Eur J Endocrinol
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DOI: 10.1530/eje.1.01976
European Journal of Endocrinology, Vol 153, Issue 3, 367-371
Copyright © 2005 by European Society of Endocrinology
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CLINICAL STUDY

The occurrence of permanent thyroid failure in patients with subclinical postpartum thyroiditis

F Azizi

Endocrine Research Center, Shaheed Beheshti University of Medical Sciences, P O Box 19395-4763, Tehran, Islamic Republic of Iran

(Correspondence should be addressed to F Azizi; Email: Azizi{at}erc.ac.ir)


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective: The long-term effect of the subclinical form of postpartum thyroid dysfunction (PPTD) has not been well established. This study was conducted to evaluate the outcome of permanent hypothyroidism in a large cohort of women with PPTD.

Design and methods: Of 213 women with PPTD, 172 (81%) returned for follow-up. There were 27 (16%) with subclinical (group 1) and 145 (84%) with overt hypothyroidism (group 2). They were all treated with levothyroxine for 23 ± 16 months and followed-up for thyroid function after thyroxine (T4) withdrawal.

Results: In group 1, the time of occurrence of PPTD was longer, serum T4 was higher and TSH was lower than in group 2. After T4 withdrawal, 59 and 64% of patients became hypothyroid in groups 1 and 2 respectively; however, serum TSH was increased in group 2 as compared with group 1 (29.7 ± 8.4 vs 16.4 ± 15.4 mU/l, P < 0.002). The duration of euthyroidism, serum free T4 and triiodothyronine indices and thyroperoxidase antibodies were not significantly different between the two groups.

Conclusion: It was concluded that a high percentage of patients with the subclinical form of PPTD proceed to permanent thyroid failure. The timely recognition of mild to severe cases of PPTD is important for the improvement of life for mothers and infants.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Postpartum thyroid dysfunction (PPTD), a syndrome of thyroid dysfunction that has been reviewed extensively, occurs in the first year after parturition (1–3). It consists of a group of autoimmune disorders, characterized by postpartum development of transient hyperthyroidism, hypothyroidism or both (4). Depending on differences in ethnic groups, geographical locations, methodology, or the rate of follow-up visits for patients in the first year after parturition, a wide range of prevalence of PPTD ranging from 1.1 to 11.4% has been reported (4–11).

A significant number of patients with positive PPTD having the hypothyroid form of the illness develop permanent hypothyroidism (12, 13). It has been shown that multiparity, previous history of spontaneous abortion, age and some immunogenetic factors including Human Leukocyte Antigen (HLA)-DRW9, HLA-B51 and anti-thyroid antibodies may be related to the development of permanent hypothyroidism (13–16).

In one epidemiologic study, only 48% of patients had moderate to severe symptoms and signs of hypothyroidism requiring maintenance doses of levothyroxine (L-T4) (11). Many cases of PPTD may therefore be subclinical and escape recognition during the acute postpartum phase. Since there is a paucity of information regarding the long-term effect of subclinical PPTD, this study aimed at evaluating the characteristics of PPTD and the outcome of permanent hypothyroidism in women with subclinical hypothyroidism in the postpartum period and comparing their findings with those in women with overt postpartum hypothyroidism.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study population

Two hundred and thirteen women with diagnoses of PPTD presenting as hypothyroid were enrolled in this cohort study. Excluding criteria were past history of thyroid dysfunction, including hypothyrodism (except PPTD), Graves’ disease, and radioiodine and surgical treatment. All patients were 3 to 10 months postpartum and had at least one of the following symptoms: growth of the thyroid, lethargy, fatigue, depression, cold intolerance, dry skin, weight gain, constipation and sleepiness; 52% were referred by gynecologists, pediatricians or internists and 48% came directly to the endocrine clinic; 42% complained of an enlargement in the thyroid region and 19% had suffered an episode of transient thyrotoxicosis 2–4 months after delivery.

A physical examination was performed on each patient. Thyroid weight was estimated and goiter was classified according to WHO criteria (17). Thyroidal radioiodine uptake was carried out in those who were not breast feeding. Ultrasonographic evaluation of the thyroid and serum determination of thyroxine (T4), triiodothyronine (T3), resine T3 uptake (RT3U), thyrotropin (TSH) and antithyroglobulin and thyroperoxidase antibodies (anti-Tg and TPOAb) were carried out.

Follow-up visits

All patients required treatment because of goiter and/or symptoms, and all were therefore treated with L-T4 (Levothyroxine, Iran Hormone, Tehran, Iran). An endocrinologist saw each patient every 3–6 months and the dose of L-T4 was adjusted to maintain serum TSH levels between 0.3 and 3.0 mU/l. After 12–24 months of therapy, patients were advised to discontinue T4 therapy and to return in 1 month. Follow-up visits were scheduled every month for the first 6 months and then at 9, 12, 18, 24, 36, 48 months and yearly thereafter, until hypothyroidism occurred. The patient was advised to return to the clinic in between visits whenever she experienced symptoms of hypothyroidism. At each visit, a 10 ml blood sample was obtained for the measurements of T4, T3, RT3U and TSH.

Measurements

Hormone assays  Serum concentrations of T4 and T3 by RIA, TSH by IRMA and an RT3U test were performed using commercial kits from Orion Diagnostica, Fenzia, Finland. The free T4 index and free T3 index were then calculated. In all assays, the inter- and intra-assay coefficients of variation were below 11 and 9% respectively. Reference ranges for euthyroid subjects were: T4, 4.5–12.5 µg/dl; T3, 70–200 ng/dl; TSH, 0.2–5.9 mU/l; RT3U, 25–35%; free T4 index, 4.5–12.5; and free T3 index, 70–200.

Thyroid antibodies  TPOAb titers were measured, using ELISA kits from Radim, Pomezia, Italy. Values above 100 IU/ml were considered positive. The inter-and intra-assay coefficients of variation were 7.2 and 6.5% respectively.

Methods of analysis

On the basis of the results of serum hormone concentrations determined, patients were divided into two groups: (group 1) subclinical hypothyroid (TSH > 5.0 mU/l and T4 ≥4.5 µg/dl) and (group 2) overt hypothyroid (TSH > 5.0 mU/l and T4 < 4.5 µg/dl). Descriptive statistical descriptions such as mean, median, range, standard deviation and proportions were used. The normality of variables was tested using the one-sample Kolmogorov–Smirnov test. Since some variables did not meet the criteria of normality, their natural logarithm was taken prior to analysis. Differences between mean values for quantitative variables were evaluated using Student’s t-test. Chi square and Mann–Whitney tests were used for analysis of nominal and ordinal variables. The log rank test was employed for difference in cumulative recurrence of hypothyroidism between groups. To assess the relation between serum TSH and other factors, multiple stepwise regressions were employed. All P values were obtained from two-tailed tests, and only values below 0.05 were considered significant. The conversion ratios for T4 and T3 from µg/dl and ng/dl to nmol/l are 12.87 and 0.01536 respectively. The Research Ethics Committee of the Shaheed Beheshti University of Medical Sciences approved this study.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
One hundred and seventy-two (81%) of the 213 women who developed PPTD returned for the follow-up study. In the past, 32 (15%) had given a history of PPT after their previous pregnancy, 2–6 years prior to the current one.

There was no significant difference in age, time of occurrence of symptoms, severity of hypothyroidism and serum T4, T3, TSH and TPOAb levels between the 19 patients who did not return for follow-up and the other women.

Features of postpartum hypothyroidism

Mean ± S.D. age in 172 subjects was 29.2 ± 4.4 years. Postpartum hypothyroidism was diagnosed between 3 and 10 months after delivery with a mean ± S.D. of 5.8 ± 1.9 months. In their physical examinations all patients had a palpable goiter, and 46% had visible enlargement of the thyroid gland (grade 2). Ultrasonographic evaluation detected diffuse or multifocal hypoechogenity in 93% of patients. Radioiodine uptake of the thyroid was measured in 52 (30%) patients who were not breast feeding. In all patients, 24-h radioiodine uptake was below 7%. Positive titer of anti-thyroid antibody was found in 158 (92%) patients: 94 demonstrated both TPOAb and anti-Tg, 43 only TPOAb and 22 only anti-Tg elevation.

There were 27 (16%) and 145 (84%) patients in the subclinical and overt hypothyroidism groups respectively. Clinical and laboratory findings of the two groups are presented in Table 1Go. Time of occurrence of PPTD after delivery was longer, serum T4 was higher and serum TSH was decreased in group 1 as compared with group 2.


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  		Table 1 Clinical and laboratory findings in 172 patients at the time of postpartum thyroiditis-induced hypothyroidism. Values are means ± S.D.
 
Duration of T4 treatment

In 172 PPTD patients, the duration of T4 treatment was 12–24, 25–30, 30–36 and 36–84 months in 65, 13, 10 and 12% respectively. Duration of therapy beyond 24 months was due to patient preference or delays in clinic visits. Duration of T4 treatment was 23.7 ± 12.4 and 23.3 ± 16.9 months in groups 1 and 2 respectively.

Thyroid function at follow-up

The median (range) of follow-up from the time of T4 withdrawal until the occurrence of hypothyroidism or until the end of the study was 16 ± 19 (1–120) months. Table 2Go shows the outcome of thyroid function in the patients studied. Of 172 patients, 64 (37%), 52 (30%) and 56 (33%) were euthyroid, subclinical and overt hypothyroid respectively. There were more subclinical and overt hypothyroid patients in groups 1 and 2 respectively, but the difference was not statistically significant. Serum TSH was decreased in group 1 as compared with group 2 (16.4 ± 15.4 vs 29.7 ± 28.4 mU/l respectively, P < 0.002). There was no significant difference in duration of euthyroidism after T4 withdrawal, and T4, T3 and anti-TPOAb titers between the two groups.


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  		Table 2 Time of recurrence of hypothyroidism and serum hormone concentrations following discontinuation of L-T4 therapy in 172 patients with postpartum thyroiditis-induced hypothyroidism. Values are means ± S.D.
 
Presentation and outcome in the subclinical group

All patients in this group had free T4 index ≥4.5 at presentation with free T3 index and TSH ranging between 80 and 160 and 11 and 90 mU/l respectively. Serum TSH was between 11 and 20 in nine, between 21 and 50 in sixteen and > 50 mU/l in one patient.

Hypothyroidism occurred 1–36 months after T4 withdrawal with a mean of 11.4 ± 9.5 (median 5) months. The duration of follow-up in those who remained euthyroid was 14.4 ± 8.1 months and the duration of euthyroidism was 9.5 ± 10.1 months in those patients who became hypothyroid. There was no difference in age, time or thyroid function tests of the original presentation of postpartum hypothyroidism between those who remained euthyroid and patients who became hypothyroid after L-T4 withdrawal.

Rates of recurrence of hypothyroidism after L-T4 withdrawal are shown in Fig. 1Go. Although hypothyroidism occurred more frequently in group 2 in the first few months after discontinuation of L-T4 therapy, the difference between the two groups was significant only at 2 months after L-T4 withdrawal (Fig. 1Go).



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  		Figure 1 Rates ( ± S.E.M.) of recurrence of hypothyroidism in 172 of the original 213 patients with postpartum hypothyroidism who returned for follow-up after discontinuation of T4 therapy. The numerators are the number of patients with hypothyroidism during the previous interval, and the denominators are the number of subjects at the end of that interval. The difference between the two groups is statistically significant only at 2 months after L-T4 withdrawal.

 
Ultimately 16 of 27 patients in the subclinical group were hypothyroid. The percentage rate of the development of permanent hypothyroidism was 37, 44, 52 and 59% after 6, 12, 24 and 36 months respectively. Mean serum TPOAb concentrations were 389 ± 312 and 315 ± 298 IU/ml in hypo- and euthyroid patients respectively. The difference was not significant between the two groups.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
This study demonstrated that more than half of the women with subclinical postpartum hypothyroidism developed recurrent thyroid failure after T4 withdrawal. However, thyroid failure was of a subclinical nature in the majority of the cases. It has also been shown that in those with postpartum overt hypothyroidism, nearly two-thirds developed recurrent thyroid failure with the majority being of the overt hypothyroid nature.

Six studies of long-term follow-up evaluations on women with PPTD have been conducted. The prevalence of recurrent or permanent hypothyroidism has been reported to be 12% in 27 subjects at the end of 3 years (5), 23% in 44 subjects at a mean follow-up of 8.7 years (15), 23% in 43 subjects at a mean follow-up of 3.5 years (14), 30% in 47 subjects at the end of 5 years (16), 24.5% in 98 women at a median follow-up of 6.6 years (12) and 63% in 148 women with severe PPTD (13). The current study represents the largest cohort of PPTD subjects followed after discontinuation of T4 treatment in the literature and the only study that has separated outcome in subclinical hypothyroid cases. The difference in prevalence of hypothyroidism in various studies may be due to the differences in the length of follow-up, criteria for diagnosis and, in particular, the severity of hypothyroidism in the original episode of PPTD.

Another important factor is the length of follow-up of patients with PPTD. We had shown that PPTD patients, who remained euthyroid after T4 withdrawal, had significantly higher values for TSH, as compared with the control group and 73.3% had TPOAb above the normal limit (15). This finding is in agreement with a previous report that euthyroid women with a previous history of PPTD have a permanent subtle defect in thyroid hormone synthesis, as evidenced by an abnormal iodine-perchlorate discharge test (18). Therefore, with longer follow-up, a good number of these patients may develop thyroid failure.

In the present study, there was no difference in TPOAb titers between patients with subclinical and overt hypothyroidism. Many investigators have found a relationship between PPTD and elevated levels of maternal serum TPOAb (19). It has been shown that at least 50% of TPOAb-positive women will eventually develop PPTD (4, 20). In addition, in a long follow-up 46% of TPOAb-positive and only 1.4% of TPOAb-negative women developed permanent hypothyroidism. The role of TPOAb in the development of postpartum thyroid dysfunction and the occurrence of permanent hypothyroidism is therefore well established. However, the findings of the present study point out that other factors, in addition to TPOAb, may determine the severity of thyroid damage and the probability of permanent hypothyroidism in patients with PPTD.

This study has a few limitations. First, all women with PPTD had a palpable goiter. This is unusual, although goiter is frequent in PPTD. Although Iran reached iodine sufficiency in 1995 (21), it is possible that the palpable goiters may have, to some extent, been caused by a previous iodine deficiency (22). Secondly, more than half of the patients were referred by gynecologists, pediatricians and internists, and the rest came directly to the endocrine clinic because of goiter or symptoms of thyroid dysfunction. This group of patients has therefore mostly been selected and does not represent the entire population of PPTD patients. Thirdly, one-fifth of the cohort was lost to follow-up and these may have been patients with less severe symptoms, indicating that the true prevalence of subclinical hypothyrodism may exceed that demonstrated by the present report.

In conclusion, this study has demonstrated that even the subclinical form of PPTD which presents only with an enlargement of the thyroid may proceed to permanent thyroid failure, both subclinical and overt, although in less severe forms than would the overt form of PPTD. Clinicians should carefully screen for diagnosis and long-term follow-up of patients with both subclinical and overt PPTD should be carried out. The above-mentioned finding calls for a comprehensive cost-beneficial investigation of screening for PPTD. The timely recognition of mild to severe cases of PPTD, their diagnosis and proper clinical management is important and improves the quality of life for both mothers and their infants.


   Acknowledgements
 
The author would like to thank all participants, the staff of Research Laboratory of Endocrine Research Center, N Shiva for editing the English, M Padyab for statistical assistance and T Fakhimi for her help in preparing the manuscript. Funds were provided by the Endocrine Research Center.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received 29 March 2005
Accepted 1 June 2005




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