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Post-partum Thyroid Dysfunction and Autoimmunity

Paul G. Walfish, MD, FRCP(C), FACP
Professor of Medicine and Pediatrics, University of Toronto Medical School
Director, Thyroid Research Laboratory, Mount Sinai Hospital Research Institute
Head, Division of Endocrinology and Metabolism, Mount Sinai Hospital, Toronto

Over the past decade there has been an increasing awareness that several disturbances of thyroid function may occur in mothers after delivery which may be more prevalent than previously appreciated. Also, patients with previous thyroid problems before pregnancy may have recurrences. In particular, a transient destructive (inflammatory) type of post-partum hyperthyroidism has been recognized which may be painless (i.e., silent). Preliminary surveys on the prevalence of such disorders post-partum have suggested that it is surprisingly common, being several fold more frequent that post-partum Graves' hyperthyroidism. The importance of assessing thyroid function in mothers who present with clinical problems after parturition merits emphasis because the signs and symptoms of post-partum hyperthyroidism may often be confused with other non-thyroidal diseases commonly considered to occur after delivery such as "post-partum blues" or depression, and "the tired mother syndrome".

To permit the survival of the foreign fetus, a successful pregnancy also requires alterations in the maternal immune system to prevent its rejection. Accordingly, the maternal immune response becomes increasingly suppressed during pregnancy by a variety of mechanisms which can also influence the clinical course of a number of diseases of autoimmune etiology to result in an amelioration of their activity in pregnancy followed by a relapse post-partum when such adaptations are removed. Hence, post-partum exacerbation may occur not only for such non-thyroidal autoimmune diseases as rheumatoid arthritis and systemic lupus erythematosus, but also for such autoimmune thyroid diseases as Hashimoto's thyroiditis and Graves' disease.

Transient post-partum hypothyroidism, occurring three to eight months after delivery, was initially observed in Japanese women, the majority of whom also had evidence of autoimmune thyroiditis, by Amino and co-workers. At the same time, our Clinic in Toronto documented an earlier post-partum phase of transient and spontaneously resolving hyperthyroidism occurring two to four months after delivery in association with a low 24-hour radioactive iodine thyroidal uptake, which was then followed by variable degrees of transient or persistent hypothyroidism. The clinical and laboratory features of the post-partum inflammatory destructive syndrome that we documented were similar to the syndrome of painless thyroiditis which had been described several years earlier in non-post-partum subjects wherein needle biopsy evidence and increased positivity of anti-thyroid antibodies suggested it was a variant form of destructive autoimmune thyroiditis. Long-term follow-up of patients with these syndromes one to ten years later has indicated the persistence of such abnormalities as moderate goiter, biopsy evidence of lymphocytic thyroiditis, elevated basal TSH, and augmented TSH response to thyrotropin releasing hormone (TRH), as well as positive antithyroid antibodies in approximately 30% of patients, thereby adding further support for the likelihood of an underlying autoimmune cause rather than a transient infectious etiology. Subsequently, other workers in Canada, England, the United States, Japan, Europe and Australia have documented the occurrence of the post-partum thyroiditis syndrome.

Our experience in Toronto has indicated that approximately 50% of female patients in the childbearing years with an episode of painless thyroiditis could be related to a recent pregnancy, and were likely that of the transient post-partum painless thyroiditis syndrome. Hence, any female who presents with overt or subclinical primary hypothyroidism within four to eight month after delivery with a small goiter and positive antimicrosomal antibody titer could have evolved from a painless thyroiditis to a transient or persistent hypothyroidism. Also, 10-25% of women who experience one episode of the painless thyroiditis and transient thyrotoxicosis syndrome, whether or not related to pregnancy, have also been observed to be a risk for another episode of this syndrome in a subsequent pregnancy. When post-partum recurrences occur, they appear to be identical in type and time of onset.

While the precise pathogenic mechanisms involved in the post-partum painless thyroiditis inflammatory syndrome with transient hyperthyroidism and hypothyroidism have not been definitively elucidated and may have either an unknown, infectious, chemical or autoimmune cause, the propensity of the painless thyroiditis inflammatory syndrome to occur in the early post-partum period, as well as a number of preliminary studies from our laboratory features as noted above, combined with the results of human leukocyte antigen (HLA) typing, as well as studies using new methodology for assessing peripheral lymphocyte subsets of activated T-cells, favour the conclusion that this syndrome is distinctly different from Graves' disease and more likely to be a variant of a subacute destructive syndrome of goitrous autoimmune (Hashimoto's) thyroiditis.

Prevalence of Post-Partum Thyroid Dysfunction
From estimates of surveys in Japan, the United States, Sweden and Canada on the prevalence of thyroid dysfunction after parturition, it appears that the painless thyroiditis syndrome accounts for over 80% of post-partum hyperthyroidism, in comparison to Graves' disease contributing 10-15%, and the remaining 3-5% resulting from toxic nodular goiters, typical painful subacute thyroiditis, and various miscellaneous causes. Post-partum hypothyroidism is most frequently the result of the painless thyroiditis syndrome which has evolved form previous destructive hyperthyroidism, or represents a reactivation of autoimmune thyroiditis of either a goitrous or atrophic type. While the incidence of hyperthyroidism in pregnancy has been estimated to be 0.05% live births, the prevalence of post-partum hyperthyroid episodes in various surveys varied form 1-4% of which the vast majority are transient hyperthyroidism which resolves spontaneously 1-3 months post-partum and are followed by hypothyroidism of varying degrees of severity between 4-8 months after delivery.

In Osaka, Japan, a survey of mothers 3-8 months after delivery observed on overall incidence of thyroid dysfunction at 5.5% among 507, of whom 70% had transient hyperthyroidism and only a few persistent hypothyroidism. In Uppsala, Sweden, the prevalence of biochemical post-partum thyroid dysfunction was 6.5% in a group of 460 women, representing an overall prevalence of 4.2% among the 644 women who entered the study. Our studies in Toronto over the last several years have demonstrated the prevalence of thyroid dysfunction and autoimmunity in testing mothers 6-24 weeks after delivery, have found a 7.1% incidence of abnormalities, among which 18 of the 27 mothers (67%) had laboratory evidence of hyperthyroidism; 89% of these were transient and only 11% represented persistent Graves' hyperthyroidism. After delivery, 80% of patients discovered to have transient post-partum hyperthyroidism had positive thyroidal antimicrosomal antibody titers with a marked 3-4 fold increase in mean titer by 4-6 months post-partum in comparison to their previous values several days after delivery.

Clinical and Laboratory Features
The most common symptoms of post-partum hyperthyroidism occurring 6-12 weeks after delivery were fatigue, increased sweating, palpitations, and perhaps nervousness and weight loss; and subsequently, common symptoms occurring 12-24 weeks post-partum included fatigue, weight gain, lethargy and depression in the hypothyroid phase. Some of the risk factors observed in predisposing individuals to post-partum hypothyroidism are a previous episode (either related or unrelated to pregnancy), a positive family history of autoimmune thyroid disease, non-thyroidal autoimmune diseases in first degree relatives, and previous episodes of Graves' disease or post-partum Graves' disease, and previous active thyroid disease and autoimmunity, with positive antithyroid antibody tests. To determine most accurately the correct course of post-partum hyperthyroidism, a thyroidal radioactive iodine uptake test is required in the hyperthyroid phase, while ceasing breast-feeding for several days. An abnormally low thyroid uptake value is observed in the painless thyroiditis syndrome compared to a high value when Graves' disease is present to account for hyperthyroidism. In the absence of such a test, only serial clinical and laboratory assessments which document a rapid and spontaneous resolution of post-partum hyperthyroidism followed by a subsequent hypothyroid phase can diagnostically affirm the post-partum painless thyroiditis syndrome and differentiate it from transient or persistent Graves' hyperthyroidism. Post-partum hypothyroidism can only be transient if a preceding spontaneously resolving hyperthyroid phase was documented, but may also represent the transient or persistent occurrence of typical autoimmune Hashimoto's thyroiditis, which was not preceded by a hyperthyroid phase when thyroid gland enlargement is more that twice normal size and is associated with very high antithyroid antibody serum levels.

Treatment of Post-Partum Thyroid Dysfunction
Management of the painless thyroiditis syndrome in the transient thyrotoxic phase involved no therapy when relatively mild and asymptomatic. However, when hyperthyroid symptoms are present, only conservative therapy with beta-adrenergic blockers to reduce the heart rate, with sedatives and/or tranquilizers for nervousness is indicated. Close follow-up is essential for detection and management of possible subsequent hypothyroid phase, which may be symptomatic but is seldom permanent. Follow-up of female patients previously suspected of episodes of hyperthyroidism or hypothyroidism due to painless thyroiditis syndrome or Graves' disease, either related or unrelated to pregnancy, should be obtained in subsequent pregnancies, particularly at delivery, because of their increased risk for another episode which could benefit by early diagnosis and appropriate treatment.

Patients with underlying Graves' disease may also have remissions of their disease in pregnancy and relapses post-partum, with or without a previous history of Graves' disease. Depending upon clinical manifestation, patient and physician preferences, post-partum Graves' may be treated by one of several choices of conventional therapy involving either thyroid medication and surgery or, when no future pregnancies are planned, radioactive iodine therapy may be the treatment of choice in most North American centers followed by long-term observation for possible subsequent hypothyroidism and the need for life-long hormone replacement therapy.

Summary
The importance of recognizing the frequent occurrence of disturbances of thyroid function post-partum has been reviewed. There is a surprisingly high prevalence in Japan, Europe and North America of the post-partum autoimmune thyroid disease syndromes occurring in approximately 4 to 7% of post-partum mothers, of whom the majority have a destructive painless thyroiditis syndrome. The frequency of these syndromes likely reflects changes in peripartum immune network regulation. Hence, mothers who develop post-partum complaints which have been previously attributed to non-thyroidal diseases should be carefully assessed for the possibility of a post-partum disturbance in thyroid function and autoimmunity, particularly in those subjects with a previously known history of autoimmune thyroid disease or a family predisposition, and be followed for the possibility of repeated episodes in subsequent pregnancies.

References
Amino, N., Miyai, K., Onishi, T., et al. Transient hypothyroidism after delivery in autoimmune thyroiditis. J. Clin. Endocrinology & Metabolism 1976, 42, 296-301. Amino, N., Mori, H., Iwatani, Y., et al. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N. Engl. J. Med. 1982, 306, 849-52. Farid, N.R., Hawe, B.S., Walfish, P.G. Increased frequency of HLA-DR3 and 5 in the syndromes of painless thyroiditis with transient thyrotoxicosis: Evidence for an autoimmune etiology. Clin. Endocrinology (Oxf.) 1983, 19, 699-704. Ginsburg, J., Walfish, P.G. Post-partum transient thyrotoxicosis with painless thyroiditis. Lancet, 1977, 1, 1125-8. Walfish, P.G., Chan, J.Y.C. Post-partum hyperthyroidism. Clinics in Endocrinology and Metabolism, 1985, 14, 417-47.

Reprinted from Thyrobulletin, Vol. 7, No. 2.
To order a reprint ($2 P&H) contact the National Office or your local chapter.

Reviewed 2000