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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 4000-4005
Copyright © 1999 by The Endocrine Society

Original Studies

Postpartum Thyroiditis in Women with Hypothyroidism Antedating Pregnancy?

A. Caixàs, M. Albareda, A. García-Patterson, J. Rodríguez-Espinosa, A. de Leiva and R. Corcoy

Servei d’Endocrinologia i Nutrició, Servei de Bioquímica (J.R.-E.), Hospital de Sant Pau, Barcelona, Spain

Address all correspondence and requests for reprints to: Dr. R. Corcoy, Servei d’Endocrinologia i Nutrició, Hospital de Sant Pau, Avda Sant Antoni Ma Claret 167, 08025 Barcelona, Spain.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In women with hypothyroidism, levothyroxine (LT) requirements after delivery are assumed to return to prepregnancy values. The occasional observation of discordances prompted this study. Forty-one women (31 receiving LT replacement therapy and 10 receiving suppressive therapy for thyroid carcinoma) were followed during the first year after delivery. A control group of 31 nonpregnant women with hypothyroidism (n = 21) or thyroid carcinoma (n = 10) were also followed during a similar period. Twenty-three patients of 41 (56.1%) had discordant requirements at follow-up after delivery vs. 3 of 31 in the control group (9.7%; P < 0.001). The patterns of discordance in the postdelivery group were hyperthyroidism in 12, increase in LT dose in 5, hyper- and hypothyroidism in 5, and recurrence of Graves’ disease in 1 women. Those in the control group were increase in LT dose, hyperthyroidism, and hypo- and hyperthyroidism. The rate of patients with discordant prepregnancy-postpartum LT doses was higher in the noncarcinoma subgroup (67.7% vs. 20.0%; P < 0.01), whereas in the control group, both subgroups displayed a similar rate of discordance (9.5% vs. 10%; P = NS). In conclusion, this study documents that women with hypothyroidism antedating pregnancy display changes in LT requirements in the first year after delivery that suggest postpartum thyroiditis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DURING PREGNANCY, changes in serum thyroid hormones are well documented (1), and in women with prepregnancy hypothyroidism, an increment in levothyroxine (LT) dose is usually required (2, 3, 4, 5, 6, 7, 8). After delivery, the LT dose is either assumed to return to the prepregnancy value (4, 6, 8, 9, 10) or is not mentioned (5, 11). The occasional observation of discordance between prepregnancy and postpartum LT requirements in women with hypothyroidism antedating pregnancy and the scant objective information in the literature about this issue prompted this study.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Caucasian women with hypothyroidism antedating pregnancy seen in the Endocrinopathies and Pregnancy Clinic over a 4-yr period (1995–1998) were considered eligible if they fulfilled inclusion criteria: 1) available information about autoimmunity and 2) at least one TSH level in the target range in the year before conception (0.25–5 IU/L for women receiving replacement therapy and less than 0.25 IU/L for women receiving suppressive therapy). Forty-one women were included in the study. Thirty-one women (group A) were receiving replacement doses of LT because of ablative therapy for Graves’ disease (n = 9) or primary hypothyroidism with (n = 18) or without autoimmunity (n = 4). Autoimmunity was considered present if positivity for antithyroid antibodies (either antithyroglobulin or antithyroperoxidase) was documented, the patient had a diagnosis of Graves’ disease, or hypothyroidism had been detected during the first year after delivery in a previous pregnancy. In the last case, hypothyroidism was considered definitive because LT could not be withdrawn. One patient with Pendred syndrome and three patients with subtotal thyroidectomy for multinodular goiter were classified as having hypothyroidism without autoimmunity. Ten women (group B) were receiving suppressive LT therapy because of papillary/follicular thyroid carcinoma.

A control group of 31 nonpregnant Caucasian women of similar age consecutively attending the Thyroid Clinic for either autoimmune hypothyroidism (group C; n = 21) or thyroid carcinoma (group D; n = 10) with TSH values within the target range and documented follow-up for a similar period were included as controls. All patients and controls gave informed consent.

Methods

Peripheral blood for measurement of thyroid function was obtained at different intervals according to clinical needs. Free T4 (FT4) was measured in cases where TSH was below the target range or higher than 15 mU/L. Changes in LT doses were performed according to TSH and (if available) FT4 measurements.

Study subjects. In addition to prepregnancy tests, TSH was measured at 2-month intervals during pregnancy and at least twice after delivery to document that TSH was within the target range. Eighty-three percent of women had TSH monitored in the first trimester after delivery, 63.4% in the second, 46.3% in the third, and 53.7% in the fourth. Data were collected in the context of a prospective study about changes in LT requirements during pregnancy to document their transient nature. At delivery, the LT prepregnancy dose was resumed except in two patients who required big adjustments during pregnancy.

Control subjects. Information about TSH levels was collected during the usual clinical follow-up.

Assays

Serum TSH concentrations were measured using a two-site chemiluminometric immunoassay (Corning, Inc., Medfield, MA).

FT4 levels were measured using a chemiluminescent immunoassay ACS 180 Chiron Corp. (East Walpole, MA).

Definitions

Discordant LT doses. The LT requirements to achieve the therapeutic goal (replacement or suppressive therapy) are different at baseline and during follow-up.

Hyperthyroidism. The previous adequate LT dose is associated with TSH suppression (replacement therapy) or excessive FT4 (suppressive therapy).

Hypothyroidism. The previous adequate LT dose is associated with a TSH elevation out of the target range.

Recurrence of Graves’ disease. The previous adequate LT dose is associated with TSH suppression and high FT4. The persistence of high FT4 leads to discontinuation of LT, confirmation of high radioactive iodine uptake and the initiation of antithyroid drugs.

Statistics

The SPSS-PC(+) 7.5 for windows statistical package (SPSS, Inc., Chicago, IL) was used. Differences between prepregnancy and postpartum LT doses were assessed using Wilcoxon test for paired data. {chi}2/Fisher’s exact test was used for qualitative variables. Different logistic regression models were constructed using discordant prepregnancy-postpartum LT doses as the dependent variable and patient group (carcinoma vs. noncarcinoma), prepregnancy dose related to weight, and autoimmunity as independent ones, entered either alone or in combination. In the last case a forward conditional method was used. Prepregnancy dose related to weight was entered either as a continuous or dichotomous variable (<1.6 µg/kg·day, less than replacement dose; >= 1.6 µg/kg·day, full replacement/suppressive dose).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the patients before pregnancy (groups A and B) and of the control subjects (groups C and D) are shown in Table 1Go. During pregnancy, 12 of 31 patients from group A (38.7%) and 7 of 10 patients from group B (70%; P = NS) were required to increase their LT dose. The mean change was 13.7 ± 28.2 µg/day for group A and 40.0 ± 45.9 µg/day for group B (P < 0.05).


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  		Table 1. Baseline characteristics of hypothyroid women followed after delivery and their nonpregnant controls

 
At postpartum both groups were followed during a similar period (39.2 ± 18.4 vs. 40.0 ± 29.2 weeks for groups A and B, respectively; P = NS). At the last postpartum evaluation, the LT dose was similar to the prepregnancy dose in both groups [group A: 90.7 ± 45.1 µg LT/day; 1.56 ± 0.85 µg/kg·day (P = NS vs. prepregnancy); group B: 187.5 ± 24.3 µg LT/day; 3.16 ± 0.60 µg/kg·day (P = NS vs. prepregnancy)]. Twenty-three patients of 41 (56.1%) had discordant prepregnancy-postpartum doses. Twelve of them had hyperthyroidism (Fig. 1AGo), five had hypothyroidism (Fig. 1BGo), five had hyperthyroidism followed by hypothyroidism (Fig. 1CGo), and one had a recurrence of Graves’ disease. Illustrative examples of the main three patterns of discordance are shown in Table 2Go. The highest FT4 levels (23.8 ± 8.5 pmol/L) in women with hyperthyroidism and the highest TSH levels (31.5 ± 33.5 mU/L) in women with hypothyroidism were observed at 19.4 ± 15.2 and 26.5 ± 11.1 weeks after delivery, respectively (P < 0.05). The rate of patients with discordant prepregnancy-postpartum LT doses was higher in group A than in group B (67.7% vs. 20.0%; P < 0.01; Table 3Go). Women with autoimmune diseases had a 70.3% rate of discordance: 77.8% in women with Graves’ disease, 66.7% in women with autoimmune hypothyroidism, and 66.7% in women with hypothyroidism after postpartum thyroiditis in a prior pregnancy. The patterns of discordance according to previous disease are shown in Table 4Go.



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  		Figure 1. Discordances in TSH levels between prepregnancy and postpartum using the same LT dose during both periods have been grouped in the three main patterns: hyperthyroidism (A), hypothyroidism (B), and hyperthyroidism followed by hypothyroidism (C). Note that patients with previous carcinoma are depicted in a pointed line with sunburst.

 

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  		Table 2. Examples of patients showing patterns of prepregnancy-postpartum discordance in LT requirements

 

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  		Table 3. Follow-up of hypothyroid women after delivery and their nonpregnant control group

 

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  		Table 4. Patterns of discordance according to previous disease in the hypothyroid women followed after delivery

 
In the logistic regression analysis, patient group (carcinoma vs. noncarcinoma) adequately predicted the presence/absence of LT requirements discordance at postpartum in 71% of patients with an odds ratio of 8.4 for the noncarcinoma group (P < 0.05). Autoimmunity was also able to predict discordance in 71% of patients with an odds ratio of 6.1 for the autoimmune group (P < 0.05). Prepregnancy dose related to weight, entered either as a continuous or a dichotomous variable, was not a significant predictor. When the three independent variables were combined, only patient group continued to be predictive.

In the control group, 3 of 31 women (9.7%) presented a discordance in LT requirements at follow-up (P < 0.001 vs. patient group). One of them had a carcinoma and was required to increase her LT dose. The other 2, whose hypothyroidism was due to autoimmune thyroid disease, presented a pattern of hyperthyroidism, and in 1 of them it was preceded by hypothyroidism.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
There is scant information in the literature about LT requirements in hypothyroid women after delivery, when thyroid doses are either not mentioned or are assumed to be those at prepregnancy. Mandel et al. (3) followed hypothyroid women for a short time after delivery (1–7 months) and found discordances in 33% of patients, but this phenomenon was not discussed. In a study about recurrence of postpartum thyroiditis, a patient with previous hypothyroidism needed to increase LT dose after delivery (12). In other reports (13, 14, 15, 16) about the recurrence of postpartum thyroiditis, only patients in remission after the first episode are included.

In this study, in women with hypothyroidism antedating pregnancy, LT requirements differed from prepregnancy requirements in 67.7% of patients at some point of follow-up in the first year postpartum. This percentage of discordance was higher than that in patients with thyroid carcinoma followed after delivery (20%; P < 0.01) and higher than that in a control group of nonpregnant women of similar age and more recent diagnosis followed during a similar period of time (9.5%; P < 0.001).

As the number of TSH measurements was higher in the group of hypothyroid women after delivery, the higher percentage of LT dose discordance in this group could be attributed to this fact. The reason for more TSH measurements in the after delivery group is that a discordant TSH measurement led to an additional test. Besides, a 68% increase in TSH measurement cannot be responsible for a 5.7-fold increase in the rate of discordance. We ruled out potential causes of discordance between prepregnancy and postpartum LT dose. In cases of excessive therapy, pill ingestion immediately before blood drawing was ruled out. In cases of insufficient therapy, patients who had been carefully advised to take any multivitamin pill at least 3 h later than LT were asked about treatment noncompliance and drugs influencing LT absorption (8). Passage of LT to maternal milk could be suggested as an explanation, but it only amounts to 0.002 µg/L (17), and most mothers were not breastfeeding their babies by the time that TSH increased (6 months postpartum). Another potential explanation for increasing LT demands could be natural progression of hypothyroidism both in patients with Hashimoto’s thyroiditis and in patients with Graves’ disease after 131I therapy. This also does not seem to be the case, as we would expect a similar or even more important progression in the control women who had a shorter duration of the disease. Moreover, neither LT passage to maternal milk nor the natural progression of the disease would explain the situations of transient hyperthyroidism.

At this point, although we did not measure thyroid antibodies or radioactive iodine uptake, we suggest that postpartum lability in women receiving replacement LT therapy could be due to thyroiditis, as there is not an alternative explanation and the patterns of discordance are precisely those of postpartum thyroiditis. So, our interpretation is that women receiving replacement therapy can have a viable thyroid remnant (the prepregnancy dose is lower than full replacement one) (18) where thyroiditis can take place. By contrast, patients with hypothyroidism after ablative therapy for thyroid carcinoma would not be prone to this phenomenon, because residual thyroid tissue is absent, and this would explain the lower rate of discordant prepregnancy-postpartum LT requirements in this group. Nevertheless, two women with previous carcinoma (10%) presented changes in LT requirements postpartum. As the rate of discordance is the same as that in both control groups, we do not consider it postpartum related.

The overall 56% rate of postpartum LT discordance in this study is higher than the cumulative 9.3% incidence of postpartum thyroiditis in the background population (19), probably because the study group was clearly biased to higher risk.

Both recurrence (20, 21, 22) and silent thyroiditis (20, 23, 24, 25) are known to be very common in the first year after delivery of women with Graves’ disease in remission. An evident recurrence took place in one of the women with Graves’ disease, but in the other patients with previous Graves’ disease and transient hyperthyroidism, both recurrence and postpartum thyroiditis could be possible explanations.

Regarding the distribution of patterns of T4 dosage discordance, we cannot rule out the possibility of an undetected hyperthyroid phase in patients with a hypothyroidism pattern or even some undetected discordant cases, because thyroid function was not measured according to a standard schedule. In any case, the importance of this study lies in the presence of discordance rather than its specific pattern, and if there were any missing cases, they would probably increase the percentage of discordance in the noncarcinoma group. However, the 70% rate of postpartum discordance in women with autoimmune hypothyroidism is higher than the 45% rate of postpartum thyroid function test changes reported in women with thyroid antibodies in the first trimester of pregnancy (26). The explanation probably lies in the definition of discordance, as we have not taken into account peripheral thyroid hormones.

In conclusion, this study documents that women with hypothyroidism antedating pregnancy display changes in LT requirements during the first year after delivery that suggest postpartum thyroiditis. Confirmation of the pathogenesis of postpartum lability in LT dose would require a prospective study with control subjects matched for disease and years of hypothyroidism and measurement at fixed intervals of thyroid hormones, antibodies, and markers of thyroid destruction in both groups. However, being aware of the frequent transient changes that women with hypothyroidism experience in the first year postpartum has an immediate application in clinical practice. After delivery, LT therapy dose should be resumed with the prepregnancy dose, and it should not be modified unless the patient has distinct symptoms of hypo- or hyperthyroidism.

Received April 2, 1999.

Revised July 1, 1999.

Accepted August 2, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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