The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 1816-1819
Copyright © 1999 by The Endocrine Society
The Time Is Not Ripe To Screen
Lawrence M. Crapo
Division of Endocrinology
Stanford University School of Medicine and Santa Clara Valley
Medical Center
San Jose, California 95128
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Introduction
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AT FIRST GLANCE, screening for postpartum
thyroiditis (PPT) appears to be an attractive and possibly even a
cost-effective strategy. The disorder is quite common, affecting in the
range of 4–6% of all postpartum women (1). In the United States,
where there are approximately 4 million live births annually (2), this
means that PPT afflicts nearly 200,000 women each year. The symptoms
associated with PPT are often subtle and difficult to distinguish from
symptoms frequently present during the postpartum period. Those women
at high risk for PPT are easy to identify because PPT is an autoimmune
disease in which most patients have elevated serum levels of thyroid
autoantibodies. It is generally assumed that over 20% of women with
PPT will eventually develop permanent hypothyroidism within a 5-yr
period (3, 4). Finally, PPT is easy to treat when symptoms are present
by employing beta-blockers for the hyperthyroid phase and levothyroxine
for the hypothyroid phase of the disorder (5).
On closer scrutiny, however, the screening strategy loses some of its
initial appeal. Although PPT is common, symptoms during the
hyperthyroid and hypothyroid phases of the illness are often mild in
degree and brief in duration and, consequently, may not require
treatment. When symptoms are moderate or severe in degree they should
be recognized clinically, although this will require more education of
primary care physicians and postpartum patients about PPT. Which
thyroid autoantibody assay should be used for screening and when the
assay should be performed have not been completely resolved.
Furthermore, there is a lack of knowledge about how to follow patients
with a positive antibody assay. Should a serum TSH level be done only
when they are symptomatic, or should serial TSH levels be done and, if
so, at what intervals? Finally and most importantly, there has been no
prospective diagnostic and therapeutic trial to date that tells us
whether or not a screening program would be beneficial.
We will initially discuss screening for thyroid disease in general to
set the stage for a detailed discussion of screening for PPT. Available
data and studies on these important issues will lead to the conclusion
that the time is not yet ripe to recommend a screening program for all
pregnant or postpartum women to identify those who are at risk for or
who have PPT.
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Screening for thyroid disease in general
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In general, screening may be defined as testing for the presence
of a disease or the risk of a disease when no known signs or symptoms
of the disease are present, with the purpose of improving health
outcomes in the target population (6). Screening recommendations for
thyroid disease involve an assessment of age, gender, family history,
and associated physiologic or pathophysiologic conditions. In addition
to specifying who should be screened, such recommendations also need to
specify which tests should be employed, how frequently they should be
employed, and where they should be employed.
Presently, there is only one universally agreed-upon strategy in
screening for thyroid disease, which is that neonates should be
screened for congenital hypothyroidism with a blood TSH or total T4
assay shortly after birth in the hospital. In 1990, the American
Thyroid Association (ATA) recommended against screening for thyroid
disease in asymptomatic subjects in the general population who were not
at high risk for thyroid disease and its consequences (7). The Canadian
Task Force on the Periodic Health Examination in 1994 (8), and the
United States Preventative Services Task Force (USPSTF) in 1996 (9),
concurred in this recommendation against general screening. All
agencies recommend screening for hypothyroidism in neonates even though
it is infrequent (1 case per 4,000 births). The ATA recommends
screening with tests of thyroid function in certain higher risk
situations, such as in elderly patients, those with a family history of
thyroid disease, individuals with autoimmune diseases such as type I
diabetes mellitus, and in postpartum women at 4–8 weeks (7). The
USPSTF adds the high risk group of persons with Down’s syndrome, and
notes that at the present time there is insufficient evidence to
recommend for or against screening for thyroid disease in any of the
childhood or adult high risk groups, including postpartum women (9).
They do recommend that clinicians should remain alert for subtle signs
and symptoms of thyroid dysfunction and keep a low threshold for
evaluating thyroid status in such high risk subjects.
Recently, one study has demonstrated by cost-utility decision analysis
that it is cost-effective to screen for mild thyroid failure with a
serum TSH assay at 5-yr intervals starting at age 35 yr for both men
and women, and that such screening is especially recommended for
elderly women (10). More recently, the American College of Physicians
has recommended screening for unsuspected but symptomatic
hypothyroidism and hyperthyroidism in women over 50 yr of age,
employing a sensitive serum TSH assay (11, 12). They further note that
there is insufficient evidence at present to recommend for or against
screening for subclinical hypothyroidism or subclinical
hyperthyroidism, although this latter recommendation has been
criticized (13).
Thus, from the general literature on screening for thyroid disease,
there is little to help guide us in a decision about screening for PPT,
and what there is remains controversial. In the presence of conflicting
recommendations from prestigious national agencies, and in the absence
of published cost-benefit analyses or prospective controlled clinical
trials, we are compelled to form a conclusion about the merits of
screening for PPT on other grounds, employing available studies on the
epidemiologic, laboratory, and clinical characteristics of PPT.
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Screening for postpartum thyroiditis
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In order to develop a strategy of screening for PPT it is
necessary to review the epidemiology of the disorder and assess its
varied clinical manifestations so we can answer the questions of what
are we screening for, what tests should we use for screening, when we
should screen, and whether or not screening is superior to clinical
ascertainment of PPT.
PPT is an autoimmune disorder characterized by a destructive
lymphocytic infiltration of the thyroid gland, very often with
accompanying circulating thyroid autoantibodies, which can manifest
itself as transient hyperthyroidism, transient hypothyroidism, or
permanent hypothyroidism. These manifestations result from activation
of immunological changes that occur in the first postpartum year. The
symptoms of PPT are those of hyperthyroidism or hypothyroidism added to
a background of symptoms commonly found in the postpartum period, such
as fatigue, tiredness, depression, emotional lability, and anxiety.
These symptoms can be mild or severe and transient or prolonged. Thus,
PPT is a protean disorder with varied presentations at varied times
hiding in the shadow of common postpartum symptoms, which renders the
development of a screening strategy very difficult. The epidemiology of
PPT is presented in Table 1
,where the outcome of 1,000 hypothetical unselected postpartum women is
traced, assuming that 5% of the women will develop PPT, 10% of the
women will be positive for serum thyroid peroxidase autoantibodies
(TPO-Ab), nearly 50% of the women with a positive TPO-Ab titer will
develop PPT, and that 90% of women with PPT will have a positive
TPO-Ab titer. The data in this table have been derived from several
reviews of numerous studies on the incidence of PPT and the prevalence
of positive TPO-Ab titers in postpartum women (1, 14). The incidence of
PPT in these studies varies by over an order of magnitude from 1.1% to
16.7%, which may be explained in part by variations in geographical
location, definition of PPT, duration of studies, and frequency of
testing. A critical evaluation of many of the studies suggests that the
incidence of symptomatic PPT is about 5% (1). The incidence data on
permanent overt hypothyroidism in Table 1 and Table 2 hasbeen derived from 5 separate studies in which patients with PPT
have been followed for 3–5 yr (3, 4, 15, 16, 17).
What is the purpose of screening for PPT? The simple answer to this
question is that the purpose is to alleviate symptoms from
hypothyroidism and transient hyperthyroidism and to identify women who
are at risk for subsequent permanent hypothyroidism, as well as PPT in
future pregnancies. But is screening really necessary to carry out this
purpose, or could the purpose be accomplished without screening through
careful attention to clinical detail by physicians who care for
postpartum women? Unfortunately, no prospective studies have yet been
conducted that answer this question. The symptoms of hyperthyroidism
and hypothyroidism blend with and are notoriously difficult to separate
from other symptoms associated with the postpartum state. Some of the
symptoms of hyperthyroidism and hypothyroidism may be found more
frequently in postpartum women with PPT and/or positive TPO-Ab titers,
compared to those without PPT (18, 19, 20). However, the clinical
distinction between these two groups of postpartum women can be quite
difficult. Depression may be more frequent and severe in women with PPT
(21, 22, 23). Nevertheless, when symptoms are mild in degree and transient
in duration, it is unlikely that treatment is necessary, and equally
unlikely that patients will seek medical attention. If symptoms are
severe enough in degree and duration to bring patients to medical
attention, then clinicians should test for thyroid dysfunction anyway,
and screening would not be necessary. All postpartum women, whether or
not screening is done, should be encouraged by their physicians to seek
medical attention if they have troublesome symptoms and not
automatically attribute a lack of well-being to the postpartum state.
In particular, all postpartum women with depression should be tested
for thyroid dysfunction as depression can be a life-threatening
disorder and needs to be treated promptly.
If a screening program for PPT is employed, what tests should be used
and when should they be done? If all postpartum women were screened
with a sensitive TSH assay at 2- to 3-month intervals, then nearly all
cases of PPT would be detected. However, this strategy is clearly
impractical and too costly. In the United States, where there are 4
million live births per year, this would entail approximately 12
million TSH assays at a cost of about 250 million dollars per year. A
more reasonable strategy would be to screen all postpartum women with a
sensitive thyroid autoantibody assay, such as TPO-Ab, and then follow
the women testing positive with several TSH assays during the 1-yr
postpartum period. From the data in Table 1
, this would entail 4
million TPO-Ab assays and about 1.2 million TSH assays per year at a
cost of about 100 million dollars per year to detect 200,000 cases of
PPT at a cost of $500 per case detected, many of which would be mild
and would not need treatment. A clinical approach to detection of PPT
would cost 30–50 million dollars per year, assuming that 30–50% of 4
million postpartum women were symptomatic and tested with a single TSH
assay, and that all postpartum women received a $2 pamphlet alerting
them to the symptoms of PPT. It is possible that benefits from a
program employing clinical astuteness would be comparable to a
screening program. However, an accurate cost-benefit is not possible
until good studies are available detailing the clinical presentation of
PPT and how they respond to therapy. Unfortunately, no study has yet
been published to demonstrate that such a screening strategy would be
superior in cost or in benefit to thorough clinical assessment of
postpartum women. Although the sensitivity of the TPO-Ab assay in
identifying women who will develop PPT is generally about 90%, the
range in a number of studies is from 50–100% (14). In a recent,
thorough study from The Netherlands the sensitivity was 67%. This
means that screening with a TPO-Ab assay would miss 33% of the women
who develop PPT and, thus, casts doubt on the recommendation of this
strategy for all countries (24, 25). Certain women with a known high
risk for PPT, such as those with type I diabetes mellitus, previous
autoimmune thyroid disease (AITD), or a strong family history of AITD
should be followed closely under any circumstances by thorough clinical
and, if necessary, biochemical scrutiny (26, 27, 28).
Even if screening for PPT is not superior to careful clinical
assessment in the diagnosis and treatment of symptomatic transient
hyperthyroidism or hypothyroidism, should screening be employed to
identify postpartum women who are at risk for permanent overt
hypothyroidism? The long-term sequelae of PPT have been recently
reviewed (29), and the results of those studies that have followed
patients with PPT for 3 yr or longer are summarized in Table 2. Several
important observations can be extracted from this table. First, the
mean rate of progression from PPT to permanent overt hypothyroidism
over a 5-yr period in the 5 studies is 3.6% per year. This is very
close to the rate at which all adult women in the community with a
positive TPO-Ab titer progress to spontaneous overt hypothyroidism as
determined in the renowned Wickham survey, which observed rates of
4.3% per year when the serum TSH level was elevated, and 2.1% per
year when the TSH level was normal (30). Second, the mean rate of
progression of all postpartum women to permanent overt hypothyroidism
over a 5-yr period in the 5 studies is 1.8 cases/1000 women/yr, very
close to the rate at which all women develop spontaneous hypothyroidism
(3.5 cases/1000 women/yr for all women, and 1.4 cases/1000 women/yr for
young women in their child-bearing years) seen in the Wickham survey
(30). Thus, the rate of progression to spontaneous permanent
hypothyroidism in postpartum women with and without PPT is virtually
the same as the rate seen in the Wickham survey in all young women with
and without positive TPO-Ab titers.
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Conclusion
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The time is not yet ripe to recommend a screening program for all
postpartum women to detect PPT, even though the disorder is common. The
basic problem is that there is a lack of knowledge at present about how
to screen, when to screen, and whether or not treatment makes a
difference for those women with unrecognized mild or moderate thyroid
dysfunction. Permanent hypothyroidism occurs at about the same rate of
incidence in postpartum women as in all young women, and in both groups
is confined almost exclusively to those with preexisting AITD. Whether
or not young women, including postpartum women, should be screened to
detect those who have or are at risk for permanent hypothyroidism
remains an open question until further studies clarify the issue.
Finally, a recommendation against screening postpartum women for PPT at
the present time should not be construed to mean that clinical
vigilance is not warranted. In general, the thorough care that women
receive during their pregnancy has no counterpart during their first
postpartum year, as attention in the family and in the medical system
shifts from the mother to the infant. Thus, there is a compelling need
to educate postpartum women and the physicians who care for them about
PPT and other important postpartum afflictions.
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Introduction
Screening for thyroid disease...
