THYROID Volume 2, Number 1, 1992 Mary Ann Liebert, Inc., Publishers
Postpartum Thyroid Dysfunction DIANA L. LEAROYD, HEDY Y. M. FUNG, and ALAN M. McGREGOR
ABSTRACT
Postpartum thyroid dysfunction (PPTD) refers to the syndromes of transient hyperthyroidism, transient hypothyroidism, or both, occurring sequentially in the first 12 months postpartum. Approximately 5 to 9% of women develop the disorder in this period. PPTD is most often subclinical but some women will experience symptoms such as lack of energy and depression in the hypothyroid phase. The thyroid gland, which normally enlarges during pregnancy, will remain enlarged or enlarge further in the postpartum period in a significant number of affected women, instead of returning to the prepregnancy size as in unaffected women. The gland is painless and histologically demonstrates lymphocytic infiltration. PPTD is strongly associated with the presence of antimicrosomal and/or antithyroglobulin antibodies, which occur in up to 76% of cases. Antibody activity tends to increase in the postpartum period and to peak at the time of onset of the disorder. TSFf receptor antibodies are not seen and the gland has low radioiodine uptake, distinguishing PPTD from Graves' disease. The HLA associations are controversial, as is the role of dietary iodine. The etiology of PPTD is almost certainly immunological, reflecting the phenomenon of rebound from the relative immune tolerance of pregnancy. Detection of the disorder is important in order to reassure or treat those who are symptomatic and because PPTD may recur in subsequent pregnancies. In addition, up to one third of affected women will go on to develop permanent hypothyroidism 2 to 4 years later. The role of screening for PPTD remains to be clarified.
INTRODUCTION
The term postpartum thyroid dysfunction (PPTD) usually refers to the more common collection of syndromes characterized by transient hyperthyroidism, transient hypothyroidism, or both occurring sequentially in the first 12 months postpartum. The disorder almost certainly has an autoimmune basis, resulting from altered immune tolerance following pregnancy-induced immunosuppression in women with latent or subclinical autoimmune thyroid disease (AITD). It is strongly associated with the presence of antimicrosomal or antithyroglobulin antibodies or both. The hyperthyroid phase of PPTD may be distinguished from Graves' thyrotoxicosis by the low radioiodine uptake and the absence of TSH receptor antibodies. This collection of syndromes of postpartum thyroid dysfunction is the main subject of this review.
IS ASSOCIATED with a complex series of changes function and the immune state. The former in both changes enable the mother to remain euthyroid despite the metabolic demands and altered physiology of pregnancy. The latter changes enable her to display immunologie tolerance to the fetus. The changes occurring in pregnancy have particularly important implications in the postpartum period for women with disorders of an autoimmune nature. These disorders tend to remit during pregnancy and relapse postpartum. Alterations in thyroid function may occur in the postpartum period and be due to a variety of causes. Such conditions as toxic nodular goiter, painful subacute thyroiditis. and thyrotoxicosis factita may account for up to 7% of cases ( 1 ). Graves' disease may account for up to 10% of postpartum hyperthyroid cases, whether this be a relapse of preexisting disease that had improved during pregnancy or newly developed Graves' disease (2). Similarly, lymphocytic thyroiditis may occur de novo or relapse post-
PREGNANCYthyroid
PREGNANCY-INDUCED CHANGES IN THYROID FUNCTION The
partum. Department of Medicine, King's College School of Medicine.
nancy
London. United
73
changes are
that occur in thyroid function in normal pregoutlined briefly, although they are reviewed more
Kingdom.
74
LEAROYD ET AL.
extensively elsewhere (3). They are important in the understanding of the transition from pregnancy to the postpartum state. There is an increase in the basal metabolic rate by 15-20% in pregnancy, rising slowly between 4 and 8 months gestation. This is a consequence of both the increase in oxygen consumption of the fetoplacental unit and the increase in maternal cardiac output (4). Iodide uptake by the thyroid gland increases, compensating for urinary losses that cannot be explained fully by the increased glomerular filtration rate (GFR) of pregnancy. There is a reduction in the plasma inorganic iodide concentration from the 16th week of pregnancy (5). Estrogen-induced synthesis of thyroid hormone binding proteins leads to a significant elevation of thyroxine binding globulin (by about 50%) and also of total T4 and T3. There is an increase also in free T4 levels in early pregnancy almost certainly due to the stimulatory effect of hCG on thyroid cell growth and iodine uptake. This effect has been demonstrated directly in cultured thyroid cells (6,7) and reflects the common alpha-subunit shared by TSH and hCG. Thyroid gland size increases through pregnancy, and histologically the gland shows well-developed follicles with abundant colloid. Glinoeretal. showed an increase in thyroid volume of, on average, 20% in the majority of pregnant women by ultrasound techniques (5). A diffuse goiter as defined by thyroid volume of greater than 23 mL was found in 9% of pregnant women at the end of pregnancy, although the study was performed in areas of marginal iodine deficiency. Increases in thyroglobulin through pregnancy also were common, correlating with the change in thyroid volume, leading the authors to suggest that thyroglobulin reflects anatomic change and is a marker of increased thyroid volume. Establishment of a normal range for the parameters of thyroid function during pregnancy and indeed postpartum has been fraught with the problems of interassay variability and population selection bias. The large study by Fung et al. in Wales sought to address this problem before going on to study the spectrum of thyroid dysfunction in the postpartum period (8,9).
One hundred twenty normal women without a family history of thyroid disease and without detectable thyroid autoantibodies were studied. The investigators found a state of "compensated hypothyroidism" occurring as pregnancy progressed, with significant reductions in free T4 and free T3 and increases in TSH, serum thyroglobulin, and goiter size in the later stages (Table 1 ). A postpartum range for these parameters also was established after a 12-month follow-up. Postpartum thyroid dysfunction was defined as being present when two or more consecutive results greater than 2 standard deviations (SD) outside the normal range were detected in these women who were seen at 6-week intervals for 12 months postpartum.
IMMUNOLOGIC CHANGES IN PREGNANCY
Pregnancy is a state of relative immune tolerance, the mechanism for which is multifactorial and not fully clarified. A number of changes occur in circulating lymphocytes during pregnancy and include a reduction in the CD4 + population and a decrease in natural killer cell activity (10). Other factors have been implicated in modifying the maternal immune response and include hormones, prostaglandins, lymphokines, and plasma proteins. The role of the placenta in protecting-4he infant is doubtless of great importance (11). Amino and Miyai have studied maternal disease activity in women with AITD during pregnancy (12). There is spontaneous improvement of thyrotoxicosis in late pregnancy, and mild cases of hypothyroidism may remit spontaneously. Antimicrosomal and antithyroglobulin antibodies fall in women with autoimmune thyroid disease during pregnancy, as do thyroid-stimulating immunoglobulin titers in women with Graves' disease. It is well known that other autoimmune diseases, such as rheumatoid arthritis and myasthenia gravis, also improve during pregnancy
Table 1. Alterations in Serum Free Thyroxine (FT4), Free Triiodothyronine AND THYROTROPIN (TSH) IN 120 CONTROLS THROUGH PREGNANCY and in 12 Months Postpartum Weeks Antenatal 8-16 17-25 26-34 35-43
Delivery
Postnatal 6-8 9-16 17-24 25-32 33-40 41-48 49-56
"Mean ± 2 SD. *p < 0.05 and Student's f-test.
:
*p
Postpartum Thyroid Dysfunction DIANA L. LEAROYD, HEDY Y. M. FUNG, and ALAN M. McGREGOR
ABSTRACT
Postpartum thyroid dysfunction (PPTD) refers to the syndromes of transient hyperthyroidism, transient hypothyroidism, or both, occurring sequentially in the first 12 months postpartum. Approximately 5 to 9% of women develop the disorder in this period. PPTD is most often subclinical but some women will experience symptoms such as lack of energy and depression in the hypothyroid phase. The thyroid gland, which normally enlarges during pregnancy, will remain enlarged or enlarge further in the postpartum period in a significant number of affected women, instead of returning to the prepregnancy size as in unaffected women. The gland is painless and histologically demonstrates lymphocytic infiltration. PPTD is strongly associated with the presence of antimicrosomal and/or antithyroglobulin antibodies, which occur in up to 76% of cases. Antibody activity tends to increase in the postpartum period and to peak at the time of onset of the disorder. TSFf receptor antibodies are not seen and the gland has low radioiodine uptake, distinguishing PPTD from Graves' disease. The HLA associations are controversial, as is the role of dietary iodine. The etiology of PPTD is almost certainly immunological, reflecting the phenomenon of rebound from the relative immune tolerance of pregnancy. Detection of the disorder is important in order to reassure or treat those who are symptomatic and because PPTD may recur in subsequent pregnancies. In addition, up to one third of affected women will go on to develop permanent hypothyroidism 2 to 4 years later. The role of screening for PPTD remains to be clarified.
INTRODUCTION
The term postpartum thyroid dysfunction (PPTD) usually refers to the more common collection of syndromes characterized by transient hyperthyroidism, transient hypothyroidism, or both occurring sequentially in the first 12 months postpartum. The disorder almost certainly has an autoimmune basis, resulting from altered immune tolerance following pregnancy-induced immunosuppression in women with latent or subclinical autoimmune thyroid disease (AITD). It is strongly associated with the presence of antimicrosomal or antithyroglobulin antibodies or both. The hyperthyroid phase of PPTD may be distinguished from Graves' thyrotoxicosis by the low radioiodine uptake and the absence of TSH receptor antibodies. This collection of syndromes of postpartum thyroid dysfunction is the main subject of this review.
IS ASSOCIATED with a complex series of changes function and the immune state. The former in both changes enable the mother to remain euthyroid despite the metabolic demands and altered physiology of pregnancy. The latter changes enable her to display immunologie tolerance to the fetus. The changes occurring in pregnancy have particularly important implications in the postpartum period for women with disorders of an autoimmune nature. These disorders tend to remit during pregnancy and relapse postpartum. Alterations in thyroid function may occur in the postpartum period and be due to a variety of causes. Such conditions as toxic nodular goiter, painful subacute thyroiditis. and thyrotoxicosis factita may account for up to 7% of cases ( 1 ). Graves' disease may account for up to 10% of postpartum hyperthyroid cases, whether this be a relapse of preexisting disease that had improved during pregnancy or newly developed Graves' disease (2). Similarly, lymphocytic thyroiditis may occur de novo or relapse post-
PREGNANCYthyroid
PREGNANCY-INDUCED CHANGES IN THYROID FUNCTION The
partum. Department of Medicine, King's College School of Medicine.
nancy
London. United
73
changes are
that occur in thyroid function in normal pregoutlined briefly, although they are reviewed more
Kingdom.
74
LEAROYD ET AL.
extensively elsewhere (3). They are important in the understanding of the transition from pregnancy to the postpartum state. There is an increase in the basal metabolic rate by 15-20% in pregnancy, rising slowly between 4 and 8 months gestation. This is a consequence of both the increase in oxygen consumption of the fetoplacental unit and the increase in maternal cardiac output (4). Iodide uptake by the thyroid gland increases, compensating for urinary losses that cannot be explained fully by the increased glomerular filtration rate (GFR) of pregnancy. There is a reduction in the plasma inorganic iodide concentration from the 16th week of pregnancy (5). Estrogen-induced synthesis of thyroid hormone binding proteins leads to a significant elevation of thyroxine binding globulin (by about 50%) and also of total T4 and T3. There is an increase also in free T4 levels in early pregnancy almost certainly due to the stimulatory effect of hCG on thyroid cell growth and iodine uptake. This effect has been demonstrated directly in cultured thyroid cells (6,7) and reflects the common alpha-subunit shared by TSH and hCG. Thyroid gland size increases through pregnancy, and histologically the gland shows well-developed follicles with abundant colloid. Glinoeretal. showed an increase in thyroid volume of, on average, 20% in the majority of pregnant women by ultrasound techniques (5). A diffuse goiter as defined by thyroid volume of greater than 23 mL was found in 9% of pregnant women at the end of pregnancy, although the study was performed in areas of marginal iodine deficiency. Increases in thyroglobulin through pregnancy also were common, correlating with the change in thyroid volume, leading the authors to suggest that thyroglobulin reflects anatomic change and is a marker of increased thyroid volume. Establishment of a normal range for the parameters of thyroid function during pregnancy and indeed postpartum has been fraught with the problems of interassay variability and population selection bias. The large study by Fung et al. in Wales sought to address this problem before going on to study the spectrum of thyroid dysfunction in the postpartum period (8,9).
One hundred twenty normal women without a family history of thyroid disease and without detectable thyroid autoantibodies were studied. The investigators found a state of "compensated hypothyroidism" occurring as pregnancy progressed, with significant reductions in free T4 and free T3 and increases in TSH, serum thyroglobulin, and goiter size in the later stages (Table 1 ). A postpartum range for these parameters also was established after a 12-month follow-up. Postpartum thyroid dysfunction was defined as being present when two or more consecutive results greater than 2 standard deviations (SD) outside the normal range were detected in these women who were seen at 6-week intervals for 12 months postpartum.
IMMUNOLOGIC CHANGES IN PREGNANCY
Pregnancy is a state of relative immune tolerance, the mechanism for which is multifactorial and not fully clarified. A number of changes occur in circulating lymphocytes during pregnancy and include a reduction in the CD4 + population and a decrease in natural killer cell activity (10). Other factors have been implicated in modifying the maternal immune response and include hormones, prostaglandins, lymphokines, and plasma proteins. The role of the placenta in protecting-4he infant is doubtless of great importance (11). Amino and Miyai have studied maternal disease activity in women with AITD during pregnancy (12). There is spontaneous improvement of thyrotoxicosis in late pregnancy, and mild cases of hypothyroidism may remit spontaneously. Antimicrosomal and antithyroglobulin antibodies fall in women with autoimmune thyroid disease during pregnancy, as do thyroid-stimulating immunoglobulin titers in women with Graves' disease. It is well known that other autoimmune diseases, such as rheumatoid arthritis and myasthenia gravis, also improve during pregnancy
Table 1. Alterations in Serum Free Thyroxine (FT4), Free Triiodothyronine AND THYROTROPIN (TSH) IN 120 CONTROLS THROUGH PREGNANCY and in 12 Months Postpartum Weeks Antenatal 8-16 17-25 26-34 35-43
Delivery
Postnatal 6-8 9-16 17-24 25-32 33-40 41-48 49-56
"Mean ± 2 SD. *p < 0.05 and Student's f-test.
:
*p
