THERAPEUTIC CONTROVERSY
Screening for Postpartum Thyroiditis
NOBUYUKI AMINO, HISATO TADA, YOH HIDAKA, LAWRENCE M. CRAPO, AND
ALEX STAGNARO-GREEN
“Therapeutic Controversies” are an occasional feature ofThe Journal of Clinical Endocrinology &
Metabolism.They present the opposing views of invited contributors on a topic. All reprints must include the complete Therapeutic Controversy, so that each section can be read in context.
Screening for Postpartum Thyroid Dysfunction in the General Population Is Beneficial
Nobuyuki Amino, Hisato Tada, and Yoh Hidaka Department of Laboratory Medicine
Osaka University Medical School Osaka 565-0871, Japan
P
OSTPARTUM thyroid dysfunction is recognized as a common disease among postpartum women (1), with a prevalence rate of around 5%,i.e.1 in 20 pregnant women suffers from thyroid dysfunction after parturition (2–14). To discuss whether screening for postpartum thy-roid dysfunction is beneficial, we shall examine the fol-lowing questions:1. Are there any effective tests or protocols to screen post-partum thyroid dysfunction?
2. What is the benefit of the screening for postpartum thyroid dysfunction?
3. Does the effectiveness meet the costs?
There are effective protocols to screen postpartum thyroid dysfunction
Postpartum autoimmune thyroid dysfunction is briefly characterized as a postpartum exacerbation of subclinical autoimmune thyroid disease, wherein some immunolog-ical abnormalities are observed before the onset of thyroid dysfunction. Therefore, we can detect the high-risk group for postpartum thyroid dysfunction by screening, in early pregnancy, those with subclinical autoimmune thyroid-itis. Among several methods for detecting thyroid auto-immunities, the measurement of anti-thyroid microsomal antibody (MCAb) or thyroid peroxidase (TPO) antibody is the most useful marker for detecting subclinical autoim-mune thyroiditis and, therefore, for predicting the occur-rence of postpartum thyroid dysfunction. When MCAb is
positive, there is always lymphocytic infiltration into the thyroid, indicating subclinical autoimmune thyroiditis (15) that may be exacerbated after delivery. Sixty to sev-enty percent of women with positive MCAb in early preg-nancy develop postpartum thyroid dysfunction (1). Other investigators have also reported that MCAb-positive sub-jects had approximately 20 –23 times the relative risk (over normal subjects) for developing postpartum thyroid dys-function (16, 17). On the other hand, the prevalence of postpartum thyroid dysfunction in the MCAb-negative subjects in early pregnancy is estimated as 1/100 of that in MCAb-positive subjects (Fig. 1). So, when we screen 1000 early pregnant women in the general population, we can expect to find about 50 patients with postpartum thy-roid dysfunction.
Although MCAb is a good marker for the occurrence of postpartum thyroid dysfunction, it gives no information about the type of dysfunction that will occur. Among the various types of dysfunctions, postpartum Graves’ disease is clinically the most important and is predicted by the measurement of thyroid-stimulating antibodies (TSAb) with a sensitive bioassay (18). Our subsequent study (19) revealed that pregnant women with positive TSAb in early pregnancy had a much higher risk of developing post-partum Graves’ disease. We observed 71 pregnant women with positive MCAb from early pregnancy through the postpartum period. Among them, 7 showed positive TSAb, and 5 of those 7 (71%) developed postpartum Graves’ disease. Thyrotoxicosis in 3 of those 5 was tran-sient and spontaneously improved within a year. Graves’ disease did not occur in the TSAb-negative subjects. Anti-TSH receptor (Anti-TSHR) antibodies (TRAb) with conven-tional radio-receptor assay (thyrotropin binding inhibi-tory immunoglobulin; TBII) were not useful in predicting postpartum Graves’ disease.
Figure 2 shows a protocol that we have tentatively em-ployed to screen for postpartum thyroid dysfunction at the outpatient maternity clinic of the Osaka University Hos-pital for several years. In the protocol, MCAb-positive mothers are examined for thyroid status, measuring serum free thyroxine (FT4), serum free triiodothyronine (FT3), serum thyrotropin (TSH), anti-TSHR antibody (TRAb), and antithyroglobulin (TgAb), and are observed every Accepted March 8, 1999.
Address correspondence and requests for reprints to: Alex Stagnaro-Green, MD, Dean for Student Affairs and Medical Education, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1255, New York, New York 10029-6574. E-mail: [email protected]. Re-prints of the Therapeutic Controversies will include all authors and all pages, as shown in the journal.
4 – 8 weeks. We believe that this close observation protocol for MCAb-positive subjects is practical in only a few countries, such as Japan, where the national health
insur-ance system is well-established. It should be modified according to the situation and health system of each country.
FIG. 1. The prevalence of antithyroid MCAb and the occurrence of postpar-tum thyroid dysfunction among preg-nant women in the general population.
FIG. 2. A protocol to screen and follow MCAb-positive mothers. MCAb, anti-thyroid microsomal antibody; FT4, free thyroxine; FT3, free triiodothyronine; TSH, thyrotropin; TRAb, anti-TSH re-ceptor antibody.
The benefits of screening postpartum thyroid dysfunction
Although postpartum thyroid dysfunction may be tran-sient in many cases (20), we should pay close attention to the possibility that mothers with thyroid dysfunction already tired from the birth and from taking care of a newborn, may feel terribly worn out and helpless or may become ill in bed. Postpartum depression, which in severe cases may result in a forced double suicide of mother and baby (called “Shinjuh” in Japanese), can be screened by MCAb measurement, al-though postpartum depression may occur not in association with thyroid dysfunction (17, 21–23) but with antithyroid MCAb (24, 25). The main benefit of screening for postpartum thyroid dysfunction is the opportunity to improve the qual-ity of life of mothers who may suffer from the above symp-toms. Even when the patient does not want drug therapy, she benefits by being informed about what is happening to her. From our experience, patients with mild to moderate thyroid dysfunction can live well with the support of family without medication. Further, prevention of future episodes of post-partum thyroid dysfunction may be possible. We have ex-perienced one case of successful prevention. The patient had developed severe postpartum thyroid dysfunction in each of her previous parturitions, and she did not want to repeat the condition after the next delivery. Moderate doses of glu-cocorticoid, gradually decreased and stopped in one month, suppressed her thyroid dysfunction to only a small fluctu-ation within the normal range.
Postpartum Graves’ disease accounts for 11.4% of post-partum thyroid dysfunctions (occurring in 0.54% of all moth-ers in the general population) (19). Convmoth-ersely, 40% of Graves’ patients 20 –39 yr old, who have had one or more deliveries, developed their disease during the postpartum period (26). Diagnosis of postpartum Graves’ disease early, while it is mild, may easily lead to remission and may reduce Graves’ disease in older age. In our experience, the early start of antithyroid therapy reduces the period of therapy by half (19). Antithyroid therapy may be a good choice for first-line therapy (27) because postpartum Graves’ hyperthyroidism is often transient and because mothers may not want to inter-rupt breast-feeding to undergo radioiodine therapy.
An additional benefit to screening with MCAb anti-bodies in early pregnancy may be not only to find postpar-tum thyroid dysfunction, but also to find mothers at high risk for spontaneous abortion. In our prospective study, the spon-taneous abortion rate in MCAb-positive mothers was twice as high as that in MCAb-negative mothers (28).
There has been no analysis of the cost-effectiveness of screening for postpartum thyroid dysfunction
The cost of MCAb measurement to screen for the occur-rence of postpartum thyroid dysfunction is low when we use semiquantitative particle agglutination tests. However, thy-roid function tests and anti-TSHR antibody measurement for MCAb-positive subjects are not cheap, especially when pa-tients are observed closely and are tested repeatedly. On the other hand, the main benefit of screening for postpartum thyroid dysfunction is improving the mother’s quality of life, which is difficult to numerically assess. Heyslip et al. (29) tried to estimate the costs of several screening methods and
concluded that MCAb measurement is the most cost-effec-tive, but their report compares only the screening methods for postpartum thyroid dysfunction; they did not analyze the benefit of mothers’ quality of life, nor did they discuss cost-effectiveness compared with the screening for other diseases or other health services. Indeed, there seems no analysis of the cost-effectiveness of screening for postpartum thyroid dysfunction (23, 30). However, the observation protocol we describe can be modified to be less expensive, and screening subjects may be restricted to certain high-risk groups, such as the patients with IDDM. We believe an optimized system of screening will be found whose costs are acceptable for each society.
We experimentally applied TSAb to the second-line screening of MCAb-positive mothers and found that TSAb gives predictive information on potential development of postpartum Graves’ disease. TSAb measurement is obvi-ously too expensive, and the procedure is too complicated to apply screening to the general population. However, we expect the development of a more sensitive radioreceptor assay may change the situation (31).
Conclusion
The benefit of screening for postpartum thyroid dysfunc-tion mainly concerns elusive, nonquantitative parameters— the quality of life of mothers—that can be difficult to assess. However, we would hope to find an acceptable, cost-effec-tive system of screening for postpartum thyroid dysfunction.
References
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2.Amino N, Mori H, Iwatani Y, et al.1982 High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N Engl J Med. 306:849 – 852. 3.Jansson R, Bernander S, Karlsson A, Levin K, Nilsson G.1984 Autoimmune
thyroid dysfunction in the postpartum period. J Clin Endocrinol Metab. 58:681– 687.
4.Walfish P, Chan J.1985 Postpartum hyperthyroidism. Clin Endocrinol Metab. 14:417– 447.
5.Freeman R, Rosen H, Thysen B.1986 Incidence of thyroid dysfunction in an unselected postpartum population. Arch Intern Med. 146:1361–1364. 6.Nikolai TF, Turney SL, Roberts RC.1987 Postpartum lymphocytic thyroiditis.
Prevalence, clinical course, and long-term follow-up. Arch Intern Med. 147:221–224.
7.Lervang HH, Pryds O, Kristensen HP.1987 Thyroid dysfunction after deliv-ery: incidence and clinical course. Acta Med Scand. 222:369 –374.
8.Fung HYM, Kologlu M, Collison K, et al.1988 Postpartum thyroid dysfunc-tion in Mid Glamorgan. Br Med J. 296:241–244.
9.Rasmussen NG, Hornnes PJ, Hoiter-Madsen M, Feldt-Rasmussen U, Hege-dus L.1990 Thyroid size and function in healthy pregnant women with thyroid autoantibodies. Acta Endocrinol (Copenh). 123:395– 401.
10. Rajatanavin R, Chailurkit LO, Tirarungsikul K, Chalayondeja W, Jittivanich U, Puapradit W.1990 Postpartum thyroid dysfunction in Bangkok: a geo-graphical variation in the prevalence. Acta Endocrinol (Copenh). 122:283–287. 11. Roti E, Bianconi L, Gardini E, et al.1991 Postpartum thyroid dysfunction in an Italian population residing in an area of mild iodine deficiency. J Endocrinol Invest. 14:669 – 674.
12. Lo¨big H, Bohn W, Mau J, Schatz H.1991 Prevalence of postpartum thyroiditis in two iodine-deficient regions of Germany. In: Scherbaum W, Bogner U, Weinheimer B, and Bottazzo G, eds. Autoimmune thyroiditis. Berlin: Springer-Verlag; 185–193.
13. Walfish PG, Meyerson J, Provias JP, Vargas MT, Papsis FR.1992 Prevalence and characteristics of post-partum thyroid dysfunction: Results of a survey from Toronto, Canada. J Endocrinol Invest. 15:265–272.
14. Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Wallenstein S, Da-vies TF.1992 A prospective study of lymphocyte-initiated immunosuppres-sion in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endocrinol Metab. 74:645– 653.
antibodies with lymphocytic infiltration of the thyroid gland: studies of sev-enty autopsied cases. J Clin Endocrinol Metab. 46:859 – 862.
16. Solomon BL, Fein HG, Smallridge RC.1993 Usefulness of antimicrosomal antibody titers in the diagnosis and treatment of postpartum thyroiditis. J Fam Pract. 36:177–182.
17. Pop VJM, de Rooy HA, Vader HL, van der Heide D, van Son MM, Komproe IH.1993 Microsomal antibodies during gestation in relation to postpartum thyroid dysfunction and depression. Acta Endocrinol (Copenh). 129:26 –30. 18. Tamaki H, Amino N, Aozasa M, Mori M, Tanazawa O, Miyai K.1987 Serial
changes in thyroid-stimulating antibody and thyrotropin binding inhibitor immunoglobulin at the time of postpartum occurrence of thyrotoxicosis in Graves’ disease. J Clin Endocrinol Metab. 65:324 –330.
19. Hidaka Y, Tamaki H, Iwatani Y, Tada H, Mitsuda N, Amino N.1994 Pre-diction of postpartum onset of Graves’ thyrotoxicosis by measurement of thyroid stimulating antibody in early pregnancy. Clin Endocrinol (Oxf). 41:15–20.
20. Amino N, Tada H, Hidaka Y.1996 The spectrum of postpartum thyroid dysfunction: diagnosis, management, and long-term prognosis. Endocr Pract. 2:406 – 410.
21. Harris B, Fung H, Johns S, et al.1989 Transient postpartum thyroid dysfunc-tion and postnatal depression. J Affect Disord. 17:243–249.
22. Pop VJM, Rooy HAM, Vader HL, et al.1991 Postpartum thyroid dysfunction and depression in an unselected population. New Engl J Med. 324:1815–1816. 23. Lazarus JH, Harris B, Parkes AB.1996 Antenatal screening of thyroid
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24. Harris B, Othman S, Davies JA, et al.1992 Association between postpartum thyroid dysfunction and thyroid antibodies and depression. BMJ. 305:152–156. 25. Pop VJ, Maartens LH, Leusink G, et al.1998 Are autoimmune thyroid
dys-function and depression related? J Clin Endocrinol Metab. 83:3194 –3197. 26. Tada H, Hidaka Y, Itoh E, et al.1994 Prevalence of postpartum onset of disease
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29. Haylip CC, Fein HG, O’Donnel VM, et al.1988 The value of serum antimi-crosomal antibody testing in screening for symptomatic postpartum thyroid dysfunction. Am J Obstet Gynecol. 159:203–209.
30. Ball S.1996 Antenatal screening of thyroid antibodies. Lancet. 348:906 –907. 31. Watabnabe Y, Tada H, Hidaka Y, et al.1999 Polyethylene glycol increases the detection of anti-thyrotropin (TSH) receptor antibodies by a radioreceptor assay. Clin Chem. 45:407– 409.
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
A
T FIRST GLANCE, screening for postpartum thyroid-itis (PPT) appears to be an attractive and possibly even a cost-effective strategy. The disorder is quite common, af-fecting 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 symp-toms frequently present during the postpartum period. Those women at high risk for PPT are easy to identify be-cause 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, symp-toms 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 pri-mary care physicians and postpartum patients about PPT. Which thyroid autoantibody assay should be used for screen-ing and when the assay should be performed have not been completely resolved. Furthermore, there is a lack of knowl-edge 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 post-partum women to identify those who are at risk for or who have PPT.
Screening for thyroid disease in general
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 pur-pose 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 strat-egy 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) recom-mended against screening for thyroid disease in asymptom-atic subjects in the general population who were not at high risk for thyroid disease and its consequences (7). The Cana-dian 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 screen-ing for hypothyroidism in neonates even though it is infre-quent (1 case per 4,000 births). The ATA recommends screen-ing 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
re-main alert for subtle signs and symptoms of thyroid dys-function and keep a low threshold for evaluating thyroid status in such high risk subjects.
Recently, one study has demonstrated by cost-utility de-cision analysis that it is cost-effective to screen for mild thy-roid 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 recom-mended screening for unsuspected but symptomatic hypo-thyroidism and hyperhypo-thyroidism 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 recom-mend for or against screening for subclinical hypothyroidism or subclinical hyperthyroidism, although this latter recom-mendation 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 pres-tigious 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 char-acteristics of PPT.
Screening for postpartum thyroiditis
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 de-structive lymphocytic infiltration of the thyroid gland, very often with accompanying circulating thyroid autoantibodies, which can manifest itself as transient hyperthyroidism, tran-sient hypothyroidism, or permanent hypothyroidism. These manifestations result from activation of immunological changes that occur in the first postpartum year. The symp-toms 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 ren-ders 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 de-velop 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 lo-cation, definition of PPT, duration of studies, and frequency of testing. A critical evaluation of many of the studies sug-gests that the incidence of symptomatic PPT is about 5% (1). The incidence data on permanent overt hypothyroidism in Table 1 and Table 2 has been derived from 5 separate studies in which patients with PPT have been followed for 3–5 yr (3, 4, 15–17).
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 hyperthy-roidism and to identify women who are at risk for subse-quent 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 phy-sicians who care for postpartum women? Unfortunately, no prospective studies have yet been conducted that answer this question. The symptoms of hyperthyroidism and hypothy-roidism blend with and are notoriously difficult to separate from other symptoms associated with the postpartum state. Some of the symptoms of hyperthyroidism and hypothy-roidism may be found more frequently in postpartum women with PPT and/or positive TPO-Ab titers, compared to those without PPT (18 –20). However, the clinical distinc-tion between these two groups of postpartum women can be quite difficult. Depression may be more frequent and severe in women with PPT (21–23). 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 en-couraged by their physicians to seek medical attention if they have troublesome symptoms and not automatically attribute TABLE 1. Epidemiology of postpartum thyroiditis
Total number of women
Women with positive TPO-Ab titers
Women with negative TPO-Ab titers
Postpartum women 1000 100 900
Women with PPT 50 45 5
Women with permanent hypothyroidism by 5 yr 9 9 0
The data in this table assumes that, for 1,000 unselected postpartum women, 5% will develop postpartum thyroiditis (PPT), and 90% of these women will be positive for serum thyroid peroxidase autoantibodies (TPO-Ab). It is further assumed that nearly 50% of women with positive serum TPO-Ab titers will develop PPT, and that, in these women, permanent hypothyroidism develops at an average rate of 3.6% per yr, with an overall incidence rate of 1.8 cases/1000 women/yr. See the text and Table 2 for references and calculations to support these assumptions.
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 post-partum 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 ther-apy. Unfortunately, no study has yet been published to dem-onstrate that such a screening strategy would be superior in cost or in benefit to thorough clinical assessment of post-partum women. Although the sensitivity of the TPO-Ab as-say 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 neces-sary, biochemical scrutiny (26 –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 re-nowned 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 wom-en/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.
Conclusion
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 dys-function. 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, TABLE 2. Progression of postpartum thyroiditis to permanent overt hypothyroidism
Patients with PPT Patients with permanent HYPO Years of follow-up
Progression to permanent HYPO (per 100 women with PPT/yr)
Progression to permanent HYPO (per 1000 postpartum women/yr)
Study (ref) 25 3 3 4.0 2.0 Nikolai (16) 44 9 5 4.1 2.1 Taichi (3) 31 5 5 3.2 1.6 Jansson (15) 43 4 3.5 2.7 1.4 Othman (4) 40 6 4 3.7 1.9 Soloman (17)
This table presents the rate of progression from postpartum thyroiditis (PPT) to permanent overt hypothyroidism (HYPO) in percent per year based on long-term follow-up data from five separate studies. It also presents the rate of progression of 1000 normal postpartum women to permanent hypothyroidism in cases per year by assuming that patients with PPT represent about 5% of their original cohort of all postpartum women.
the thorough care that women receive during their preg-nancy 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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Postpartum Thyroiditis: The Case For Selective Screening
Alex Stagnaro-Green
Division of Endocrinology and Metabolism Department of Medicine
Mount Sinai School of Medicine New York, New York 10029
P
OSTPARTUM thyroiditis is one of the most common diseases of the thyroid and has important clinical se-quelae. In studies in North America postpartum thyroiditis affects between 6.0 – 8.8% of all pregnant women (1–3). Post-partum thyroiditis also has clearly defined morbidities. Women with postpartum thyroiditis may experience symp-toms in both the hyperthyroid and hypothyroid phase, and may have an increased incidence of postpartum depression (4, 5). Long-term follow-up reveals that approximately 25% of women with postpartum thyroiditis develop permanent primary hypothyroidism within 5 yr of delivery (6, 7). Fur-thermore, the presence of thyroid autoantibodies in the first trimester of pregnancy is associated with an increased rate of spontaneous abortion (8 –11). Given both the prevalence of the disorder and the associated morbidities, the argument for screening for postpartum thyroiditis seems iron clad, and one can only wonder why a screening program for postpar-tum thyroiditis has not already been instituted.On the other hand, screening for postpartum thyroiditis is an enormous undertaking with tremendous fiscal implica-tions. Every pregnant women would need to be screened for the presence of thyroid peroxidase autoantibodies. Women who test positive would require a minimum of two mea-surements of TSH in the postpartum (3 and 6 months). Fur-thermore, the following three unproven assumptions under-lie the argument for screening; a) that the optimal screening strategy is known, b) that treating women with postpartum thyroiditis would decrease the incidence or severity of post-partum depression, and c) that treating postpost-partum thyroid-itis would decrease the incidence of, or the symptoms asso-ciated with, long-term primary hypothyroidism. Given these arguments, it now appears that screening for postpartum thyroiditis is premature and a questionable use of limited fiscal resources.
Given the powerful but conflicting, scientific, fiscal, and emotional arguments for screening for postpartum thyroid-itis the clinician is left in a quandary. A rational approach to resolve the screening debate requires the following four questions be addressed:
1. Is postpartum thyroiditis a common enough clinical entity to warrant screening?
2. Are there important morbidities associated with post-partum thyroiditis?
3. Can the morbidities of postpartum thyroiditis be pre-vented with levothyroxine therapy?
4. Is there an inexpensive, easily available, and accurate screening test?
Prevalence
Worldwide, the prevalence of postpartum thyroiditis var-ies widely, from 1.1% in Thailand to 16.7% in the United Kingdom (12, 13). The disparity is explained both by true geographic differences in prevalence rates as well as by crit-ical study design issues such as the length of follow-up in the postpartum period and the frequency of screening. Studies performed in the United States and Canada that extend be-yond three months postpartum have revealed similar prev-alence rates (6% in Canada, 6.7% in Wisconsin, and 8.8% in the New York Metropolitan area) (1–3). In women with Type I diabetes mellitus, another autoimmune disorder, the prev-alence in North America is substantially higher at 25% (14 –15).
The highest prevalence rates of postpartum thyroiditis are found in women with a prior history of postpartum thy-roiditis. Lazaruset al.(16) found that 69% of women who had a history of postpartum thyroiditis developed a recurrence with a subsequent pregnancy. Twenty-five percent of women who were antibody positive in the initial pregnancy, but euthyroid in the postpartum period, developed postpar-tum thyroiditis after the next delivery.
Associated morbidities
Women with postpartum thyroiditis develop both short-term and long-short-term complications. Although few women require treatment in the hyperthyroid phase, and in fact many women are not diagnosed until they develop hypo-thyroidism, studies have revealed an increase in palpitations, heat intolerance, and tremulousness during the hyperthy-roid period (3). Classical symptoms of hypothyhyperthy-roidism, as well as concentration and memory deficits, are present in the hypothyroid phase of postpartum thyroiditis (5). The final short-term complication is an increased incidence of post-partum depression. Studies have indicated a 38 –53% inci-dence of nonpsychotic depression in women affected with postpartum thyroiditis (4, 5). One study has even found an increased incidence of postpartum depression in women who were thyroid autoantibody positive but who did not develop postpartum thyroiditis (17). Finally, long-term fol-low of women with postpartum thyroiditis has revealed an incidence of long term primary hypothyroidism of approx-imately 25% (6, 7).
The correlation between thyroid autoantibodies and an increase in spontaneous abortions is also pertinent to the screening debate. Four studies have revealed a 2- to 3-fold doubling in the rate of spontaneous miscarriage in un-selected women who screened positive for thyroid autoan-tibodies in the first trimester of pregnancy (8 –11). In women with recurrent abortion, defined as three or more spontane-ous miscarriages without an intervening live birth, the data has been mixed. Three of five studies have shown an
in-creased incidence of thyroid autoantibodies in women with recurrent abortion (18 –22).
Intervention/prevention
The impact of levothyroxine therapy on the short- and long-term complications of postpartum thyroiditis is largely unknown. Beta blockers during the hyperthyroid phase and levothyroxine therapy in women who are hypothyroid are effective interventions. However, whether or not levothy-roxine therapy alters the incidence or severity of the depres-sion associated with postpartum thyroiditis has not been evaluated.
Studies attempting to prevent the occurrence of postpar-tum thyroiditis through the administration of iodide or levo-thyroxine in antibody positive women have been unsuccess-ful (23). Furthermore, at present there are no known interventions which, administered during the hyperthyroid or hypothyroid phase, would result in a decrease in the high rate of permanent hypothyroidism.
A recent study has demonstrated a decrease in the rate of recurrent abortion in women who were thyroid antibody positive through the administration of intravenous immu-noglobulin before conception and throughout the first 8 months of pregnancy (24). Replication of these results are required before their implementation outside of a research setting.
Screening
A successful screening strategy for postpartum thyroiditis depends on the availability of an accurate test. As defined in theGuide to Clinical Preventive Services,accuracy relates to the sensitivity, specificity, and reliability of a screening test. In short, “The test must be able to detect the target condition earlier than without screening and with sufficient accuracy to avoid producing large numbers of positive and false-negative results. . .” (25).
Thyroid peroxidase antibody is the potential screening test of choice for postpartum thyroiditis. It is widely available, easily reproducible, and relatively cheap. Screening for thy-roid peroxidase antibodies would need to occur early in pregnancy in order to identify women who were going to develop postpartum thyroiditis before its manifestation. Given the dramatic and well documented decrease (often to undetectable levels) in thyroid antibodies during pregnancy, screening at delivery would miss a large percentage of the cases and consequently would have an unacceptably high false negative rate.
Five studies have prospectively followed a cohort of an-tibody positive and anan-tibody negative women during preg-nancy and into the postpartum (1, 13, 26 –28). The positive predictive value of thyroid peroxidase (defined as the per-centage of women who have thyroid antibodies during pregnancy and who subsequently develop postpartum thy-roiditis) was relatively low and ranged from 30 –52%. Fur-thermore, 9 –39% of the women who developed postpartum thyroiditis in these studies were antibody negative during pregnancy. The positive predictive value of thyroid perox-idase could be increased by focusing on women with high
titers of thyroid peroxidase, but this would result in an in-creased false negative rate.
The positive predictive value of thyroid peroxidase in women with Type I diabetes mellitus was also limited, rang-ing from 33– 67% (14, 15, 29). Similarly, 17–57% of women with Type I diabetes who developed postpartum thyroiditis, tested negative for thyroid peroxidase antibodies during pregnancy.
Conclusion
Despite the high prevalence of postpartum thyroiditis in the general population, screening of all women cannot be justified at present. The limited positive predictive value of thyroid peroxidase antibodies, the presence of a substantial number of antibody negative women who develop postpar-tum thyroiditis, and the unproven efficacy of levothyroxine in preventing postpartum depression or long-term primary hypothyroidism, makes screening all pregnant women un-tenable. Furthermore, the conflicting data on the association of thyroid antibodies and recurrent abortion (despite the clear association between thyroid antibodies and spontane-ous miscarriage in unselected women) requires further elu-cidation before it could be used as a rationale for screening. Two specific populations however, would clearly benefit from testing for postpartum thyroiditis. Specifically, women with a prior history of postpartum thyroiditis (prevalence of recurrent thyroiditis— 69%) and individuals with Type I di-abetes mellitus (prevalence of postpartum thyroiditis—25%) should have TSH determinations at 3 and 6 months post-partum. In these select groups screening with thyroid per-oxidase antibodies offers no advantages. Women who ex-hibit either suppressed or elevated TSH levels would require further evaluation. Whether or not women with a history of another autoimmune disorder (such as systemic lupus ery-thematosus or Sjogren’s disease), or who have a strong fam-ily history of autoimmune disease, should be screened is at present an unresolved question.
Research in the future should focus on refining screening strategies for postpartum thyroiditis and determining the efficacy of levothyroxine in preventing or ameliorating post-partum depression and primary hypothyroidism. In the in-terim, a dedicated effort to educate obstetricians, internists, pediatricians, family practitioners, and psychiatrists is needed so that the acute symptoms associated with the hy-perthyroid and hypothyroid phase can be recognized, diag-nosed, and appropriately treated.
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