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Association of Postpartum Thyroid Dysfunction with Antepartum Hormonal and Immunological Changes

Departments of Medicine (A.A.K., A.B.P., L.D.K.E.P., J.H.L.) and Medical Biochemistry (R.J.), University of Wales College of Medicine, Cardiff CF14 4XN, Wales, United Kingdom

Address all correspondence and requests for reprints to: Prof. J. H. Lazarus, Department of Medicine, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, Wales, United Kingdom.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Postpartum thyroid dysfunction (PPTD) develops during the first 9 months in up to 50% of women who have thyroid peroxidase antibodies (anti-TPOAb +ve). Humoral immunity in PPTD has been well documented, but the cellular immunological events accompanying the Th2 to Th1 state postpartum are less clear. Peripheral blood lymphocyte cytokine secretion was examined in 48 TPOAb +ve and 33 TPOAb -ve women at 36 wk gestation and at 6, 12, and 24 wk postpartum. Eighteen women with PPTD had significantly greater secretion of interferon and IL-4 than euthyroid women at 36 wk gestation with no significant differences in cytokine secretion at other time points. Also, at 36 wk gestation, the median plasma cortisol concentration in the PPTD group was significantly lower than the euthyroid group (442 nmol/liter vs. 567 nmol/liter, P < 0.02). There were no differences between the groups in levels of prolactin, progesterone, or estradiol. These data suggest that there may be less immunological suppression at 36 wk in TPOAb +ve women destined to develop PPTD possibly because of lower levels of cortisol. Thus, the immunological determinants of PPTD may in part occur antenatally, although the mechanism(s) for this is still unclear.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
POSTPARTUM THYROIDITIS (PPT) is characterized by the development of thyroid dysfunction, hyperthyroidism, hypothyroidism, or both in the postpartum period in up to 50% of the 10% of women found to be antithyroid peroxidase antibody positive (TPOAb +ve) in early gestation (1, 2). The other 50% of TPOAb +ve women remain euthyroid postpartum (PPTE).

In about a third of women with postpartum thyroid dysfunction (PPTD), permanent hypothyroidism develops at this stage. This hypothyroid phase is often symptomatic and requires treatment with T₄. In most reported series of PPT patients (but not all) (3), the condition arises almost exclusively in women who are TPOAb +ve (4). The pathogenesis of PPT is unclear, but attention has been paid to the fact that, although pregnancy is an immune state dominated by so-called Th2-immune responses, there is a rapid switch to a Th1 status immediately postpartum (5, 6). It is also appreciated that the immune rebound postpartum is associated with exacerbation of other immune and autoimmune diseases (7).

In addition to the Th2 status in pregnancy, it is known that the immune regulation is complex and hormonal factors are also involved. Hormones such as estradiol, progesterone, and cortisol are in high concentration during gestation and have immunological effects designed to maintain the developing fetus and ensure the adequate length of the pregnancy (8, 9).

To further understand the immunological and hormonal factors that may be associated with the onset of PPTD, we have evaluated aspects of the Th2/Th1 shift and hormonal status of TPOAb +ve women during gestation and the postpartum period.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Sera obtained at the antenatal booking clinics at Llandough Hospital (Cardiff, UK) from women between 12 and 16 wk gestation were screened for anti-TPO antibodies (see below). All women whose antibody activity exceeded 19.4 kIU/liter were invited to participate in the study by attending a thyroid pregnancy research clinic held in the afternoon. Women were seen at 36 wk gestation and again at 6, 12, and 24 wk postpartum by two endocrinologists (J.H.L. and L.D.K.E.P.). For logistical reasons, samples were not obtained from all women at all time points. On completion of the study, telephone inquiry was made to all patients to check their thyroid status between 24 and 36 wk postpartum. One patient was transferred from the euthyroid to the hypothyroid group as a result.

At each visit, inquiry was made about symptoms of thyroid dysfunction in addition to any history of allergy. Examination for goiter was performed and a venous blood sample was obtained. A group of TPOAb -ve women matched for gestational age served as controls. This group could not be followed up serially, and a variable number were studied cross-sectionally at each time point. Their plasma cortisol samples were available only as morning samples and are, therefore, not compared with those of the patients. Women were withdrawn from the study if they were found to be hypothyroid during gestation or, after an initial visit, could not cooperate further in the study protocol. Women with a family history of thyroid disease were not excluded from the TPOAb +ve group. The study was approved by the ethical committee, and all study subjects gave their written informed consent.

The antenatal gestational age was calculated from the result of an early ultrasound scan. Postnatal weeks were calculated from the day of delivery.

Methods

Free T₄ (FT4), free T₃ (FT3), TSH, cortisol, estradiol, progesterone, and prolactin (PRL) were measured by immunochemiluminometric assays on an ADVIA Centaur immunoassay system (Bayer Corp. Diagnostics Division, Newbury, Berkshire, UK). The between-assay precision for each of the analytes at the following mean concentrations were respectively as follows: FT4 coefficient of variation (CV) 3.1% and 2.8% at mean FT4 of 16.9 and 38.8 pmol/liter, FT3 CV 2.0% and 1.8% at mean FT3 of 7.35 and 13.7 pmol/liter, TSH CV 4.2% and 4.2% at mean TSH of 4.4 and 19.1 mU/liter, cortisol CV 5.8% and 5.4% at mean cortisol of 471 and 1037 nmol/liter, estradiol CV 5.8% and 5.4% at mean estradiol of 614 and 1652 pmol/liter, progesterone CV 3.0% and 3.2% at mean progesterone of 30 and 89 nmol/liter, and PRL CV 2.9% and 3.4% at mean PRL of 232 and 565 mU/liter. Thyroid peroxidase autoantibodies (TPOAb) were measured by ELISA (10) standardized against NIBSC 66/387 the antithyroid microsome serum (National Institute for Biological Standards and Control, London, UK). Antibody activity was considered to be normal when levels were less than 19.4 kIU/liter. The intra- and interassay variation was 4.9% (at a mean of 155 kIU/liter) and 7.6% (at a mean of 149 kIU/liter), respectively. The levels quoted are the mean of quadruplicate measurements. Steroid 21-hydroxylase activity was measured by immunoprecipitation (11), and TSH stimulating antibodies were measured using a bioluminescence assay system (12).

Peripheral blood mononuclear cells were separated from blood samples collected in EDTA (20 ml) by gradient centrifugation using Histopaque-1077 (Sigma, St. Louis, MO) within 24 h of collection. The lymphocytes, viability better than 95% by the Trypan Blue exclusion test, were resuspended at about 2 x 10⁶ cells/ml in a freezing mixture (50% fetal calf serum, 40% RPMI 1640, 10% dimethyl sulfoxide). Tubes containing 1-ml aliquots were then frozen at a rate of 1 C/min until the temperature reached -85 C when they were transferred for long-term storage to liquid nitrogen. Plasma samples obtained during the separation were aliquoted and stored for biochemical analysis.

Intracellular cytokine staining

Cells were defrosted quickly and transferred immediately on thawing to a tube containing 10 ml of prewarmed culture medium [RPMI 1640 supplemented with L-glutamine (300 µg/ml), penicillin (100 U/ml), streptomycin (100 µg/ml), amphotericin B (0.25 µg/ml), and fetal calf serum (10%), RF-10]. After further washing in fresh culture medium and harvesting by centrifugation (600 x g for 5 min), the cells were resuspended at 2 x 10⁶) cells/ml, and 0.5-ml aliquots were dispensed into a 24-well flat-bottomed tissue culture plate in duplicate. Another 0.5 ml RF-10 containing phorbol-12-myristate-13-acetate (100 ng/ml), ionomysin (8 µmol/liter), and monensin (12 µmol/liter) was added to one of the wells; 0.5 ml RF-10 with monensin alone was added to the second, control well. The culture plate was placed in a humidified incubator at 37 C, gas phase 5% CO₂ in air, for 4 h. Aliquots (350 µl) from the stimulated and unstimulated wells were transferred into fluorescence-activated cell sorter (FACS) tubes and the surface antigen (CD3 and CD4) was stained by adding 5 µl conjugated antibody (R-phycoerythrin-Cy5 conjugated mouse antihuman CD3, DAKO Corp. Ltd., Ely, UK; fluorescein isothiocyanate-conjugated mouse antihuman CD4, Serotec Ltd., Oxford, UK) and incubated in the dark for 30 min. The cell suspensions were washed by centrifugation with phosphate buffer (10 mmol/liter, pH 7.4) containing sodium chloride (150 mmol/liter), sodium azide (200 mg/liter), and BSA (2 g/liter) (PBS) at 300 x g for 5 min at 4 C. The supernatant was discarded and 50 µl fixation and permeablization reagent A (Haralaan Sera-Lab, Loughborough, UK) was added and incubated for 15 min in the dark. After another washing step, 50 µl fixation and permeablization reagent B (Haralaan Sera-Lab) and conjugated antibody against IL-4 (phycoerythrin conjugated rat antihuman IL-4, PharMingen, Becton Dickinson and Co., Oxford, UK) or interferon (IFN)- (phycoerythrin-conjugated mouse antihuman IFN-, Serotec Ltd.) was added, vortexed at low speed for 1–2 sec, and incubated for 20 min in the dark.

After a final wash with PBS, the cells were fixed with 200 µl 1% paraformaldehyde and the suspension stored at 4 C. Analysis was undertaken within 24 h using a FACScan flow cytometer (Becton Dickinson and Co., Franklin Lakes, NJ); 20,000 events were collected using Lysis II software (Cellquest Beckton Dickinson, San Jose, CA).

The transferred data were then analyzed using the WinMDI2.8 software (provided by J. Trotter, Scripps Research Institute, La Jolla, CA). T lymphocytes were gated on the bases of right-angle light scatter and CD3 staining characteristics and plotted against CD4 positivity; the quadrants were set according to the negative controls (Fig. 1). Cytokine expression in the various groups of patients were grouped on the basis of their cell surface marker expression as CD4 (CD3+/CD4+) or CD8 (CD3+/CD4, i.e. non-CD4 T cells).

View larger version (34K): [in this window] [in a new window]   Figure 1. Graphical output from the FACScan analyzer (Becton Dickinson and Co.). Before analysis lymphocytes were stained with R-phycoerythrin-Cy5 mouse antihuman CD3 fluorescein isothiocyanate-conjugated mouse antihuman CD4 together with either phycoerythrin-conjugated rat antihuman IL-4 or phycoerythrin-conjugated mouse antihuman IFN-. The output was gated on the basis of side scatter and CD3 staining. Shown are control cells in the left panels and stimulated cells in the right panels. Lymphocytes gated for right-angle light scatter and CD3 staining (a and b), CD4 expression (c and d), IL-4 expression (c–f), and IFN- expression (e and f) are shown.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
The three groups of women studied (Table 1) did not differ in age or parity. The PPTD group had higher TPOAb levels in early gestation, compared with the PPTE group. The PPTD group comprised five women with isolated hyperthyroidism, nine with hypothyroidism, and four with biphasic disease. The maximum median TPOAb level postpartum was significantly higher in the PPTD group, compared with the PPTE group (373 kIU/liter vs. 134; P = 0.0001), and TPOAb levels were also higher at all time points postpartum in the PPTD group. None of the women with hyperthyroidism had TSH receptor antibodies. One woman had a positive test for steroid 21-hydroxylase autoantibodies. These antibodies were negative in the PPTE group. With regard to the 36-wk antenatal blood sample, there were no significant differences between the PPTE and PPTD groups in the median gestational age (as calculated by early gestational ultrasound at time of sample) or median time difference between sample time and delivery. The median gestational age at delivery was 39.5 and 39.3 wk, respectively (NS).

There was no significant difference in the percentage CD4 or CD8 cells secreting IL-4 or IFN- during the postpartum among the three groups despite the changes in thyroid function observed in the PPTD group. However, in the women destined to develop PPTD, a significantly higher percentage of cells of the CD8 subset (approximately 8-fold vs. PPTE or control groups) secreted IL-4, whereas CD4 cells expressed 1.5 times more IFN- when compared with the PPTE or 2.5 times more than the control group at 26 wk gestation (Table 2 and Fig. 2). Inspection of the individual results for percentage cells secreting IL-4 and IFN- (Fig. 2) does show considerable overlap. Nevertheless, although the IFN /IL-4 ratio from CD4 cells did not change significantly from 36 wk antenatally to the 6-wk postpartum point in any patient group, this ratio, expressed as the logarithm, did rise significantly in the CD8 subset from the PPTD group at this time (1.37 to 1.67; P = 0.018).

View this table: [in this window] [in a new window]   Table 2. Percentage of CD4 and CD8 T-lymphocytes expressing IL-4 or IFN- in the three study groups at 36 wk antepartum

View larger version (19K): [in this window] [in a new window]   Figure 2. Percentage of CD4 and CD8 cells secreting IL-4 or IFN- in the control (), PPTE (), and PPTD () patients all studied at 36 wk gestation; the median percentage is indicated by a horizontal bar. The statistical significance between the marked groups was determined using the Mann-Witney U test.

View larger version (16K): [in this window] [in a new window]   Figure 3. Median, 25/75 centiles, and range of plasma cortisol levels in the PPTE and PPTD groups of patients at 36 wk antepartum (n = 30 and 15, respectively; clear boxes) and 6 wk postpartum (n = 21 and 9, respectively; shaded boxes). The median cortisol level in the PPTE group was significantly higher than in the PPTD groups at 36 wk antepartum (P < 0.022; Mann-Witney U test). There was no significant difference between the two groups at 6 wk postpartum.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Previous studies of lymphocyte subsets in normal pregnancy and the postpartum period have suggested decreases in the serum soluble CD4 concentration and the ratio of soluble CD4/CD4+ cells together with an increase in the soluble CD8/CD8+ cells ratio may be important immunological factors in pregnancy (14). Furthermore, there are also data to suggest that changes in so-called suppressor and helper T cells during early and late pregnancy may relate to mechanisms for fetal acceptance and maintenance of gestation (15). These workers have also shown that the postpartum increase of helper and cytotoxic T cells and other subsets may contribute to the exacerbation of autoimmune diseases at this time. More recently, attention has been paid to the NKT cells as the controlling agents that may affect the Th1/Th2 balance at the fetomaternal interface (16).

There are limited data relating to functional analysis of T cells in postpartum thyroiditis. However, activated T cells are increased and a rise in the ratio of CD4⁺ to CD8⁺ cells has been observed (17, 18). Thyroidal accumulation of B and T lymphocytes occurs (CD4⁺/CD8⁺ ratio about 3) (19) Our data relating to CD4/CD8 ratios differ from a previous study (13) in that we found a higher ratio in the euthyroid group in late gestation, whereas this ratio was reported to be higher in the PPTD group at 6 months postpartum. The methodology of the lymphocyte identification was different in the two studies however. The present study is still limited by the fact that only peripheral blood lymphocytes could be studied, this being less optimal than examining immune reactions in the thyroid gland itself. However, the data relating to the expression of IFN- (Th1) and IL-4 (Th2) by CD4 and CD4- lymphocytes at 36 wk gestation suggest that there is more immune stimulation of a generalized nature in the women destined to develop PPTD. This change in cytokine pattern at 36 wk antenatally was the only indication that the immunological background to PPTD may occur at this time. It is of interest that we did not find any significant differences in cytokine expression between groups of TPOAb +ve women at any time point postpartum. The changes in Th2/Th1 ratios that were noted were due to the more rapid fall in IL-4 secretion in the PPTD group, suggesting that the switch to the postpartum Th1 state was accelerated in this group. The data also indicate that the concept of Th1 and Th2 immune responses in the human is less clear than in the mouse (20), e.g. as evidenced by the cytokines studied in this report. Whether the expression of other type 1 or type 2 cytokines studied in these patients would clarify the picture further is not known. It may be of importance to document the cytokine expression in the well-characterized subsets of CD4⁺ cells because the current results most likely may represent an underestimate of the specific cytokine expression. The PPTD group did have a higher level of TPOAb in early pregnancy, compared with the euthyroid postpartum group.

IL-4 may be an important costimulatory factor in the regulation of IgG isotype switching following B-cell activation by antigen. In particular, this cytokine appears to be important in the switch to IgG₄ subclass antibody synthesis (21, 22, 23). This is of importance because antibodies of this IgG subclass, which are unable to activate the classical complement pathway and as such may act as blocking antibodies (24), form a relatively higher proportion of the anti-TPO antibody activity seen in women with PPTE, compared with women with PPTD during the active phase of the syndrome (25, 26).

Recent data in women with normal pregnancies have shown that during the third trimester, IL-12 production was increased and TNF was lower than postpartum values (9). Plasma cortisol, which together with other hormones can contribute to the suppression of IL-12 and TNF, is found to be elevated, compared with postpartum values (9). These authors have previously suggested that the changes in pregnancy and the expression of autoimmune diseases may be linked through differential regulation of Th1 and Th2 responses (27). We found that the women destined to develop PPTD had significantly lower plasma cortisol values, compared with the euthyroid group at 36 wk gestation when both groups were euthyroid. In general, the cortisol levels were in the range described for pregnant women by Magiakou et al. (28). Although we were unable to assess the hypothalamic pituitary axis by dynamic testing in these pregnant women, it is noted that all the blood samples were taken at the same time of day and there was no difference in the obstetric data relating to delivery (see Results). Also, only one woman had steroid 21-hydroxylase autoantibodies, suggesting that incipient autoimmune adrenal failure was not the cause of the lower plasma cortisol concentrations. Plasma cortisol levels were not different postpartum between patients with PPTD and PPTE (data not shown). Although it has been suggested that a critical element facilitating the development of autoimmune thyroid disease is relative hypocortisolism postpartum, we feel that difference in cortisol levels antepartum may contribute to the immunological setting whereby other post partum factors may interact.

Pregnancy is marked by an increased production of glucocorticoid and other hormones. The increase in cortisol is mediated by placental production of CRH acting through the hypothalamic pituitary axis (29). We suggest, therefore, that there was less immunosuppression in the PPTD group even before parturition and the increased expression of cytokines at this stage could contribute to the subsequent development of thyroid dysfunction. Of course, other background factors such as human leukocyte antigen haplotype restriction and a previous history of autoimmune thyroid disease are also predisposing factors (2). Furthermore, there are data to suggest that the phenomenon of microchimerism (30, 31) may have an important role in the development of the thyroid dysfunction. In conclusion, evidence has been presented to suggest that the immunopathogenesis of postpartum thyroid dysfunction commences during late gestation and may be related to the loss of the normal immunosuppression of pregnancy because of reduction in plasma cortisol concentrations at this time.

	Acknowledgments

 
We thank Lynn Taylor for laboratory assistance and Adrienne French for nursing help. We are grateful to Claire Bennett and obstetricians at Llandough Hospital for their assistance. We are grateful to Terry Hoy for help with FACS analysis and Firs Laboratories RSR Ltd., Cardiff, for measurement of 21 hydroxylase autoantibodies. We thank Dr. F. Al-Khafaji for TSH receptor antibody measurements and Dr. F. Dunstan for statistical advice.

	Footnotes

 
This work was supported by a grant from Saudi Arabia (to A.A.K.).

Abbreviations: CV, Coefficient of variation; FACS, fluorescence-activated cell sorter; FT3, free T₃; FT4, free T₄; IFN, interferon; PPT, postpartum thyroiditis; PPTD, postpartum thyroid dysfunction; PPTE, euthyroid postpartum; TPOAb, thyroid peroxidase autoantibodies; TPOAb +ve, antithyroid peroxidase antibody positive.

Received August 2, 2002.

Accepted December 11, 2002.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kokandi, A. A. Articles by Lazarus, J. H. Search for Related Content PubMed PubMed Citation Articles by Kokandi, A. A. Articles by Lazarus, J. H.