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Department of Internal Medicine, Thyroid Investigation Clinic, University Hospital Saint Pierre, B-1000 Brussels, Belgium
Address all correspondence and requests for reprints to: Daniel Glinoer, M.D., Ph.D., Professor of Internal Medicine, Chief, Thyroid Investigation Clinic, University Hospital Saint Pierre, B-1000 Brussels, Belgium. E-mail: dglinoer{at}ulb.ac.be.
The article by Negro et al. (1) in this issue of JCEM aimed at examining whether pregnant women who were euthyroid in the early stages of pregnancy but who have positive thyroid autoantibodies (TPO-Abs) would benefit from levothyroxine administration to improve the outcome of pregnancy and, more specifically, reduce the rate of spontaneous miscarriage and premature delivery. For this purpose, a large group of Caucasian pregnant women (n = 984) was investigated between November 2002 and October 2004. Measurements of TPO-Abs and thyroid function tests (TFTs) were carried out at the first prenatal visit. TFTs were repeated at 20 and 30 wk gestation and finally 3 d after delivery. Among the cohort, 115 women (11.7%) were shown to have positive thyroid autoantibodies (referred to hereafter as TAI positive). The first interesting observation of the study was that TAI-positive women were significantly older than the control population (mean age 30 vs. 28 yr; P < 0.05).
The TAI-positive women were randomly assigned to two groups: group A (n = 57) received levothyroxine; group B (n = 58) received no treatment. TAI-negative women served as controls for TFTs and pregnancy outcome. Thus, the trial design in this study was randomized and prospective but not placebo controlled and hence not double blind (which is undoubtedly an inherent weakness). However, the medical participants to the study were kept unaware of the groups to which the patients belonged. Another possible criticism concerns the design of the intervention branch of the study. The rationale for deciding to administer 0.5 µg/kg·d of levothyroxine (when serum TSH was < 1 µU/ml), 0.75 µg/kg·d (when TSH was 1–2 µU/ml), and 1 µg/kg·d (when TSH was > 2 µU/ml or presence of a high TPO-Ab titer: > 1500 kIU/liter) was somewhat arbitrary although quite reasonable altogether. Median levothyroxine dosage in group A women was 50 µg/d. Once started, levothyroxine dosage was maintained unchanged throughout pregnancy. At the time of treatment onset (within 1 wk after the first gynecological visit), mean gestational ages were similar among the different groups (10.3–10.4 wk), although there was inevitably some variation in gestational ages within each group. One of the remarkable features of the present study was that levothyroxine administration was started quite early, between 5 and 10 wk gestation, in the majority of women in group A (37 of 57).
A second interesting finding in the present study was that the mean serum TSH values, although normal, were already significantly higher at booking in TAI-positive women, compared with controls. A third interesting finding was that in group B women (TAI positive and no treatment), serum TSH levels increased progressively as gestation progressed, from a mean 1.7 µU/ml (12th wk) to 3.5 µU/ml (term), with 19% of untreated TAI-positive women having a supranormal serum TSH value at delivery. It should be noted that serum TSH levels also increased progressively in the control group but much less, from 1.1 µU/ml (12th wk) to 2.1 µU/ml (term), probably as the result of mild iodine deficiency in the population (2). Not only was the spontaneous serum TSH increment quantitatively significantly less marked in controls, compared with group B women, but also the control and group A (treated) women were able to maintain normal (unchanged) serum free T4 levels, whereas serum free T4 levels decreased by 30% during gestation in group B women, from 14.6 pmol/liter (10th wk) to 12.4 pmol/liter (30th wk; P < 0.05) and 10.2 pmol/liter (term; P < 0.05), as the consequence of a reduced functional thyroid reserve associated with chronic autoimmune thyroiditis (3).
The fourth, and most novel and important, result of the study was that levothyroxine administration to TAI-positive women allowed for a significant decrease in the rate of obstetrical complications, with the miscarriage rate reduced by 75% (from 13.8 to ± 3.5%) and the frequency of premature delivery by 69% (from 22.4 to ± 7%). These results confirm entirely data produced previously by other authors showing an association between thyroid autoimmunity features and adverse obstetrical effects, even in the absence of thyroid dysfunction. They are important because, for the first time in a prospective, randomized study, they clearly show beneficial effects of levothyroxine administration on the outcome of pregnancy in women with thyroid autoimmunity and without an evident perturbation of thyroid function in early gestational stages (4, 5).
An association between the risk of a miscarriage and autoimmune thyroid disease (AITD) was first reported 15 yr ago (6, 7). Since then, the statistical strength of this association has been largely confirmed in several population studies, leading authors to conclude that AITD without overt thyroid dysfunction was significantly associated with a 3- to 5-fold increase in overall miscarriage rate (8). In a recent review, a more detailed classification was attempted by examining separately the association between AITD and miscarriage (five studies), AITD and recurrent miscarriage (seven studies), and finally AITD and early pregnancy loss after in vitro fertilization (five studies). Overall and with only a few exceptions, all studies documented a statistically significant relationship between AITD and increased pregnancy loss (9). Finally, a recent metaanalysis of all case-controlled and longitudinal studies published since 1990, after the association between miscarriage and AITD was first described, amply confirmed that the overall relative risk of miscarriage was increased approximately 3-fold in women with AITD (10).
Finding an association does not imply a causal relationship, and the etiology of increased pregnancy loss in women with AITD remains largely unknown. Three working hypotheses have been proposed. The first hypothesis holds that pregnancy loss is not directly related to the presence of circulating thyroid antibodies and, in this view, AITD could represent only a marker of an underlying, yet-to-be-defined, more generalized autoimmune imbalance that, in turn, would explain a greater rejection rate of the fetal graft. The second hypothesis holds that despite apparent euthyroidism, the presence of AITD could be associated with a subtle deficiency in thyroid hormone concentrations or a lesser ability of thyroid function to adapt adequately to the changes associated with the pregnant state because of a reduced functional reserve characteristic of the thyroid gland in chronic autoimmune thyroiditis. The third hypothesis holds that AITD could act by delaying the occurrence of a conception because of its known association with infertility. In this view, TAI-positive women would tend to become pregnant at an older age (3–4 yr older, on the average), and older women are more prone to pregnancy loss. These hypotheses do not contradict one another, and it remains plausible that the increased risk of pregnancy loss associated with AITD is multifactorial, resulting eventually from a combination of several independent deleterious factors (11, 12).
If underlying mild thyroid hypofunction plays a role to explain increased pregnancy loss, this would then constitute a reasonable argument to systematically screen women for the presence of thyroid autoantibodies and/or mild thyroid insufficiency (either before conception when they express the desire of being pregnant or as soon as pregnancy has started) and give them the potential benefit of levothyroxine treatment.
Until the present study by Negro et al. (1), only three studies have investigated whether medical intervention would benefit women with thyroid autoimmunity. In a prospective study by Vaquero et al. (13), 27 TAI-positive women with two previous first-trimester miscarriages were subdivided into 11 TAI-positive women who received iv Igs during pregnancy and 16 TAI-positive women who received levothyroxine, started before conception and continued during pregnancy. The pregnancy success rate was 81% in the thyroxine-treated group, compared with 55% in the other group. Despite its inherent limitations (small number of cases and absence of randomization, etc.), the study by Vaquero et al. (13) constituted the first intervention trial showing a positive effect of thyroid hormone administration in women who were habitual aborters. In 2005 Negro et al. (14) also reported the results of levothyroxine administration in euthyroid TAI-positive infertile women who underwent in vitro fertilization. The authors showed that the miscarriage rate was reduced to 33%, compared with 52% in untreated controls. The study, however, failed to reach statistical significance, perhaps because of the small number of cases (14). Finally, in a slightly different clinical setting, a study by Abalovich et al. (4) showed that it was not so much the diagnosis of overt vs. subclinical hypothyroidism that mattered in relation with pregnancy outcome but mainly the adequacy of levothyroxine treatment. The outcome of pregnancy was compared in 27 women with hypothyroidism already known before pregnancy and who received an adequate levothyroxine treatment with 24 women in whom levothyroxine treatment was not adequately adjusted during gestation and who, hence, did not reach euthyroidism. When the treatment was not adequate, pregnancy ended with abortion in 60 and 71% of overt and subclinical hypothyroid women, respectively, with an increased prevalence of preterm deliveries. Conversely, in hypothyroid pregnant women who received an adequate treatment, the frequency of abortions was minimal and pregnancies carried to term without complications.
First the facts, and then the interpretation and perspective will be discussed. In summary, what are the lessons to be learned from the study of Negro et al. (1)? First, there is a confirmation of previously known findings, namely that: 1) euthyroid women with thyroid autoantibodies tend to be older when they become pregnant; 2) even though euthyroid in early gestational stages, these women tend to have a reduced thyroid functional reserve; 3) they have an increased risk for obstetrical complications (miscarriage and premature delivery); and 4) when given the benefit of treatment with thyroid hormone, they normalize thyroid function tests and behave as control women. Furthermore, the study clearly showed the benefits of levothyroxine administration in pregnant women with AITD not only to correct maternal thyroid function but also to reduce markedly the rate of undesired obstetrical events and lower their prevalence down to that found in healthy controls. There is no reason to believe that levothyroxine administration played a role in altering underlying autoimmunity. Also, the age difference between TAI-positive and control women was not large enough to explain the different rates of miscarriage and premature birth and obviously even less the changes observed in such rates after treatment with levothyroxine. The present study therefore leads us to conclude that among the three hypotheses evoked above, the second one, i.e. a subtle deficiency in thyroid hormone concentration and/or a lesser ability of maternal thyroid function to adapt adequately in women with AITD, was the main reason for the beneficial effects of thyroid hormone administration. If confirmed by future studies, these results would constitute an additional argument to screen pregnant women systematically for the presence of asymptomatic chronic autoimmune thyroiditis and/or mild thyroid underfunction to give such women the benefit of thyroid hormone treatment.
Footnotes
This work was supported by the Ministère de la Communauté Française (Administration Générale de l’Enseignement et de la Recherche Scientifique), within the framework of Actions de Recherche Concertée (convention 04/09-314).
Abbreviations: AITD, Autoimmune thyroid disease; TAI positive, positive thyroid autoantibodies; TFT, thyroid function test; TPO-Ab, thyroperoxidase antibody.
Received April 18, 2006.
Accepted April 27, 2006.
References
This article has been cited by other articles:
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  E. E. Wasserman, K. Nelson, N. R. Rose, W. Eaton, J. P. Pillion, E. Seaberg, M. V. Talor, L. Burek, A. Duggan, and R. H. Yolken Maternal Thyroid Autoantibodies during the Third Trimester and Hearing Deficits in Children: An Epidemiologic Assessment Am. J. Epidemiol., March 15, 2008; 167(6): 701 - 710. [Abstract] [Full Text] [PDF]
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 B. Biondi and D. S. Cooper The Clinical Significance of Subclinical Thyroid Dysfunction Endocr. Rev., February 1, 2008; 29(1): 76 - 131. [Abstract] [Full Text] [PDF]
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