of 0.9, which increased to 1 if treated. To derive the
utility of treated gestational hypertension, we surveyed
three obstetricians with experience in high-risk preg-
nancies, and we averaged the given values. Similarly, to
obtain the utility of having a child with IQ %85, we
averaged the values given by five pediatricians that
we surveyed. We only assigned a utility decrement to
the mother of the child with IQ %85, for her lifetime.
We also obtained utility estimates for the child with low
IQ and his/her second parent (0.66 and 0.75 respect-
ively); however, we did not include those utilities in our
base-case analyses.
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158 Thyroid screening in pregnancy is cost-effective 845

Table 1 Model input variables and sourcesa.

Variable Base-case estimate Range Source

Test characteristics (%)
Sensitivity of anti-TPO Ab 90 80–100 (50–52)
Specificity of anti-TPO Ab 95 90–100 (50–52)
Anti-TPO Ab positivity in pregnant women 10.4 7–15 (1–3)
High TSH in anti-TPO Ab positive women 12 8–16 (2, 3)
High TSH in anti-TPO Ab negative women 1 Not variedb (2, 3)
Probability TSH high 2.2 1.3–2.6 (2, 3)
Probability TSH normal (for pregnancy) 95 93–97 Definition
FT4 low in anti-TPO Ab positive women with high TSH 23 10–30 (2, 3)
FT4 low in anti-TPO Ab negative women with high TSH 8 5–11 (2, 3)
Treatment variables (%)
Treatment compliance in pregnant women 90 80–100 Estimate
Treatment compliance in non-pregnant women 80 60–100 Estimate
Annual new compliance among non-compliant patients 25 10–80 Estimate
Adverse outcome variables
Symptoms in SH (%) 28 10–50 (16)
GHTN in adequately treated women with OH (%) 7.9 5–10 (6)
GHTN in adequately treated women with SH (%) 7.9 5–10 (6)
GHTN in inadequately treated women with OH (%) 36 20–50 (6)
GHTN in inadequately treated women with SH (%) 25 7.6–40 (6)
GHTN in women with normal TSH (%) 7.6 5–10 (6)
PPT in anti-TPO Ab-positive women (%) 50 30–70 (7, 8)
PPT in anti-TPO Ab-negative women (%) 0.5 0.3–2.5 (7, 8)
Symptoms given PPT (%) 68 33–88 (35)
Diagnosing PPT in unscreened or anti-TPO Ab-negative women (%) 25 10–75 (35)
Infant IQ%85 in adequately treated maternal OH or SH (%) 5 2–8 (9)
Infant IQ%85 in inadequately treated maternal OH (%) 19 10–30 (9)
Infant IQ%85 in inadequately treated maternal SH (%) 9.5 5–19 Estimate
Infant IQ%85 if maternal TSH not high (%) 5 2–8 (9)
Average IQ point loss in children of women with untreated maternal OH 9.2 0–15 (14)c
Average IQ point loss in children of women with untreated maternal SH 4.2 0–10 (14)c
Natural history variables (annual) (%)
Development of OH in anti-TPO Ab-positive women with high TSH 4.3 3–5 (28)
Development of OH in anti-TPO Ab-positive women with not high TSH 2.1 1–3 (28)
Development of OH in anti-TPO Ab-negative women with high TSH 2.6 1.6–3.6 (28)
Development of OH in anti-TPO Ab-negative women with not high TSH 0.3 0.1–0.5 (28)
Rate of diagnosis of OH in unscreened women with OH or symptomatic SH 25 10–80 Estimate
Costs ($ 2004)
Thyroid peroxidase Ab test 20.33 10–50 (31)
Thyroid stimulating hormone test 23.47 10–50 (31)
Free thyroxine test 12.6 5–30 (31)
Levothyroxine sodium 1 year supply 130.67 100–200 (33)
Outpatient visit, new, 30 min 69.45 50–100 (32)
Outpatient visit, established, 10 min 23.52 20–50 (32)
Gestational hypertension 3890 1860–5920 (34)
PPT 536.10 220–660 (35)
Workup of unscreened women with OH, symptomatic SH, or symptomatic PPT 309 165–490 (16)
Cost per one IQ point loss 15 513 13 652–18 383 (36)
Utilities
Euthyroid 1 Not varied Definition
Subclinical hypothyroidism, asymptomatic 1 Not varied Estimate
Subclinical hypothyroidism, symptomatic, untreated 0.90 0.70–0.95 Estimate
Subclinical hypothyroidism, symptomatic, treated 1 Not varied Estimate
Overt hypothyroidism, untreated, first year 0.7085 0.60–0.80 (37, 38)
Overt hypothyroidism, untreated second year 0.6053 0.50–0.70 (37, 38)
Overt hypothyroidism, treated, first year or later 0.8557 0.70–0.95 (37, 38)
PPT, asymptomatic 1 Not varied Estimate
PPT, symptomatic, undiagnosed 0.81 0.73–0.89 (35)
PPT, symptomatic, correctly diagnosed 0.89 0.82–1 (35)
Gestational hypertension, treated 0.90 0.85–0.95 Expert
Having a child with IQ%85 0.75 0.60–0.90 Expert
Other variables
Discount rate, annual (%) 3 0–5 (27)

Anti-TPO Ab, anti-thyroid peroxidase antibody; TSH, thyroid stimulating hormone; PPT, postpartum thyroiditis; GHTN, gestational hypertension; OH, overt
hypothyroidism; SH, subclinical hypothyroidism; IQ, intelligence quotient.
a
The base-case estimate represents the best estimate for each value. Costs are expressed in 2004 US dollars.
b
Variable is a function of other variables.
c
Adjusted for difference in socioeconomic status between hypothyroid subjects and controls (based on data in (9)).

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846 C Dosiou and others
Table 2 Variation of the prevalence of anti-TPO Abs, the probability of TSH in the high or middle range, and the probabilities of anti-TPO Ab
positivity in the different TSH subgroups according to age.
Prevalence of
anti-TPO Abs Prob TSH high Prob TSH
Age (years) (%) (%) midrange (%)
15 6.7 1.79 3.20
25 10.4 2.23 2.77
35 12.6 2.49 2.51
45 15.8 2.86 2.14
The prevalence of anti-TPO antibodies was varied by age, according to the data from the Third National Health and Nutrition Examination Survey (1). The
probability that TSH is normal/low was defined as 95% in all age groups. The probability of anti-TPO antibody positivity in subjects with TSH in the midrange
was estimated, and the ratio of that probability to the probability of anti-TPO antibody positivity in subjects with high TSH was assumed to be constant. All other
probabilities were calculated using the data from (2, 3). Anti-TPO Abs, anti-thyroid peroxidase antibodies; Prob, probability; TSH, thyroid stimulating hormone.
Assumptions of the model
The following additional assumptions were made:
1) Hyperthyroidism is diagnosed much more readily than
hypothyroidism through symptoms, while subclinical
hyperthyroidism has no adverse impact on pregnancy
outcomes (39). We therefore did not include
hyperthyroid patients in the model.
2) Free T4 is assessed in assays that have pregnancy-
specific reference ranges and only defined as low when
lower than the manufacturer-specific and trimester-
specific reference ranges.
3) Women diagnosed with subclinical hypothyroidism
during pregnancy get treated until 12 months
postpartum. We made this assumption based on the
detrimental effects of high TSH, even in the absence of
overt hypothyroidism, on pregnancy complications
and fetal IQ (6, 9) and the current consensus
recommendations of treating such pregnant women
(19). Treatment was continued in the first postpartum
year, given the high incidence of PPT during that
period in susceptible women. Since treatment of
subclinical hypothyroidism in non-pregnant patients
has questionable benefits (19), we did not continue
treatment after 12 months postpartum.
4) Women with overt hypothyroidism are all sympto-
matic. Once they get diagnosed, they require lifelong
therapy and follow-up.
5) Among the unscreened patients and those who screen
negative, patients with symptomatic subclinical
disease during pregnancy, have a 25% probability of
diagnosis and treatment by 12 months postpartum.
Asymptomatic patients are not diagnosed. The
patients who develop symptomatic subclinical disease
after the first postpartum year do not get diagnosed
until they become overtly hypothyroid.
6) All compliant patients are successfully treated and
therefore assumed to no longer have high TSH.
7) The diagnosis of PPT is correctly made in all
symptomatic patients (68% of PPT patients) (35) in
the screened, anti-TPO antibody-positive group.
Symptomatic patients with PPT who screen anti-
TPO antibody-negative or are not screened, have only
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
Prob anti-TPO
Prob anti-TPO Prob anti-TPO AbCif TSH
Prob TSH nor- AbCif TSH AbCif TSH normal/low
mal/low (%) high (%) midrange (%) (%)
95 47.13 27.63 5.23
95 59.03 34.61 8.55
95 64.15 37.61 10.59
95 69.96 41.02 13.60
a 25% chance of correct diagnosis; the remaining 75%
incur additional cost of workup of their symptoms
($309) (35).
8) The probability of child IQ %85 in untreated
subclinically hypothyroid mothers is half of the
probability corresponding to overtly hypothyroid
mothers (0.095 vs 0.19). This was based on the fact
that the follow-up to the Haddow study (14) showed
that children born to mothers with the highest TSH
(mean TSH of 32 mU/l) had a ten-point IQ difference
compared with controls, whereas children born to
mothers with slighter TSH elevations (mean TSH of
9 mU/l) had a five-point IQ difference compared with
controls (before adjusting for socioeconomic status).
Since the IQ deficit was halved in mothers with milder
TSH elevations, we assumed that the percentage of
children with IQ %85 born to mothers with
subclinical hypothyroidism would be half that of
children born to mothers with overt disease.
Results
Base-case analysis
Under base-case assumptions, screening pregnant
women with TSH in the first trimester was cost-saving
(saved $102) and increased quality-adjusted life expect-
ancy by 5.84 days relative to no screening. Screening
with anti-TPO antibodies increased quality-adjusted life
expectancy by 5.11 days at a cost of $212 relative to TSH
screening, for an incremental cost-effectiveness ratio
(ICER) of $15 182 per QALY (Table 3).
Sensitivity analyses
Screening with TSH or anti-TPO antibodies remained
cost-effective across a wide range of parameters tested. In
one-way sensitivity analysis, TSH screening continued to
dominate no screening across all parameters varied over
a clinically valid range. The analysis was most sensitive
to the annual probability of diagnosing overt hypothy-
roidism in women who are unscreened or those with
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158 Thyroid screening in pregnancy is cost-effective 847

Table 3 Health and economic outcomes.

Incremental QALY Incremental Incremental

Strategy Cost ($) cost ($) (years) QALYs (days) C-E ratio ($/QALY)

No screen 970 26.854

Screen with TSH 868 K102 26.870 5.84 Dominates
Screen with anti-TPO 1080 212 26.884 5.11 15 182
Ab

Dominates, the ‘screen with TSH’ strategy is less costly and more effective than the ‘no screen’ strategy and is therefore said to ‘dominate’ the no-screening
strategy; QALY, quality-adjusted life year; C-E, cost-effectiveness; TSH, thyroid stimulating hormone; anti-TPO Ab, anti-thyroid peroxidase antibody.

negative screening tests. This probability was varied
across a very wide range (0.1–0.8), because the
estimation of the base-case value was based on clinical
experience. Screening using TSH became cost-saving
compared with anti-TPO screening when that probability
was 0.78 or larger (data not shown).
Screening using TSH remained cost-saving at all ages
(Table 4), whereas screening using anti-TPO antibodies
became more cost-effective compared with TSH
screening as maternal age increased (Table 4), reflecting
the higher prevalence of autoimmune thyroid disease in
older women. When we doubled the costs associated with
the screening and diagnostic tests, TSH screening
continued to dominate no screening, while the cost-
effectiveness of anti-TPO antibody screening compared
with TSH screening decreased (ICER: $21 550/QALY,
Table 4). Recognizing that the occurrence of hypothy-
roidism can differ among various populations of women,
we varied the probability of high TSH across a wide
range (1.3–2.6%) and found no significant changes in
the cost-effectiveness of the screening strategies
compared with the base-case scenario (data not shown).
Cost- effectiveness at different scenarios of low
IQ variables
We explored the effects of low IQ in the children of
untreated mothers with hypothyroidism by varying
simultaneously a number of parameters associated with
low IQ. When we assumed that untreated hypothyroidism
(both overt and subclinical) during pregnancy had no
adverse effect on child IQ, TSH screening was cost-effective
compared with no screening (ICER: $4956/QALY), and
anti-TPO antibody screening remained cost-effective
compared with TSH screening (ICER: $9133/QALY;
Table 4). When we assumed no treatment benefit with
levothyroxine regarding low child IQ, we obtained similar
results (Table 4).

Table 4 Sensitivity analysis results for other select variables.

Cost-effectiveness ratio ($QALY)

Anti-TPO Ab screening versus Anti-TPO Ab screening versus
Sensitivity analysis scenario TSH versus no screening no screening TSH screening

Base-case analysis TSH dominates 3637 15 182

No adverse effect of untreated 4956 7769 9133
maternal SH or OH on child IQ
No improvement of child IQ with 5029 7566 9105
levothyroxine treatment of OH and SH
mothers during pregnancy
Screening and diagnostic test costs TSH dominates 8185 21 550
doubled
Anti-TPO Ab ($40)
TSH ($50)
FT4 ($25)
Maternal age (base case: 25 years)
15 years TSH dominates 5242 23 999
25 years TSH dominates 3642 15 182
35 years TSH dominates 2995 13 186
45 years TSH dominates 2270 11 613
Annual probability of diagnosing hypothyroidism in unscreened or those with a negative screen (base case: 25%)
10% TSH dominates 1759 6102
50% TSH dominates 9983 53 922
80% TSH dominates 27 234 TSH dominates

Dominates, the ‘screen with TSH’ strategy is less costly and more effective than the ‘no screen’ strategy and is therefore said to ‘dominate’ the no-screening
strategy; TSH, thyroid stimulating hormone; anti-TPO Ab, anti-thyroid peroxidase antibody; QALY, quality-adjusted life year; SH, subclinical hypothyroidism;
OH, overt hypothyroidism; IQ, intelligence quotient; FT4, free thyroxine.

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848 C Dosiou and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158

Table 5 Multi-way sensitivity analysis of different low IQ variables: effects of varying the probability of low IQ and IQ point loss in children of
women with untreated SH, and the cost of low IQ on the incremental cost-effectiveness of anti-TPO Ab versus TSH screening.

Incremental cost-effectiveness ratio ($/QALY)

IQ point loss in children of
women with SH Cost per unit IQ lost $13 652 Cost per unit IQ lost $15 513 Cost per unit IQ lost $18 383

Prob IQ%85 in children of women with untreated SH: 0.05

0 10 258 10 376 10 558
4.2 11 559 11 854 12 309
9.2 13 108 13 614 14 395
Prob IQ%85 in children of women with untreated SH: 0.095
0 11 812 11 948 12 157
4.2 14 658 15 182 15 989
9.2 18 040 19 032 20 551
Prob IQ%85 in children of women with untreated SH: 0.19
0 17 365 17 564 17 871
4.2 25 732 27 072 29 139
9.2 35 694* 38 392* 42 553*

Base-case conditions are denoted in bold. *Anti-TPO Ab screening dominates no screening under these conditions (i.e. is less costly and more effective). Anti-
TPO Ab, anti-thyroid peroxidase antibody; TSH, thyroid stimulating hormone; IQ, intelligence quotient; QALY, quality-adjusted life year; Prob, probability; SH,
subclinical hypothyroidism.

We further explored the effects of various low IQ
variables on the cost-effectiveness of screening by
focusing on subclinically hypothyroid women, who
constitute O85% of the subjects with elevated TSH.
Screening using anti-TPO antibody remained cost-
effective compared with TSH screening as the probability
of child IQ %85 in untreated women increased, the
number of IQ points lost increased, or the cost per unit IQ
increased (Table 5), although the cost-effectiveness
decreased as the number of IQ points lost increases
(Table 5). Screening with anti-TPO antibody became
cost-saving compared with no screening if we assumed a
probability of IQ %85 of 0.19 (base case: 0.095) and an
IQ loss of 6.93 points or greater (base case: 4.2) in
children of untreated mothers (data not shown).
Discussion
Screening pregnant women in the first trimester with
TSH is cost-saving compared with no screening, while
screening with anti-TPO antibodies is cost-effective
compared with TSH screening, at $15 182/QALY. This
compares favorably with the cost-effectiveness of other
well accepted screening practices (Table 6). The increase
in quality-adjusted life expectancy by screening in our
study (5.84 days) is similar to that estimated in other
studies for screening the general population for HIV
(4.70 days) (40), 40-year-old asymptomatic women for
hypertension (4 days) (41), and adult women over 35
years for TSH (6 days) (16). Screening using TSH
continued to dominate the no-screening strategy and
anti-TPO antibody screening continued to be the most
favorable screening strategy economically in sensitivity
analyses. Importantly, because of its other benefits,
screening remained highly cost-effective even in scenarios
where we assumed no adverse effects of maternal
hypothyroidism on child IQ or no efficacy of levothyroxine
in improving IQ outcomes.
This is the first cost-effectiveness analysis of screening
pregnant women for autoimmune thyroid disease. The
increased benefits derived from improving gestational

Table 6 Cost-effectiveness of other well established screening practices compared with screening for thyroid disease, adjusted to 2004
US dollars.

Incremental cost-effectiveness
Analysis ratio $/QALY Reference

Screening practice
Hypertension screening in asymptomatic 40-year-old women 33 015 (41)
Hypertension screening in asymptomatic 40-year-old men 23 152 (41)
Mammography every 2 years in 45- to 69-year-old women 18 170 (53)
Fecal occult blood screening in 50-year-old women 2520 (54)
Fecal occult blood screening in 50-year-old men 3762 (54)
Screening for thyroid disease
TSH screening every 5 years in 35- to 75-year-old women 10 956 (16)
TSH screening every 5 years in 35- to 75-year-old men 26 841 (16)
Anti-TPO antibody screening compared with TSH screening in first 15 182 Current analysis
trimester of pregnancy in women of 15–45 years old

QALY, quality-adjusted life year; TSH, thyroid stimulating hormone; TPO, thyroid peroxidase.

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
hypertension, correctly diagnosing PPT, improving
intellectual ability of children of affected mothers, and
more promptly diagnosing overt thyroid disease when it
develops, make screening in pregnant women economi-
cally favorable. Screening using TSH results in both
reduced costs and improved quality of life compared with
no screening, making the case for TSH screening very
strong. Further research regarding the potential benefits
of treatment of the anti-TPO antibody-positive women,
regardless of TSH level, would be very valuable in more
accurately assessing the cost-effectiveness of the anti-
TPO antibody screening strategy.
Our study has several important strengths. The testing
and treatment strategy is comprehensive, including all
appropriate physician and laboratory follow-up. We take
into account subject compliance and transition to
compliance in non-compliant subjects. Finally, the base-
case analysis is based on very conservative estimation of
parameters, potentially resulting in underestimation of
cost-effectiveness. We have also not included some other
potential benefits of screening and treatment. The risk of
developing permanent overt hypothyroidism has been
shown to be even higher in the subset of anti-TPO
antibody-positive women who experience PPT, compared
with women who do not experience PPT (42).
Furthermore, a recent study of euthyroid pregnant
women with autoimmune thyroid disease demonstrated
that levothyroxine treatment significantly reduced mis-
carriage rates (43). Such additional benefits of screening
would make screening for autoimmune thyroid disease
even more cost-effective than demonstrated in the
current calculation.
A limitation of our analysis is that the probabilities of
low IQ in children of treated or untreated mothers are
based on retrospective studies, which can be flawed if one
fails to control for important potential confounders. The
Haddow study has been criticized for the fact that the
parental IQ was not directly measured. However, we
believe that every effort was made to control for parental
IQ in that study both by matching subjects to controls
according to number of years of education in the design
phase, and by taking into account small differences that
were noted in the socioeconomic status of the different
study groups, in the analysis phase of the study (9). We
also took this into account in our analysis using the
socioeconomic status-adjusted difference in IQ, rather
than the total IQ difference noted. Unfortunately, there
are no prospective studies yet regarding the effects of
treated versus untreated maternal hypothyroidism on
child IQ. Two randomized controlled trials are underway
to address the effect of treatment of hypothyroid women
on the IQ of their children: one in the United Kingdom
(44) and one in the United States (45). We await those
results with much anticipation; however, the studies
are still in the early enrollment phase and data on child
IQ at 5 years of age are not going to be available in the
near future. In the meantime, recent basic science
discoveries strongly support a role of thyroid hormone
Thyroid screening in pregnancy is cost-effective 849
in fetal neurodevelopment (46–48). In addition, even
though randomized controlled trials on the effect of
levothyroxine in reversing neurodevelopmental abnorm-
alities are not yet available, this has been clearly
demonstrated in a recent animal study (46) and is
further supported by three observational clinical studies,
where treatment of hypothyroid mothers with levothyr-
oxine (9, 10) or spontaneous increase of FT4 in mothers
with hypothyroxinaemia in early pregnancy (12)
resulted in normal child IQ.
Even though there is no agreement in current position
statements from the various medical societies regarding
universal screening of pregnant women for autoimmune
thyroid disease, all societies support aggressive case-
finding. Screening only high-risk women, however,
would fail to diagnose one-third of women with high
TSH (49). The current study demonstrates that screening
all pregnant women for autoimmune thyroid disease is a
good use of our healthcare dollars.
In conclusion, screening pregnant women with TSH in
the first trimester of pregnancy is cost-saving compared
with no screening, while screening using anti-TPO
antibodies is an economically favorable screening
strategy. The medical community should strongly
consider screening pregnant women for autoimmune
thyroid disease using either anti-TPO antibodies or TSH
at the first prenatal visit.
Acknowledgements
We would like to thank Dr Kristin Cobb for editorial
assistance.
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Received 20 February 2008
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